Radiopharmaceutical compositions targeting ephrin type-a receptor 2 and uses thereof

Abstract

Provided herein are radiopharmaceutical conjugate compositions targeting EphA2 and uses thereof. In one aspect, provided herein are conjugates that comprise a peptide with avidity to EphA2 and a metal chelator configured to bind with a radionuclide. The conjugates described herein can further comprise a linker connecting the chelator and the peptide. The conjugates described herein can further comprise a radionuclide. In another aspect, provided herein are conjugates that comprise a peptide with avidity to EphA2 and a covalently bound radionuclide. The conjugates described herein can further comprise a linker connecting the radionuclide and the peptide. Further provided herein are methods of treating cancer by administering the described conjugates and compositions.

Description

[0001] RADIOPHARMACEUTICAL COMPOSITIONS TARGETING EPHRIN TYPE-A RECEPTOR 2 AND USES THEREOF CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 411,307, filed on September 29, 2022, and U.S. Provisional Application No.63 / 411,380, filed on September 29, 2022, each of which is incorporated herein by reference in its entirety. JOINT RESEARCH AGREEMENTS

[0002] Subject matter disclosed herein was developed, and the claimed invention was made by, or on behalf of, one or more parties to a Joint Research Agreement (JRA), within the meaning of 35 U.S.C. § 100(h) and 37 C.F.R. § 1.9(e), that was in effect on or before the effective filing date of the claimed invention. Said one or more parties to the JRA consist of PeptiDream, Inc. (Kanagawa, Japan) and RayzeBio, Inc. (San Diego, CA, U.S.A.). The claimed invention was made as a result of activities undertaken within the scope of said Joint Research Agreement. SEQUENCE LISTING

[0003] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on September 28, 2023, is named 59541-729_601_SL.xml and is 2,096,382 bytes in size. BACKGROUND

[0004] In the United States, cancer is the leading cause of death for those under 65 years of age, and it accounted for about 21% of all death in 2018. Traditional radiotherapies such as external beam radiation therapy have been used for decades as a standard-of-care treatment for diagnosed cancer patients. While some patients respond to external beam radiation therapy, many others do not. Further, metastasis and circulating tumor cells can spread and remain in the bloodstream or bodily fluids after standard-of-care treatment and lead to resistance to therapy. The presence of cancer cells in various parts of the body reduces the therapeutic efficacy of traditional radiotherapies. Accordingly, strategies for targeted radiotherapies are being developed, and there remains a need for targeted radiotherapies that have the desired affinity, stability, and exertion profile. SUMMARY

[0005] In one aspect, the present disclosure relates to a radiopharmaceutical conjugate comprising: (a) a cyclic peptide that has avidity for ephrin type-A receptor 2 (EphA2), wherein the peptide comprises an amino acid sequence of Formula (I), or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) wherein, X1 is an amino acid; X2 is an amino acid comprising an aromatic ring, an N-methylated amino acid thereof, or a variant thereof; X3 is a hydrophilic amino acid (e.g. N, Q, Cit, K or a variant thereof), glycine (G), Alanine (A) or a variant thereof (e.g., da, 2-Aminoisobutyric acid (Aib)); X4 is a hydrophobic amino acid (e.g., leucine (L)), a hydrophilic amino acid (e.g., citrulline (Cit)), or a variant thereof; X5 is a hydrophilic amino acid, or a variant thereof; X6 is a hydrophilic amino acid, an amino acid comprising an aromatic ring, or an N-methylated amino acid thereof; X7 is an amino acid comprising an aromatic ring (e.g., W, F, or a variant thereof); X8 is a hydrophobic amino acid, a hydrophilic amino acid, an N-methylated amino acid, or a variant thereof; X9 is an amino acid comprising an aromatic ring (e.g., W or a variant thereof); X10 is absent or a hydrophilic amino acid (e.g., Threonine (T) or a variant thereof); X11 is absent or a hydrophilic amino acid; and X12 is cysteine (C) or a variant thereof; and (b)(i) a metal chelator configured to bind with a radionuclide, wherein the metal chelator is conjugated to the peptide; or (ii) a covalent radionuclide (or, a radionuclide covalently bound to the cyclic peptide). In some embodiments, the radiopharmaceutical conjugate comprises a metal chelator configured to bind with a radionuclide, wherein the metal chelator is conjugated to the peptide. In some embodiments, the radiopharmaceutical conjugate comprises a covalent radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a radionuclide covalently bound to the peptide. In some embodiments, the peptide is a cyclic peptide. In some embodiments, the peptide is a monocyclic peptide.

[0006] In one aspect, the present disclosure relates to a radiopharmaceutical conjugate comprising: (a) a cyclic peptide that has avidity for ephrin type-A receptor 2 (EphA2), wherein the peptide comprises an amino acid sequence including deletion, substitution, and / or addition of one or several (e.g., 1-6) amino acids in the amino acid sequence of SEQ ID NO:1: da-MeF-N-L-Hgl-MeF-W1Me-V-W1Me-T-E-C (SEQ ID NO:1) or a pharmaceutically acceptable salt thereof, wherein the cyclic peptide consists of 10 or 12 amino acid residues; and (b)(i) a metal chelator configured to bind with a radionuclide, wherein the metal chelator is conjugated to the peptide; or (ii) a covalent radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a metal chelator configured to bind with a radionuclide, wherein the metal chelator is conjugated to the peptide. In some embodiments, the radiopharmaceutical conjugate comprises a covalent radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a radionuclide covalently bound to the peptide.

[0007] In some embodiments, the radiopharmaceutical conjugate further comprises a radionuclide bound to the metal chelator. In some embodiments, the radionuclide is an alpha particle-emitting radionuclide. In some embodiments, the alpha particle-emitting radionuclide is selected from Ac-225, Bi- 213, Bi-209, Tb-149, Ra-223, Th-227, Fr-223, Gd-148, Th-229, Pb-212, and Po-213. In some embodiments, the alpha particle-emitting radionuclide is Ac-225. In some embodiments, the radionuclide is a beta particle-emitting radionuclide. In some embodiments, the beta particle-emitting radionuclide is Cu-67, Lu-177, Y-90, Rh-105, Yb-175, Tm-167, Pm-153, Sm-153, or In-111. In some embodiments, the beta particle-emitting radionuclide is Lu-177. In some embodiments, the radionuclide is a gamma particle-emitting radionuclide. In some embodiments, the gamma particle-emitting radionuclide is indium-111 or tin-117m. In some embodiments, the radionuclide is a positron-emitting radionuclide. In some embodiments, the positron-emitting radionuclide is Ga-68, Cu-62, Cu-64, Zr-89, Tb-152.

[0008] In some embodiments, the metal chelator comprises DOTA, DOTA-GA, pBn-DOTA, pBn-SCN- DOTA, NH2-DOTA, NH2-DOTA-GA, p-NCS-Bn-DOTA-GA, p-NH2-Bn-oxo-DO3A, p-SCN-Bn-oxo- DO3A, NOTA, NODA-GA, NH2-NODA-GA, p-NCS-Bn-NODA-GA, p-NH2-Bn-NOTA, p-SCN-Bn- NOTA, NCS-MP-NODA, NH2-MPAA-NODA, PCTA, p-NH2-Bn-PCTA, p-SCN-Bn-PCTA, p-SCN- Bn-HEHA, H2-MACROPA-NCS, H1-MACROPA, H2-MACROPA-NH2, H4-OCTAPA, tetra-(S, S, S, S)-Me-DOTA, tetra-(S, S, S, S)-Et-DOTA, tetra-(S, S, S, S)-iBu-DOTA, or maleimide-nBu-DOTA. In some embodiments, the metal chelator has a structure of

[0009] In some embodiments, the radiopharmaceutical conjugate further comprises a linker that connects the peptide with the metal chelator. In some embodiments, the linker covalently connects the peptide with the metal chelator.

[0010] In some embodiments, the radiopharmaceutical conjugate has a structure of: wherein represents the linker.

[0011] In some embodiments, the linker is attached to the peptide via a non-terminal amino acid residue of the peptide. In some embodiments, the linker is attached to the 5thamino acid residue or X5. In some embodiments, the linker is attached to the 8thamino acid residue or X8. In some embodiments, the linker is attached to the 11thamino acid residue or X11.

[0012] In some embodiments, the radionuclide is covalently bound to an amino acid comprising an aromatic ring. In some embodiments, the radionuclide is18F,74As,76Br,123I,124I,125I,131I, or211At. In some embodiments, the radionuclide is18F,125I,131I, or211At . In some embodiments, the radionuclide is attached to X1, X2 or MeF, X6 or MeF, X7 or W1Me, or X9 or W1Me. In some embodiments, the radionuclide is attached to a tyrosine residue. In some embodiments, the radiopharmaceutical conjugate comprises a linker that connects the peptide with the radionuclide. In some embodiments, the linker covalently connects the peptide with the radionuclide.

[0013] In some embodiments, the radiopharmaceutical conjugate has a structure of: wherein represents the linker; and R*represents the radionuclide. In some embodiments, the linker is attached to the peptide via a non-terminal amino acid residue of the peptide. In some embodiments, the linker is attached to the 5thamino acid residue or X5. In some embodiments, the linker is attached to the 8thamino acid residue or X8. In some embodiments, the linker is attached to the 11thamino acid residue or X11. In some embodiments, the linker comprises a residualizing agent. In some embodiments, the residualizing agent is chosen from i some embodiments, has a structure selected from:

[0002] wherein each k1 and k2 is independently 0 or an integer selected from 1 to 10; and R* is the radionuclide.

[0014] In some embodiments, the peptide or the pharmaceutically accepted salt thereof has a cyclic structure, wherein the first amino acid (or X1) is covalently linked to the last amino acid (or X12). In some embodiments, the peptide or the pharmaceutically accepted salt thereof has a cyclic structure having an amino acid in the first residue X1 and a cysteine residue or a variant thereof, and wherein the amino acid in X1 and the cysteine residue or a variant thereof form a covalent bond. In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NOs: 1-122, 159- 163, and 165-171, and the peptide has a cyclic structure having a cysteine residue or a variant thereof at 12th residue, and wherein the amino acid X1 and the cysteine residue or a variant thereof at 12th residue form a covalent bond (e.g., by reacting a chloroacetyl group in the amino acid of X1 with the cysteine residue or a variant thereof). In some embodiments, the peptide can be cyclized by reacting a bromoacetyl group in the amino acid of X1 with the cysteine residue or a variant thereof. In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NOs: 123-149 and 164, and the peptide has a cyclic structure having a cysteine residue or a variant thereof at 10th residue, and wherein the amino acid X1 and the cysteine residue or a variant thereof at 10th residue form a covalent bond.

[0015] In some embodiments, the radiopharmaceutical conjugate comprises a metal chelator configured to bind with a radionuclide, wherein the metal chelator is conjugated to the peptide. In some embodiments, the radiopharmaceutical conjugate comprises a covalently bound radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a radionuclide covalently bound to the peptide. In some embodiments, the peptide is a monocyclic peptide. In some embodiments, the peptide has an amino acid sequence according to Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the radiopharmaceutical conjugate comprises an amino acid sequence of Formula (I), or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) wherein, X1 is an amino acid; X2 is F, or a variant thereof that replaces the unsubstituted phenyl ring of F with (i) a phenyl ring substituted by 1 or 2 substituents each independently selected from - OH, -CN, and -C1-3alkyl, or (ii) a 6-membered heteroaryl ring optionally substituted by 1 or 2 substituents each independently selected from –OH, -CN, and -C1-3alkyl, wherein the F or the variant thereof is optionally N-methylated; X3 is a hydrophilic amino acid (e.g. N, Q, Cit, K or a variant thereof), G, Aib, Hgn, Ala,or a variant thereof (e.g., da); X4 is a hydrophobic amino acid (e.g., an amino acid having 4 or more carbon atoms in a side chain comprising a linear, branched, or cyclic carbon chain), and wherein X4 is optionally N-methylated (e.g., Cit or a variant thereof); X5 is an amino acid (e.g., a hydrophilic amino acid; Dab, Dap, R, E or a variant thereof; or an amino acid with a functional side chain); X6 is an N-methylated amino acid thereof; X7 is a W, Y, or a variant thereof (e.g., an amino acid having either a 6-membered aryl or heteroaryl, or a 9- or 10-membered bi-cyclic aryl or heteroaryl linked to the alpha-carbon through a carbon (e.g., a methylene group), wherein the 6-, 9-, and 10-membered heteroaryl has one heteroatom (e.g., N), and wherein the 6-, 9-, and 10-membered aryl or heteroaryl is optionally substituted by 1 or 2 substituents independently selected from –CH3, -ethyl, -Cl, and -F); X8 is an amino acid with –H on the alpha-amino group; X9 is W or Y or a variant thereof; (e.g., W or a variant thereof); X10 is absent, or a polar amino acid (e.g., T or a variant thereof); X11 is absent, or an amino acid (e.g., a hydrophilic amino acid; Dab, Dap, R, E or a variant thereof; or an amino acid with a functional side chain); and X12 is C or a variant thereof.

[0016] In some embodiments, the radiopharmaceutical conjugate comprises an amino acid sequence of Formula (Ia), or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X12 Formula (Ia) wherein, X1 is an amino acid (e.g., D-amino acid); X2 is an amino acid comprising an aromatic ring, an N-methylated amino acid thereof, or a variant thereof; X3 is a hydrophilic amino acid (e.g., N, Q, Cit, K or a variant thereof), G, A, or a variant thereof (e.g., da, Aib); X4 is a hydrophobic amino acid, or a hydrophilic amino acid (e.g., Cit or a variant thereof); X5 is a hydrophilic amino acid (e.g., Dab, Dap, R, E, Q, D, K), or a variant thereof); X6 is a hydrophilic amino acid, an amino acid comprising an aromatic ring (e.g., W, or F, or a variant thereof), or an N-methylated amino acid thereof; X7 is an amino acid comprising an aromatic ring (e.g., W, F, or a variant thereof); X8 is a hydrophobic amino acid, a hydrophilic amino acid, or an N-methylated amino acid; X9 is an amino acid comprising an aromatic ring (e.g., W, F or a variant thereof); and X12 is C or a variant thereof.

[0017] In some embodiments, the radiopharmaceutical conjugate comprises an amino acid sequence according to Formula (I), or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) wherein, X1 is an amino acid (e.g., D-amino acid); X2 is an amino acid comprising an aromatic ring, an N-methylated amino acid thereof, or a variant thereof; X3 is a hydrophilic amino acid (e.g., N, Q, Cit, K or a variant thereof), G, A, or a variant thereof (e.g., da, Aib); X4 is a hydrophobic amino acid, or a hydrophilic amino acid (e.g., Cit or a variant thereof); X5 is a hydrophilic amino acid (e.g., Dab, Dap, R, E, Q, D, K), or a variant thereof); X6 is a hydrophilic amino acid, an amino acid comprising an aromatic ring (e.g., W, or F, or a variant thereof), or an N-methylated amino acid thereof; X7 is an amino acid comprising an aromatic ring (e.g., W, F, or a variant thereof); X8 is a hydrophobic amino acid, a hydrophilic amino acid, or an N-methylated amino acid; X9 is an amino acid comprising an aromatic ring (e.g., W, F or a variant thereof); X10 is a hydrophilic amino acid (e.g., T, S, N, Q, K, Cit, or a variant thereof); X11 is a hydrophilic amino acid; and X12 is C or a variant thereof.

[0018] In some embodiments, the radiopharmaceutical conjugate comprises an amino acid sequence according to Formula (I), or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) wherein, X1 is da, df3CON, dkCOpipzaa, dahp, dDab-NH2-Ph3-SO2F, dDap-NH2-Ph3-SO2F, dDap-NH2- Ph4-SO2F, dCit, Aib, G, Norvaline, Norleucine, d4PyCON, or dhAla; X2 is MeF, Me3Py, MeF3CON, MeF3F, Me4Py, or MeY(Me); X3 is absent, N, Q, Cit, G, Aib, Hgn, hCit , norCit, LysAc, OrnAc, Ala, or da; X4 is L, Cbg, Chg, Cba, Cha, Ahx, Dahp, Cit, I, V, Norleucine, or Norvaline; X5 is Hgl, Hgn, Dab, Dap, DabAc, DapAc, R, hArg, E, or D; X6 is absent, MeF, MeE, Me3Py, Me4Py, MeF4F, MeF4F, MeF4C, or MeY; X7 is W1Me, W1Me7Cl, W1Me7N, W, F, 7-AzaTrp, W7Me, W1Et, W1Me7Br, W1Me7OMe, or W1Me6O7Cl; X8 is V, KCOpipzaa, N, Cit, Qglucamine, hCit, K, KAc, Aib, Alb, DapAc, OrnAc, A, T, alT, Norleucine, Norvaline, Hgl, E, Hgn, Q, I, or L; X9 is W1Me, W1Me7Cl, W1Me7N, F23dMe, W1Et, W7Me, W, F, or 7-AzaTrp; X10 is absent, T, Q, S, Hgn, Alpha-methylserine, hSer, hThr, N, OrnAc, LysAc, Cit, or hCit; X11 is absent, E, Hgn, R, hArg, Cit, hCit, Hgl, Orn, D, N, Q, DapAc, OrnAc, DabAc, norCit; and X12 is C, hCys, CdMe, C3RMe, C3SMe, Selenocysteine, dc, or Penicillamine.

[0019] In one aspect, the present disclosure relates to a radiopharmaceutical conjugate comprising: (a) a cyclic peptide that has avidity for ephrin type-A receptor 2 (EphA2), wherein the peptide consists of a sequence of Formula (I), X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) or a pharmaceutically acceptable salt thereof, wherein each of X1, X2, X3, X4, X5, X6, and X8 is independently an amino acid; X7 is W1Me or a variant thereof; X9 is W1Me or a variant thereof; each of X10 and X11 is independently absent or an amino acid; and X12 is cysteine (C) or a variant thereof; (b)(i) a metal chelator configured to bind with a radionuclide; or (ii) a covalent radionuclide (or, a radionuclide covalently bound to the cyclic peptide); and (c)(i) optionally, a linker that connects the peptide with the metal chelator; or (ii) optionally, a linker that connects the peptide with the covalent radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a metal chelator configured to bind with a radionuclide and optionally, a linker that connects the peptide with the metal chelator. In some embodiments, the radiopharmaceutical conjugate comprises a covalent radionuclide and optionally, a linker that connects the peptide with the covalent radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a radionuclide covalently bound to the peptide. In some embodiments, the radiopharmaceutical conjugate comprises a linker that connects the peptide with the covalent radionuclide.

[0020] In one aspect, the present disclosure relates to a radiopharmaceutical conjugate comprising: (a) a cyclic peptide that has avidity for ephrin type-A receptor 2 (EphA2), wherein the peptide has an amino acid sequence of Formula (I), X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) wherein, X1 is any D- or L-amino acid; X2 has a structure of , wherein ring A2 is phenyl or a 6-membered heteroaryl (e.g., heteroaryl having 1 or 2 N); RX2is each independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, SF5, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally and independently substituted with one or more RXA; kx2 is 0, 1, 2, or 3; mx2 is 0, 1, 2, 3 or 4; RNX2is H, C1-C6alkyl, or C1-C6haloalkyl; *X1 indicates the point of attachment to X1; and, *X3 indicates the point of attachment to X3; X3 has a structure kx3 is 0, 1, 2, or 3; RNX3is H, C1-C6alkyl, or C1-C6haloalkyl; RX3is H, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; *X2 indicates the point of attachment to X2; and, *X4 indicates the point of attachment to X4; X4 is a hydrophobic amino acid (e.g., amino acid having 4 or more carbon atoms in a side chain comprising a linear, branched, or cyclic carbon chain), and wherein X4 is optionally N-alkylated by a C1-3alkyl group; X5 is a hydrophilic L-amino acid, such as an amino acid having a structure of , wherein: RNX5is H, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, or heteroalkyl is optionally and independently substituted with one or more RXA; RX5is -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, SF5, -SRa, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=NRb)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, or heteroalkyl is optionally and independently substituted with one or more RXA; provided that at least one of RNX5and RX5comprises a moiety selected from -OH, -NH2, and - NH- (e.g., -NH-C(=NH)-NH2, -CO-NH2, -NH2, -COOH, -C(OH)-C0-6alkyl, -NH-CO-C1-6alkyl); *X4 indicates the point of attachment to X4; and, *X6 indicates the point of attachment to X6; X6 is wherein RNX6is H, C1-C6alkyl, or C1-C6haloalkyl; RX6is -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, SF5, -SRa, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=NRb)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally and independently substituted with one or more RXA; *X5 indicates the point of attachment to X5; and, *X7 indicates the point of attachment to X7; X7 has a structure , wherein RNX7is H, C1-C6alkyl, or C1-C6haloalkyl; ring A7 is an aryl or heteroaryl; RX7is each independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, SF5, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2-halogen, -S(=O)2NRcRd, -NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2- C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally and independently substituted with one or more RXA; kx7 is 0, 1, 2, or 3; mx7 is 0, 1, 2, 3, 4 or 5; *X6 indicates the point of attachment to X6; and, *X8 indicates the point of attachment to X8; X8 is an L-amino acid comprising an -H on the alpha-amino group; X9 has a structure , wherein RNX9is H, C1-C6alkyl, or C1-C6haloalkyl; ring A9 is an aryl or heteroaryl; RX9is each independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, SF5, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally and independently substituted with one or more RXA; kx9 is 0, 1, 2, or 3; mx9 is 0, 1, 2, 3, 4, or 5; *X8 indicates the point of attachment to X8; and, *XC indicates the point of attachment to (i) X10 or (i) when X10 and X11 are absent, X12; X10 is absent or an L-amino acid; X11 is absent or an L-amino acid; provided that when X10 is absent, then X11 is also absent; and X12 is an L-amino acid having a reactive thiol group, such as Cys and Cys variants; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R and RXAis independently halogen, -CN, -OH, -OC1-C6alkyl, SF5, -S(=O)C1-C6alkyl, - S(=O)2C1-C6alkyl, -S(=O)2NH2, -S(=O)2-halogen, -S(=O)2NHC1-C6alkyl, -S(=O)2N(C1-C6alkyl)2, -NH2, - NHC1-C6alkyl, -N(C1-C6alkyl)2, -NRbC(=NRb)NRcRd, -NHC(=O)OC1-C6alkyl, -C(=O) C1-C6alkyl, - C(=O)OH, -C(=O)OC1-C6alkyl, -C(=O)NH2, -C(=O)N(C1-C6alkyl)2, -C(=O)NHC1-C6alkyl, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; (b)(i) a metal chelator configured to bind with a radionuclide; or (ii) a covalent radionuclide; and (c)(i) optionally, a linker that connects the peptide with the metal chelator; or (ii) optionally, a linker that connects the peptide with the covalent radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a metal chelator configured to bind with a radionuclide and optionally, a linker that connects the peptide with the metal chelator. In some embodiments, the radiopharmaceutical conjugate comprises a covalent radionuclide and optionally, a linker that connects the peptide with the covalent radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a radionuclide covalently bound to the peptide. In some embodiments, the radiopharmaceutical conjugate comprises a linker that connects the peptide with the covalent radionuclide.

[0021] In some embodiments, X7 is W1Me; X8 is V; and X9 is W1Me.

[0022] In some embodiments, the radiopharmaceutical conjugate comprises an amino acid sequence according to Formula (I), or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) wherein, X1 is any amino acid X2 is an amino acid having an aromatic ring or a variant thereof X3 is N, X4 is a hydrophobic amino acid or a variant thereof; X5 is a hydrophilic amino acid or a variant thereof; X6 is a hydrophilic amino acid or amino acid having aromatic ring; X7 is W or a variant thereof; X8 is V or hydrophilic amino acid or a variant thereof, X9 is W or a variant thereof; X10 is T or a variant thereof; X11 is a hydrophilic amino acid; X12 is C or a variant thereof (such as C).

[0023] In some embodiments, the radiopharmaceutical conjugate comprises an amino acid sequence according to Formula (Ia), or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X12 Formula (Ia) wherein, X1 is any amino acid; X2 is an amino acid having an aromatic ring or a variant thereof; X3 is N or a variant thereof; X4 is a hydrophobic amino or a variant thereof, X5 is a hydrophilic amino acid or a variant thereof; X6 is a hydrophilic amino acid or amino acid having aromatic ring; X7 is W or a variant thereof; X8 is a hydrophilic amino acid or a variant thereof, X9 is W or a variant thereof; and X12 is C or a variant thereof.

[0024] In some embodiments, the peptide has a structure of Formula (I-1), wherein R1is selected from the group consisting of NH2and OH; R2is selected from the group consisting of H or C1-3alkyl; R3is selected from the group consisting of H or C1-3alkyl; wherein X1 to X11 have the definitions described in Formula (I), and wherein the attachment point to the radionuclide or the linker is not shown.

[0025] In some embodiments, the peptide of Formula (I-1) has a structure of Formula (I-2),

[0026] In some embodiments, the conjugate has a structure of Formula (III-1) wherein X1 to X11 have the definitions described in Formula (I), and wherein –Linker– represents the linker connecting the peptide and the metal chelator.

[0027] In some embodiments, the conjugate has a structure of Formula (III-1-RI) wherein X1 to X11 have the definitions described in Formula (I), and wherein represents the linker connecting the peptide and the radionuclide R*.

[0028] In some embodiments, the conjugate has a structure of Formula (III-2), wherein Lcyc is a ring closing group that covalently connects X1 with X12; –Linker– represents the linker that connects the peptide and the metal chelator; and wherein X1 to X12 have the definitions described in Formula (I).

[0029] In some embodiments, the conjugate has a structure of Formula (III-2-RI), wherein Lcyc is a ring closing group that covalently connects X1 with X12; represents the linker that connects the peptide and the radionuclide R*; and wherein X1 to X12 have the definitions described in Formula (I).

[0030] In some embodiments, the peptide or the salt thereof comprises an amino acid sequence that is at least 90% identical to a sequence selected from SEQ ID NOs: 1-171. In some embodiments, the peptide or the salt thereof consists of an amino acid sequence selected from SEQ ID NOs: 1-171. In some embodiments, the peptide or salt thereof is not SEQ ID NO: 1. In some embodiments, the peptide or salt thereof does not comprise SEQ ID NO: 1. In some embodiments, the radiopharmaceutical conjugate is not SEQ ID NO: 282.

[0031] In some embodiments, the radiopharmaceutical conjugate comprises a peptide that interacts with a human EphA2 at one or more amino acid residues selected from Asp53, Met55, Asn57, Met59, Met66, Thr101, Arg103, Phe156, Glu157, Arg159, Val161, Val189, and Ala190. In some embodiments, the peptide interacts with a human EphA2 at Asp53 and Glu157. In some embodiments, the peptide is a peptide of Formula (I) and wherein, when the peptide is bound to the human EphA2, amino acid residue X7 is located less than 10Å from the Phe156 of the human EphA2.In some embodiments, the peptide is a peptide of Formula (I) and wherein, when the peptide is bound to the human EphA2, amino acid residue X9 is located less than 10Å from the Phe156 of the human EphA2. In some embodiments, the peptide is a peptide of Formula (I) and wherein, when the peptide is bound to the human EphA2, amino acid residue X8 is located less than 10Å from the Phe156 of the human EphA2. In some embodiments, the human EphA2 comprises a sequence of SEQ ID NO: 276 or SEQ ID NO: 277.

[0032] In some embodiments, the conjugate is a compound of Tables 1, 2A, 2B, 2B-Lu, 2B-Lu-177, 2B- Ac-225, or 2C.

[0033] In one aspect, the present disclosure relates to a radiopharmaceutical conjugate, comprising: (a) a peptide that has avidity for ephrin type-A receptor 2 (EphA2), wherein the peptide competes for binding to a human EphA2 with a peptide that has an amino acid sequence including deletion, substitution, and / or addition of one or several amino acids in the amino acid of SEQ ID NO:1: da-MeF-N-L-Hgl-MeF-W1Me-V-W1Me-T-E-C (SEQ ID NO:1) or a pharmaceutically acceptable salt thereof ; and (b)(i) a metal chelator configured to bind with a radionuclide, wherein the metal chelator is conjugated to the peptide; or (ii) a covalent radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a metal chelator configured to bind with a radionuclide, wherein the metal chelator is conjugated to the peptide. In some embodiments, the radiopharmaceutical conjugate comprises a covalent radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a radionuclide covalently bound to the peptide.

[0034] In one aspect, the present disclosure relates to a radiopharmaceutical conjugate, comprising: (a) a peptide that has avidity for ephrin type-A receptor 2 (EphA2), wherein the peptide competes for binding to a human EphA2 with a peptide that has a structure of Formula (I), or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) wherein, X1 is an amino acid; X2 is an amino acid comprising an aromatic ring, an N-methylated amino acid thereof, or a variant thereof; X3 is a hydrophilic amino acid (e.g. N, Q, Cit, K or a variant thereof), glycine (G), Alanine (A) or a variant thereof (e.g., da, 2-Aminoisobutyric acid (Aib)); X4 is a hydrophobic amino acid (e.g., leucine (L)), a hydrophilic amino acid (e.g., citrulline (Cit)), or a variant thereof; X5 is a hydrophilic amino acid, or a variant thereof; X6 is a hydrophilic amino acid, an amino acid comprising an aromatic ring, or an N-methylated amino acid thereof; X7 is an amino acid comprising an aromatic ring (e.g., W, F, or a variant thereof); X8 is a hydrophobic amino acid, a hydrophilic amino acid, an N-methylated amino acid, or a variant thereof; X9 is an amino acid comprising an aromatic ring (e.g., W or a variant thereof); X10 is absent or a hydrophilic amino acid (e.g., Threonine (T) or a variant thereof); X11 is absent or a hydrophilic amino acid; and X12 is cysteine (C) or a variant thereof; and (b)(i) a metal chelator configured to bind with a radionuclide, wherein the metal chelator is conjugated to the peptide; or (ii) a covalent radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a metal chelator configured to bind with a radionuclide, wherein the metal chelator is conjugated to the peptide. In some embodiments, the radiopharmaceutical conjugate comprises a covalent radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a radionuclide covalently bound to the peptide.

[0035] In one aspect, the present disclosure relates to a radiopharmaceutical conjugate comprising: (a) a cyclic peptide that has avidity for ephrin type-A receptor 2 (EphA2), wherein the peptide consists of a sequence of Formula (I), X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) or a pharmaceutically acceptable salt thereof, wherein each of X1, X2, X3, X4, X5, X6, and X8 is independently an amino acid; X7 is W1Me or a variant thereof; X9 is W1Me or a variant thereof; each of X10 and X11 is independently absent or an amino acid; and X12 is cysteine (C) or a variant thereof; (b)(i) a metal chelator configured to bind with a radionuclide; or (ii) a covalent radionuclide; and (c)(i) a linker that connects the peptide with the metal chelator; or (ii) a linker that connects the peptide with the a covalent radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a metal chelator configured to bind with a radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a linker that connects the peptide with the metal chelator. In some embodiments, the radiopharmaceutical conjugate comprises a covalent radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a linker that connects the peptide with the covalent radionuclide.

[0036] In one aspect, the present disclosure relates to a pharmaceutical composition comprising a radiopharmaceutical conjugate as described herein, and a pharmaceutically acceptable excipient or carrier.

[0037] In one aspect, the present disclosure relates to a radiolabeled human EphA2 protein, wherein the EphA2 protein is bound to a radiopharmaceutical conjugate as described herein.

[0038] In one aspect, the present disclosure relates to a method of treating a disease or disorder characterized by overexpression of EphA2, comprising administering to the subject a radiopharmaceutical conjugate as described herein, or a pharmaceutical composition thereof. In some embodiments, the disease or disorder is cancer.

[0039] In one aspect, the present disclosure relates to a method of diagnosing or imaging a cancer in a subject in need thereof, comprising administering to the subject a radiopharmaceutical conjugate as described herein, or a pharmaceutical composition thereof.

[0040] In one aspect, the present disclosure relates to a method of treating a cancer in a subject in need thereof, comprising administering to the subject a radiopharmaceutical conjugate as described herein, or a pharmaceutical composition thereof. In some embodiments, the cancer is selected from glioblastoma, prostate cancer, lung cancer, breast cancer, gastric cancer, ovarian cancer, bladder cancer, colon cancer, esophageal cancer, multiple myeloma and fibrosarcoma. In some embodiments, the cancer is non-small cell lung carcinomas (NSCLC). In some embodiments, the cancer is triple negative breast cancer. In some embodiments, the method comprises administering (i) a first radiopharmaceutical conjugate comprising a radionuclide configured for companion diagnostic (such as PET imaging) and (ii) a second radiopharmaceutical conjugate comprising a radionuclide selected from an alpha or beta-particle emitter, wherein the first and the second conjugate have the same structure except for the radionuclide. In some embodiments, the radionuclide of the first conjugate is selected from Lu-177, In-111, Ga-68, Cu-64, and Zr-89. In some embodiments, the radionuclide of the first conjugate is selected from18F,74As,76Br,123I,124I, and125I. In some embodiments, the radionuclide of the second conjugate is selected from131I and211At.

[0041] In one aspect, disclosed herein is a pharmaceutical composition comprising a radiopharmaceutical conjugate or a salt thereof as described herein, and a pharmaceutically acceptable excipient or carrier.

[0042] In one aspect, disclosed herein is a method of treating a disease or disorder characterized by overexpression of EphA2, comprising administering to the subject a radiopharmaceutical conjugate or a salt thereof as described herein.

[0043] In one aspect, disclosed herein is a kit for use in a method of diagnosing disease or disorder characterized by over / decreased expression of EphA2 by determination of the expression level of EphA2, wherein the kit comprising a radiopharmaceutical conjugate or a salt thereof as described herein.

[0044] In one aspect, disclosed herein is a composition for use in a method of diagnosing disease or disorder characterized by over / decreased expression of EphA2, wherein the composition comprising a radiopharmaceutical conjugate or a salt thereof as described herein.

[0045] In one aspect, disclosed herein is the use of a radiopharmaceutical conjugate or a salt thereof as described herein for use in a method of diagnosing disease or disorder characterized by over / decreased expression of EphA2. INCORPORATION BY REFERENCE

[0046] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawing (also “figure” and “FIG.” herein), of which:

[0048] FIG.1 illustrates the structures of exemplary conjugates of the present disclosure, including a peptide, a linker and a metal chelator. FIG.1 discloses SEQ ID NOS 296, 433, 424, 434, 435, 436 and 437, respectively, in order of appearance.

[0049] FIG.2 illustrates the structures of exemplary conjugates of the present disclosure, including a peptide, a linker, a metal chelator, a cold lutetium. FIG.2 discloses SEQ ID NOS 292, 330, 283, 328, 334, 360 and 361, respectively, in order of appearance.

[0050] FIG.3 illustrates the structures of exemplary conjugates of the present disclosure, including a peptide, a linker, and a metal chelator.

[0051] FIG.4A illustrates exemplary metal chelators of the present disclosure, wherein represents the attachment point of a metal chelator to the remaining conjugate. FIG.4B illustrates the same metal chelators as FIG.4A, except that a part of the linker or the peptide covalently connected to the metal chelator is shown in the dashed circle .

[0052] FIG.5A illustrates exemplary metal chelators of the present disclosure, wherein represents the attachment point of a metal chelator to the remaining conjugate. FIG.5B illustrates the same metal chelators as FIG.5A, except that a part of the linker or the peptide covalently connected to the metal chelator is shown in the dashed circle .

[0053] FIG.6A illustrates exemplary metal chelators of the present disclosure, wherein represents the attachment point of a metal chelator to the remaining conjugate. FIG.6B illustrates the same metal chelators as FIG.6A, except that a part of the linker or the peptide covalently connected to the metal chelator is shown in the dashed circle .

[0054] FIG.7A illustrates exemplary metal chelators of the present disclosure, wherein represents the attachment point of a metal chelator to the remaining conjugate. FIG.7B illustrates the same metal chelators as FIG.7A, except that a part of the linker or the peptide covalently connected to the metal chelator is shown in the dashed circle .

[0055] FIG.8 illustrates the structures of representative metal chelators.

[0056] FIG.9 illustrates the structures of representative metal chelators.

[0057] FIG.10 illustrates the structures of representative metal chelators.

[0058] FIG.11 illustrates the structures of representative metal chelators.

[0059] FIG.12 illustrates the structures of representative metal chelators.

[0060] FIG.13 illustrates the structures of representative metal chelators.

[0061] FIG.14 illustrates the structures of representative metal chelators.

[0062] FIG.15 illustrates the structures of representative metal chelators.

[0063] FIG.16 illustrates the structures of representative metal chelators.

[0064] FIG.17 illustrates the structures of representative metal chelators.

[0065] FIG.18 illustrates the structures of representative metal chelators.

[0066] FIG.19 illustrates the structures of representative metal chelators.

[0067] FIG.20 illustrates the structures of representative metal chelators.

[0068] FIG.21 illustrates the structures of representative metal chelators.

[0069] FIG.22 illustrates the structures of representative metal chelators.

[0070] FIG.23 illustrates cell binding of biotinylated compounds EphA2-Biotin-21 and EphA2-Biotin- 88 tested in HCT116 cells and the binding EC50.

[0071] FIG.24A illustrates the competition cell binding for PDC_EphA2-00007196-C302, PDC_EphA2-00019440-C302, and PDC_EphA2-00019443-C302 tested against 50nM of EphA2-Biotin- 88 in HCT116 cells; FIG. 24B illustrates the competition cell binding for PDC_EphA2-00001417-C304 with the biotinylated form of a reference bicyclic peptide in H1299 cells.

[0072] FIG.25 illustrates the internalization rate of biotinylated compound EphA2-Biotin-21 and EphA2-Biotin-88 measured in PC3 cells at 10 nM and 100 nM at 2 hour time point.

[0073] FIG.26 illustrates the results of the SPR peptide binding study for PDC_EphA2-00007196- C302, PDC_EphA2-00019443-C302, PDC_EphA2-00019440-C302, and PDC_EphA2-00008010-C302. X axis represents time (s) and Y axis is response unit (RU).

[0074] FIG.27 illustrates the structures of exemplary conjugates comprising covalently bound radionuclides of the present disclosure. FIG.27 discloses SEQ ID NOS 88, 171, 114, 55, 438-440, respectively, in order of appearance.

[0075] FIG.28 illustrates the structures of exemplary conjugates comprising covalently bound radionuclides of the present disclosure. FIG.28 discloses 441-443, respectively, in order of appearance.

[0076] FIG.29 illustrates the structures of exemplary conjugates comprising covalently bound radionuclides of the present disclosure, including a peptide, a linker, and a radionuclide. DETAILED DESCRIPTION

[0077] The following description and examples illustrate embodiments of the present disclosure in detail. It is to be understood that this present disclosure is not limited to the particular embodiments described herein and as such can vary. Those of skill in the art will recognize that there are numerous variations and modifications of this present disclosure, which are encompassed within its scope.

[0078] Although various features of the present disclosure may be described in the context of a single embodiment, the features may also be provided separately or in any suitable combination. Conversely, although the present disclosure may be described herein in the context of separate embodiments for clarity, the present disclosure may also be implemented in a single embodiment.

[0079] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0080] All terms are intended to be understood as they would be understood by a person skilled in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosure pertains.

[0081] The following definitions supplement those in the art and are directed to the current application and are not to be imputed to any related or unrelated case, e.g., to any commonly owned patent or application. Although any methods and materials similar or equivalent to those described herein can be used in the practice for testing of the present disclosure, the preferred materials and methods are described herein. Accordingly, the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. I. Definitions

[0082] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0083] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included.

[0084] The term “about” or “approximately” can mean within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, up to 15%, up to 10%, up to 5%, or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, within 5-fold, or within 2-fold, of a value.

[0085] The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of” or “consist essentially of” the described features.

[0086] "Amino" refers to the –NH2radical.

[0087] "Cyano" refers to the -CN radical.

[0088] "Nitro" refers to the -NO2radical.

[0089] "Oxo" refers to the =O radical.

[0090] "Imino" refers to the =N-H radical.

[0091] "Oximo" refers to the =N-OH radical.

[0092] "Hydrazino" refers to the =N-NH2radical.

[0093] “Hydroxy” or “hydroxyl” refers to the -OH radical.

[0094] “Hydroxyamino” refers to the -NH-OH radical.

[0095] “Acyl” refers to a substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted heterocycloalkylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted heteroarylcarbonyl, amide, or ester, wherein the carbonyl atom of the carbonyl group is the point of attachment. Unless stated otherwise specifically in the specification, an alkylcarbonyl group, alkenylcarbonyl group, alkynylcarbonyl group, cycloalkylcarbonyl group, amide group, or ester group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.

[0096] “Alkyl” refers to an optionally substituted straight-chain, or optionally substituted branched- chain saturated hydrocarbon monoradical. An alkyl group can have from one to about twenty carbon atoms, from one to about ten carbon atoms, or from one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1- butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3- dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, and longer alkyl groups, such as heptyl, octyl, and the like. Whenever it appears herein, a numerical range such as “C1-C6alkyl” means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a C1-C10alkyl, a C1-C9alkyl, a C1-C8alkyl, a C1-C7alkyl, a C1-C6alkyl, a C1- C5 alkyl, a C1-C4 alkyl, a C1-C3 alkyl, a C1-C2 alkyl, or a C1 alkyl. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, -NO2, or -C≡CH. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0097] “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, - CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen. In some embodiments, the alkylene is -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH(CH3)CH2-. In some embodiments, the alkylene is -CH2-. In some embodiments, the alkylene is -CH2CH2-. In some embodiments, the alkylene is -CH2CH2CH2-.

[0098] “Alkenyl” refers to an optionally substituted straight-chain, or optionally substituted branched- chain hydrocarbon monoradical having one or more carbon-carbon double-bonds. In some embodiments, an alkenyl group has from two to about ten carbon atoms, or two to about six carbon atoms. The group may be in either the cis or trans configuration about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, and the like. Whenever it appears herein, a numerical range such as “C2-C6alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. In some embodiments, the alkenyl is a C2-C10alkenyl, a C2-C9alkenyl, a C2-C8alkenyl, a C2-C7alkenyl, a C2-C6alkenyl, a C2-C5alkenyl, a C2-C4alkenyl, a C2-C3alkenyl, or a C2alkenyl. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, - CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

[0099] The term “alkenylene” or “alkenylene chain” refers to an optionally substituted straight or branched divalent hydrocarbon chain in which at least one carbon-carbon double bond is present linking the rest of the molecule to a radical group. In some embodiments, the alkenylene is –CH=CH-, - CH2CH=CH-, or –CH=CHCH2-. In some embodiments, the alkenylene is –CH=CH-. In some embodiments, the alkenylene is –CH2CH=CH-. In some embodiments, the alkenylene is –CH=CHCH2-.

[0100] “Alkynyl” refers to an optionally substituted straight-chain or optionally substituted branched- chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds. In some embodiments, an alkynyl group has from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Whenever it appears herein, a numerical range such as “C2-C6alkynyl” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. In some embodiments, the alkynyl is a C2-C10alkynyl, a C2-C9alkynyl, a C2-C8alkynyl, a C2-C7alkynyl, a C2-C6alkynyl, a C2-C5alkynyl, a C2-C4alkynyl, a C2-C3alkynyl, or a C2alkynyl. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen. The term “alkynylene” refers to an optionally substituted straight- chain or optionally substituted branched-chain divalent hydrocarbon having one or more carbon-carbon triple-bonds.

[0101] “Alkylamino” refers to a radical of the formula -N(Ra)2where Rais an alkyl radical as defined, or two Ra, taken together with the nitrogen atom, can form a substituted or unsubstituted C2-C7heterocyloalkyl ring. Unless stated otherwise specifically in the specification, an alkylamino group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylamino is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkylamino is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkylamino is optionally substituted with halogen.

[0102] “Alkoxy” refers to a radical of the formula -ORawhere Rais an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0103] “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Hydroxyalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the hydroxyalkyl is aminomethyl.

[0104] The term “aryl” refers to a radical comprising at least one aromatic ring wherein each of the atoms forming the ring is a carbon atom. Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to phenyl, and naphthyl. In some embodiments, the aryl is phenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group). Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar-”(such as in “aralkyl”) is meant to include aryl radicals that are optionally substituted. In some embodiments, an aryl group comprises a partially reduced cycloalkyl group defined herein (e.g., 1,2-dihydronaphthalene). In some embodiments, an aryl group comprises a fully reduced cycloalkyl group defined herein (e.g., 1,2,3,4-tetrahydronaphthalene). When aryl comprises a cycloalkyl group, the aryl is bonded to the rest of the molecule through an aromatic ring carbon atom. An aryl radical can be a monocyclic or polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) ring system, which may include fused, spiro or bridged ring systems. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with halogen, amino, alkylamino, aminoalkyl, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -S(O)2NH-C1- C6alkyl, and the like. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, -NO2, -S(O)2NH2, -S(O)2NHCH3,-S(O)2NHCH2CH3, -S(O)2NHCH(CH3)2, -S(O)2N(CH3)2, or -S(O)2NHC(CH3)3. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen. In some embodiments, the aryl is substituted with alkyl, alkenyl, alkynyl, haloalkyl, or heteroalkyl, wherein each alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl is independently unsubstituted, or substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2.

[0105] The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls are saturated or partially unsaturated. In some embodiments, cycloalkyls are spirocyclic or bridged compounds. In some embodiments, cycloalkyls are fused with an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having from 3 to 10 ring atoms. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to ten carbon atoms, from three to eight carbon atoms, from three to six carbon atoms, or from three to five carbon atoms. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the monocyclic cycloalkyl is cyclopentyl. In some embodiments, the monocyclic cycloalkyl is cyclopentenyl or cyclohexenyl. In some embodiments, the monocyclic cycloalkyl is cyclopentenyl. Polycyclic radicals include, for example, adamantyl, 1,2-dihydronaphthalenyl, 1,4-dihydronaphthalenyl, tetrainyl, decalinyl, 3,4- dihydronaphthalenyl-1(2H)-one, spiro[2.2]pentyl, norbornyl and bicycle[1.1.1]pentyl. Unless otherwise stated specifically in the specification, a cycloalkyl group may be optionally substituted. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3-C15cycloalkyl), from three to ten carbon atoms (C3-C10cycloalkyl), from three to eight carbon atoms (C3-C8cycloalkyl), from three to six carbon atoms (C3-C6cycloalkyl), from three to five carbon atoms (C3-C5cycloalkyl), or three to four carbon atoms (C3-C4cycloalkyl). In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0106] “Halo” or “halogen” refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0107] “Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halogens. In some embodiments, the alkyl is substituted with one, two, or three halogens. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six halogens. Haloalkyl can include, for example, iodoalkyl, bromoalkyl, chloroalkyl, and fluoroalkyl. For example, "fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0108] “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, - N(alkyl)-), sulfur, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, –CH2-O-CH2-, –CH2- N(alkyl)-CH2-, –CH2-N(aryl)-CH2-, -OCH2CH2O-, –OCH2CH2OCH2CH2O-, or – OCH2CH2OCH2CH2OCH2CH2O-. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, - OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen. As used herein, a “heteroalkylene” refers to divalent heteroalkyl group. Examples of such heteroalkylene are, for example, –CH2-O-CH2-, –CH2-N(alkyl)-CH2-, –CH2-N(aryl)-CH2-, - OCH2CH2O-, –OCH2CH2OCH2CH2O-, or –OCH2CH2OCH2CH2OCH2CH2O-. Unless stated otherwise, a heteroalkylene can be optionally substituted.

[0109] The term “heterocycloalkyl” refers to a cycloalkyl group that includes at least one hetero ring atom, e.g., a heteroatom selected from nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, or bicyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. The nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized. The nitrogen atom may be optionally quaternized. The heterocycloalkyl radical is partially or fully saturated. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl. The term heterocycloalkyl also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 12 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring and 1 or 2 N atoms. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring and 3 or 4 N atoms. In some embodiments, heterocycloalkyls have from 2 to 12 carbons, 0-2 N atoms, 0-2 O atoms, 0-2 P atoms, and 0-1 S atoms in the ring. In some embodiments, heterocycloalkyls have from 2 to 12 carbons, 1-3 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, a heterocycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, - CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0110] “Heteroaryl” refers to a ring system radical comprising carbon atom(s) and one or more ring heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, heteroaryl is monocyclic, bicyclic or polycyclic. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, furazanyl, indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Illustrative examples of bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, heteroaryl is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl or furyl. In some embodiments, a heteroaryl contains 0-6 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 4-6 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, 0-1 P atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a C1-C9heteroaryl. In some embodiments, monocyclic heteroaryl is a C1-C5heteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, a bicyclic heteroaryl is a C6-C9heteroaryl. In some embodiments, a heteroaryl group comprises a partially reduced cycloalkyl or heterocycloalkyl group defined herein (e.g., 7,8-dihydroquinoline). In some embodiments, a heteroaryl group comprises a fully reduced cycloalkyl or heterocycloalkyl group defined herein (e.g., 5,6,7,8-tetrahydroquinoline). When heteroaryl comprises a cycloalkyl or heterocycloalkyl group, the heteroaryl is bonded to the rest of the molecule through a heteroaromatic ring carbon or hetero atom. A heteroaryl radical can be a monocyclic or polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) ring system, which may include fused, spiro or bridged ring systems. Unless stated otherwise specifically in the specification, a heteroaryl is optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, - CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0111] The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[0112] The terms “treat,” “prevent,” “ameliorate,” and “inhibit,” as well as words stemming therefrom, as used herein, do not necessarily imply 100% or complete treatment, prevention, amelioration, or inhibition. Rather, there are varying degrees of treatment, prevention, amelioration, and inhibition of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect. In this respect, the disclosed methods can provide any amount of any level of treatment, prevention, amelioration, or inhibition of the disorder in a mammal. For example, a disorder, including symptoms or conditions thereof, may be reduced by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%. Furthermore, the treatment, prevention, amelioration, or inhibition provided by the methods disclosed herein can include treatment, prevention, amelioration, or inhibition of one or more conditions or symptoms of the disorder, e.g., cancer or an inflammatory disease. As used herein, “treating” includes the concepts of “alleviating”, which refers to lessening the frequency of occurrence or recurrence, or the severity, of any symptoms or other ill effects related to a disorder and / or the associated side effects. The term “treating” also encompasses the concept of “managing” which refers to reducing the severity of a particular disease or disorder in a patient or delaying its recurrence, e.g., lengthening the period of remission in a patient who had suffered from the disease.

[0113] In certain embodiments, the term “prevent” or “preventing” as related to a disease or disorder can refer to a compound that in a statistical sample, reduces the occurrences of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.

[0114] The term "therapeutically effective amount" as used herein to refer to an amount effective at the dosage and duration necessary to achieve the desired therapeutic result. A therapeutically effective amount of the composition may vary depending on factors such as the individual's condition, age, sex, and weight, and the ability of the protein to elicit the desired response of the individual. A therapeutically effective amount can also be an amount that exceeds any toxic or deleterious effect of the composition that would have a beneficial effect on the treatment.

[0115] The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be un- substituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, - CH2CF3, -CF2CH3, -CFHCHF2, etc.).

[0116] As used herein, the term "substituent" means positional variables on the atoms of a core molecule that are substituted at a designated atom position, replacing one or more hydrogens on the designated atom, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. A person of ordinary skill in the art should note that any carbon as well as heteroatom with valences that appear to be unsatisfied as described or shown herein is assumed to have a sufficient number of hydrogen atom(s) to satisfy the valences described or shown. In certain instances one or more substituents having a double bond (e.g., "oxo" or "=O") as the point of attachment may be described, shown or listed herein within a substituent group, wherein the structure may only show a single bond as the point of attachment to the core structure. A person of ordinary skill in the art would understand that, while only a single bond is shown, a double bond is intended for those substituents.

[0117] The term “optionally substituted” or “substituted” means that the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from D, halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, oxo, -CO2H, -CO2alkyl, -C(=O)NH2, - C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, optional substituents are independently selected from D, halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, oxo, -CO2H, -CO2(C1-C4alkyl), -C(=O)NH2, -C(=O)NH(C1-C4alkyl), -C(=O)N(C1-C4alkyl)2, - S(=O)2NH2, -S(=O)2NH(C1-C4alkyl), -S(=O)2N(C1-C4alkyl)2, C1-C4alkyl, C3-C6cycloalkyl, C1- C4fluoroalkyl, C1-C4heteroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, -SC1-C4alkyl, -S(=O)C1-C4alkyl, and - S(=O)2C1-C4alkyl. In some embodiments, optional substituents are independently selected from D, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -NH(cyclopropyl), -CH3, -CH2CH3, -CF3, -OCH3, and - OCF3. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic) includes oxo (=O). When indicating the number of substituents, the term “one or more” means from one substituent to the highest possible number of substitutions, i.e. replacement of one hydrogen up to replacement of all hydrogens by substituents.

[0118] The term “unsubstituted means that the specified group bears no substituents.

[0119] Certain compounds described herein may exist in tautomeric forms, and all such tautomeric forms of the compounds being within the scope of the disclosure.

[0120] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0121] The term “peptide” as used herein refers to a compound that includes two or more amino acids. A peptide described herein can comprise one or more unnatural amino acids. The term “peptide” also encompasses peptide mimetics. In the present disclosure, the term “amino acid” is used in its broadest meaning and it embraces not only natural amino acids but also derivatives thereof and artificial amino acids. For example, the term “amino acid” encompasses unnatural amino acids.

[0122] As used herein, the term “unnatural amino acid” refers to an amino acid other than the 20 canonical amino acids. The 20 canonical amino acids refer to alanine (ala or A), arginine (arg or R), asparagine (asn or N), aspartic acid (asp or D), cysteine (cys or C), glutamine (gln or Q), glutamic acid (glu or E), glycine (gly or G), histidine (his or H), isoleucine (ile or I), leucine (leu or L), lysine (lys or K), methionine (met or M), phenylalanine (phe or F), proline (pro or P), serine (ser or S), threonine (thr or T), tryptophan (trp or W), tyrosine (tyr or Y), and valine (val or V).

[0123] The term “protein” as used herein refers to a polypeptide (i.e., a string of at least 3 amino acids linked to one another by peptide bonds). Proteins can include moieties other than amino acids (e.g., may be glycoproteins, proteoglycans, etc.) and / or can be otherwise processed or modified. A protein can be a complete polypeptide as produced by and / or active in a cell (with or without a signal sequence). In some embodiments, a protein is or comprises a characteristic portion such as a polypeptide as produced by and / or active in a cell. A protein can include more than one polypeptide chain. For example, polypeptide chains can be linked by one or more disulfide bonds or associated by other means.

[0124] The term “peptide mimetic” or “mimetic” refers to biologically active compounds that mimic the biological activity of a peptide or a protein but are no longer entirely peptidic in chemical nature, e.g.,, they can contain non-peptide bonds (that are, bonds other than amide bonds between amino acids). As used herein, the term peptide mimetic is used in a broader sense to include molecules that are no longer completely peptidic in nature, such as pseudo-peptides, semi-peptides and peptoids. Whether completely or partially non-peptide, peptide mimetics described herein can provide a spatial arrangement of reactive chemical moieties that closely resemble the three-dimensional arrangement of active groups in the subject amino acid sequence or subject molecule on which the peptide mimetic is based. As a result of this similar active-site geometry, the peptide mimetic can have effects on biological systems that are similar to the biological activity of the subject entity.

[0125] In some embodiments, the peptide mimetics are substantially similar in both three-dimensional shape and biological activity to the subject amino acid sequence or subject molecule on which the peptide mimetic is based. An example is described in the paper “Tritiated D-ala1-Peptide T Binding”, Smith C. S. et al., Drug Development Res., 15, pp.371-379 (1988). A second method is altering cyclic structure for stability, such as N to C interchain imides and lactams (Ede et al. in Smith and Rivier (Eds.) “Peptides: Chemistry and Biology”, Escom, Leiden (1991), pp.268-270). An example of this is provided in conformationally restricted thymopentin-like compounds, such as those disclosed in US4457489. A third method is to substitute peptide bonds in the subject entity by pseudopeptide bonds that confer resistance to proteolysis.

[0126] Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, as well as all intervening decimal values between the aforementioned integers such as, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. With respect to sub-ranges, “nested sub-ranges” that extend from either end point of the range are specifically contemplated. For example, a nested sub-range of an exemplary range of 1 to 50 may comprise 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction.

[0127] As used herein, C1-Cx(or C1-x) includes C1-C2, C1-C3... C1-Cx. By way of example only, a group designated as “C1-C4” indicates that there are one to four carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, “C1-C4alkyl” indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Also, by way of example, C0-C2alkylene includes a direct bond, -CH2-, and -CH2CH2- linkages.

[0128] The term “cyclized” or “cyclization” as used herein means that two amino acids apart from each other by at least one amino acid bind directly or bind indirectly to each other in one peptide to form a cyclic structure in the molecule. In some cases, the two amino acids bind via a linker or the like.

[0129] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a companion animal such as a dog or a cat. In one aspect, the mammal is a human.

[0130] The term "therapeutically effective amount" as used herein to refer to an amount effective at the dosage to achieve the desired therapeutic result. A therapeutically effective amount of a composition may vary depending on factors such as the individual's condition (e.g., age, sex, and weight), the radiopharmaceutical conjugate, and the method of administration (e.g., oral or parenteral).

[0131] Percent sequence identity can be calculated using computer programs or direct sequence comparison. Preferred computer program methods to determine identity between two sequences include, but are not limited to, the GCG program package, FASTA, BLASTP, and TBLASTN (see, e.g., D. W. Mount, 2001, Bioinformatics: Sequence and Genome Analysis, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.). The BLASTP and TBLASTN programs are publicly available from NCBI and other sources. The Smith Waterman algorithm can also be used to determine percent identity. Exemplary parameters for amino acid sequence comparison include the following: 1) algorithm from Needleman and Wunsch (J. Mol. Biol., 48:443-453 (1970)); 2) BLOSSUM62 comparison matrix from Hentikoff and Hentikoff (Proc. Nat. Acad. Sci. USA., 89:10915-10919 (1992)) 3) gap penalty=12; and 4) gap length penalty=4. A program useful with these parameters can be publicly available as the “gap” program (Genetics Computer Group, Madison, Wis.). The aforementioned parameters are the default parameters for polypeptide comparisons (with no penalty for end gaps). Alternatively, polypeptide sequence identity can be calculated using the following equation: % identity—(the number of identical residues) / (alignment length in amino acid residues)*100. For this calculation, alignment length includes internal gaps but does not include terminal gaps.

[0132] It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the disclosure, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. For example, a conjugate of this disclosure can comprise any peptide ligand described herein (e.g., a peptide ligand of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), or (Ic), or Table 1), any metal chelator described herein (e.g., a metal chelator selected from FIGs 4A, 5A, 6A, 7A, 4B, 5B, 6B, 7B and 8-22), optionally a linker described herein (e.g., a linker of Formula (II-1), (II-1a), (II-1b), or (II-2)), and optionally a radionuclide described herein (e.g., a radionuclide of Table 7 labeled “chelator”). As another example, a conjugate of this disclosure can comprise any peptide ligand described herein (e.g., a peptide ligand of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), or (Ic), or Table 1), any covalent radionuclide described herein (e.g., a radionuclide of Table 7 labeled “covalent”), and optionally a linker described herein (e.g., a linker of Formula (II-1), (II-1a), (II-1b), or (II-2) or Table 6) connecting the covalent radionuclide to the peptide. For another example, a peptide of Formula (I) (or any other formulas such as (III-1), (III-2), (III-1-RI), and (III-2-RI)) can comprise X1 to X12 amino acids as described herein, and any combinations of the embodiments of amino acids are encompassed by this disclosure (even though, in some cases, they are described in the context of separate embodiments). II. Radiopharmaceutical Conjugates

[0133] Provided herein are radiopharmaceutical conjugates that have avidity for ephrin type-A receptor 2 (EphA2) and pharmaceutical compositions comprising the conjugates. The conjugates and compositions can be useful for treating cancer. The conjugates and compositions can also be useful in imaging and disease diagnosis.

[0134] In one aspect, described herein is a conjugate that comprises a peptide that has avidity for ephrin type-A receptor 2 (EphA2) and a metal chelator that is configured to bind with a radionuclide. In some embodiments, the EphA2 is a human EphA2. In some embodiments, the conjugate or the peptide described herein does not have avidity toward human EphA1, EphA3, EphA4, EphA5, EphA6, EphA7 or EphB4. In some embodiments, the conjugate or the peptide described herein does not exhibit significant binding to human EphA1, EphA3, EphA4, EphA5, EphA6, EphA7 or EphB4. The peptide can be cyclic or acyclic, and it can be monocyclic, bicyclic or polycyclic. In one aspect, described herein is a conjugate that comprises a cyclic peptide and a metal chelator that is configured to bind with a radionuclide. In some embodiments, the peptide (such as cyclic peptide) is configured to bind to a target. A conjugate described herein can further comprises a linker that covalently attaches the peptide to the metal chelator. In some embodiments, the conjugate comprises a radionuclide such as225Ac bound to the metal chelator.

[0135] In another aspect, described herein is a conjugate that comprises a peptide that has avidity for ephrin type-A receptor 2 (EphA2) and a covalently bound radionuclide. In some embodiments, the EphA2 is a human EphA2. In some embodiments, the conjugate or the peptide described herein does not have avidity toward human EphA1, EphA3, EphA4, EphA5, EphA6, EphA7 or EphB4. In some embodiments, the conjugate or the peptide described herein does not exhibit significant binding to human EphA1, EphA3, EphA4, EphA5, EphA6, EphA7 or EphB4. The peptide can be cyclic or acyclic, and it can be monocyclic, bicyclic or polycyclic. In one aspect, described herein is a conjugate that comprises a cyclic peptide and a covalently bound radionuclide. In some embodiments, the peptide (such as cyclic peptide) is configured to bind to a target. A conjugate described herein can further comprises a linker that covalently attaches the peptide to the radionuclide. In some embodiments, the conjugate comprises a covalently bound radionuclide such as131I.

[0136] In one aspect, described herein is a radiopharmaceutical conjugate comprising: (a) a peptide that has avidity for ephrin type-A receptor 2 (EphA2), wherein the peptide comprises an amino acid sequence including deletion, substitution, and / or addition of one or several amino acids in the amino acid of SEQ ID NO:1: da-MeF-N-L-Hgl-MeF-W1Me-V-W1Me-T-E-C (SEQ ID NO:1) or a pharmaceutically acceptable salt thereof ; and (b)(i) a metal chelator configured to bind with a radionuclide, wherein the metal chelator is conjugated to the peptide; or (ii) a covalent radionuclide (or, a radionuclide covalently bound to the peptide). In some embodiments, the peptide consists of 7, 8, 9, 10, 11, 12, or 13 amino acid residues. In some embodiments, the radiopharmaceutical conjugate comprises a metal chelator configured to bind with a radionuclide, wherein the metal chelator is conjugated to the peptide. In some embodiments, the metal chelator is covalently connected to the peptide. In some embodiments, the radiopharmaceutical conjugate comprises a covalent radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a radionuclide covalently bound to the peptide.

[0137] In some embodiments, the peptide is a cyclic peptide. In some embodiments, the peptide consists of 10 or 12 amino acid residues. In some embodiments, the peptide comprises an amino acid sequence with deletion of 2 or less amino acids in the amino acid SEQ ID NO: 1. In some embodiments, 1-2 amino acids selected from the group consisting of 10th T and 11th E of SEQ ID NO:1 is deleted. In some embodiments, the 8thV is of SEQ ID NO: 1 is substituted. In some embodiments, the 11thE of SEQ ID NO: 1 is substituted.

[0138] In one aspect, described herein is a radiopharmaceutical conjugate comprising: (a) a peptide that has avidity for ephrin type-A receptor 2 (EphA2), wherein the peptide has an amino acid sequence according to Formula (I), or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) wherein, X1 is an amino acid; X2 is an amino acid comprising an aromatic ring, an N-methylated amino acid thereof, or a variant thereof; X3 is a hydrophilic amino acid (e.g. N, Q, Cit, K or a variant thereof), glycine (G), Alanine (A) or a variant thereof (e.g., da, 2-Aminoisobutyric acid (Aib)); X4 is a hydrophobic amino acid (e.g., leucine (L)), a hydrophilic amino acid (e.g., citrulline (Cit)), or a variant thereof; X5 is a hydrophilic amino acid, or a variant thereof; X6 is a hydrophilic amino acid, an amino acid comprising an aromatic ring, or an N- methylated amino acid thereof; X7 is an amino acid comprising an aromatic ring (e.g., W, F, or a variant thereof); X8 is a hydrophobic amino acid, a hydrophilic amino acid, an N-methylated amino acid, or a variant thereof; X9 is an amino acid comprising an aromatic ring (e.g., W or a variant thereof); X10 is absent or a hydrophilic amino acid (e.g., Threonine (T) or a variant thereof); X11 is absent or a hydrophilic amino acid; and X12 is cysteine (C) or a variant thereof; and (b)(i) a metal chelator configured to bind with a radionuclide, wherein the metal chelator is conjugated to the peptide; or (ii) a covalent radionuclide. In some embodiments, the peptide is a cyclic peptide. In some embodiments, the radiopharmaceutical conjugate comprises a metal chelator configured to bind with a radionuclide, wherein the metal chelator is conjugated to the peptide. In some embodiments, the metal chelator is covalently connected to the peptide. In some embodiments, the radiopharmaceutical conjugate comprises a covalent radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a radionuclide covalently bound to the peptide. In some embodiments, the peptide is a cyclic peptide. In some embodiments, the peptide is a monocyclic peptide.

[0139] In one aspect, described herein is a radiopharmaceutical conjugate comprising: (a) a peptide that has avidity for ephrin type-A receptor 2 (EphA2), wherein the peptide has an amino acid sequence according to Formula (I), or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) wherein, X1 is an amino acid; X2 is an amino acid comprising an aromatic ring, an N-methylated amino acid thereof, or a variant thereof; X3 is absent, a hydrophilic amino acid (e.g. N, Q, Cit, K or a variant thereof), glycine (G), Alanine (A) or a variant thereof (e.g., da, 2-Aminoisobutyric acid (Aib)); X4 is absent, a hydrophobic amino acid (e.g., leucine (L)), a hydrophilic amino acid (e.g., citrulline (Cit)), or a variant thereof; X5 is absent, a hydrophilic amino acid, or a variant thereof; X6 is absent, a hydrophilic amino acid, an amino acid comprising an aromatic ring, or an N-methylated amino acid thereof; X7 is an amino acid comprising an aromatic ring (e.g., W, F, or a variant thereof); X8 is a hydrophobic amino acid, a hydrophilic amino acid, an N-methylated amino acid, or a variant thereof; X9 is an amino acid comprising an aromatic ring (e.g., W or a variant thereof); X10 is absent or a hydrophilic amino acid (e.g., Threonine (T) or a variant thereof); X11 is absent or a hydrophilic amino acid; and X12 is cysteine (C) or a variant thereof; and (b)(i) a metal chelator configured to bind with a radionuclide, wherein the metal chelator is conjugated to the peptide; or (ii) a covalent radionuclide. In some embodiments, the peptide is a cyclic peptide. In some embodiments, the radiopharmaceutical conjugate comprises a metal chelator configured to bind with a radionuclide, wherein the metal chelator is conjugated to the peptide. In some embodiments, the metal chelator is covalently connected to the peptide. In some embodiments, the radiopharmaceutical conjugate comprises a covalent radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a radionuclide covalently bound to the peptide.

[0140] In one aspect, described herein is a radiopharmaceutical conjugate comprising: (a) a peptide that has avidity for ephrin type-A receptor 2 (EphA2), wherein the peptide has an amino acid sequence according to Formula (I), or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) or a pharmaceutically acceptable salt thereof, wherein each of X1, X2, X3, X4, X5, X6, and X8 is independently an amino acid; X7 is W1Me or a variant thereof; X9 is W1Me or a variant thereof; each of X10 and X11 is independently absent or an amino acid; and X12 is cysteine (C) or a variant thereof; (b)(i) a metal chelator configured to bind with a radionuclide; or (ii) a covalent radionuclide; and (c)(i) a linker that connects the peptide with the metal chelator; or (ii) a linker that connects the peptide with the covalent radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a metal chelator configured to bind with a radionuclide and a linker that connects the peptide with the metal chelator. In some embodiments, the metal chelator is covalently connected to the peptide. In some embodiments, the radiopharmaceutical conjugate comprises a covalent radionuclide and a linker that connects the peptide with the covalent radionuclide.

[0141] In some embodiments, the metal chelator is conjugated to the N-terminus of the peptide. In some embodiments, the conjugate further comprises a linker that connects the peptide with the metal chelator. In some embodiments, the linker covalently connects the peptide with the metal chelator. In some embodiments, the linker covalently attaches the metal chelator to the N-terminus of the peptide. In some embodiments, the linker covalently attaches the metal chelator to the C-terminus of the peptide. In some embodiments, the linker is attached to the peptide via a non-terminal amino acid residue of the peptide. In some embodiments, the linker is attached to amino acid X1. In some embodiments, the linker is attached to amino acid X2. In some embodiments, the linker is attached to amino acid X3. In some embodiments, the linker is attached to amino acid X4. In some embodiments, the linker is attached to amino acid X5. In some embodiments, the linker is attached to amino acid X6. In some embodiments, the linker is attached to amino acid X7. In some embodiments, the linker is attached to amino acid X8. In some embodiments, the linker is attached to amino acid X9. In some embodiments, the linker is attached to amino acid X10. In some embodiments, the linker is attached to amino acid X11. In some embodiments, the linker is attached to amino acid X12. In some embodiments, the linker is attached to amino acid X5, X8 or X11. In some embodiments, the linker is attached to a lysine of the peptide. In some embodiments, the linker comprises one or more amino acid residues. In some embodiments, the linker comprises a lysine residue, an alanine residue, or both.

[0142] In one aspect, described herein is a radiopharmaceutical conjugate with structure of , wherein represents a linker.

[0143] In one aspect, described herein is a radiopharmaceutical conjugate with structure of , wherein represents the linker connected to the C-terminus of the peptide.

[0144] In some embodiments, the radiopharmaceutical conjugate comprises a covalent radionuclide. In some embodiments, the covalent radionuclide is attached to the N-terminus of the peptide. In some embodiments, the conjugate further comprises a linker that connects the peptide with the covalent radionuclide. In some embodiments, the linker covalently connects the peptide with the covalent radionuclide. In some embodiments, the linker covalently attaches the covalent radionuclide to the N- terminus of the peptide. In some embodiments, the linker covalently attaches the covalent radionuclide to the C-terminus of the peptide. In some embodiments, the linker is attached to the peptide via a non- terminal amino acid residue of the peptide. In some embodiments, the linker is attached to amino acid X1. In some embodiments, the linker is attached to amino acid X2. In some embodiments, the linker is attached to amino acid X3. In some embodiments, the linker is attached to amino acid X4. In some embodiments, the linker is attached to amino acid X5. In some embodiments, the linker is attached to amino acid X6. In some embodiments, the linker is attached to amino acid X7. In some embodiments, the linker is attached to amino acid X8. In some embodiments, the linker is attached to amino acid X9. In some embodiments, the linker is attached to amino acid X10. In some embodiments, the linker is attached to amino acid X11. In some embodiments, the linker is attached to amino acid X12. In some embodiments, the linker is attached to amino acid X5, X8 or X11. In some embodiments, the linker is attached to a lysine of the peptide. In some embodiments, the linker comprises one or more amino acid residues. In some embodiments, the linker comprises a lysine residue, an alanine residue, or both.

[0145] In some embodiments, the covalent radionuclide is bound directly to the peptide. In some embodiments, the covalent radionuclide is bound directly to the peptide via a non-terminal amino acid residue of the peptide. In some embodiments, the covalent radionuclide is bound to an aromatic amino acid in the peptide. In some embodiments, the covalent radionuclide is bound to amino acid X1. In some embodiments, the covalent radionuclide is bound to amino acid X2. In some embodiments, the covalent radionuclide is bound to amino acid X3. In some embodiments, the covalent radionuclide is bound to amino acid X4. In some embodiments, the covalent radionuclide is bound to amino acid X5. In some embodiments, the covalent radionuclide is bound to amino acid X6. In some embodiments, the covalent radionuclide is bound to amino acid X7. In some embodiments, the covalent radionuclide is bound to amino acid X8. In some embodiments, the covalent radionuclide is bound to amino acid X9. In some embodiments, the covalent radionuclide is bound to amino acid X10. In some embodiments, the covalent radionuclide is bound to amino acid X11. In some embodiments, the covalent radionuclide is bound to amino acid X12. In some embodiments, covalent radionuclide is bound to amino acid X2, X6, X7, or X9.

[0146] In one aspect, described herein is a radiopharmaceutical conjugate with structure of wherein represents the linker; and R*represents the radionuclide.

[0147] In one aspect, described herein is a radiopharmaceutical conjugate with structure of , wherein represents the linker connected to the C-terminus of the peptide; and R* represents the radionuclide.

[0148] In one aspect, described herein is a radiopharmaceutical conjugate with structure of , wherein represents the residualizing agent or the non-residualizing agent; linker represents the linker; and R* represents the radionuclide.

[0149] In one aspect, described herein is a radiopharmaceutical conjugate with structure of , wherein represents the residualizing agent or the non-residualizing agent; linker represents the linker connected to the C-terminus of the peptide; and R* represents the radionuclide.

[0150] In some embodiments, described herein is a conjugate comprising: (a) a targeting moiety that comprises a monocyclic peptide that has avidity for ephrin type-A receptor 2 (EphA2) and (b)(i) a metal chelator configured to bind with a radionuclide; or (ii) a covalent radionuclide. In some embodiments, described herein is a conjugate comprising: (a) a monocyclic peptide that is configured to bind with EphA2 and (b)(i) a metal chelator configured to bind with a radionuclide; or (ii) a covalent radionuclide. In some embodiments, described herein is a conjugate comprising: (a) a targeting moiety that comprises a monocyclic peptide; and (b)(i) a metal chelator configured to bind with a radionuclide; or (ii) a covalent radionuclide. In some embodiments, the monocyclic peptide is cyclized by a non-disulfide bond. In some embodiments, the monocyclic peptide does not comprise a disulfide bond. In some embodiments, the monocyclic peptide comprises 5 to 20 amino acid residues. In some embodiments, the monocyclic peptide comprises 7 to 12 amino acid residues. A conjugate described herein can further comprises a linker that covalently attaches the cyclic peptide to the metal chelator or the covalent radionuclide. In some embodiments, the conjugate comprises a radionuclide such as225Ac bound to the metal chelator. In some embodiments, the conjugate comprises a covalently bound radionuclide such as18F,74As,76Br,123I,124I,125I,131I, and211At. In some embodiments, the a covalent radionuclide is attached to the peptide or linker via a residualizing agent or the non-residualizing agent.

[0151] In some embodiments, a herein-described conjugate comprises two or more peptides (i.e., a first peptide, a second peptide, etc.). For example, the conjugate can comprise two different peptides, wherein both of the peptides are configured to bind to the same target (e.g., EphA2), either at the same binding site or at different binding sites. For another example, the conjugate can comprise two different peptides, wherein the two peptides are configured to bind to different targets (including EphA2). For yet another example, the conjugate can comprise two identical peptides.

[0152] In some embodiments, a herein-described conjugate is in a salt form. In some embodiments, a herein-described conjugate is in a free-base form.

[0153] In one aspect, described herein is a conjugate comprising (a) a peptide that has avidity for ephrin type-A receptor 2 (EphA2), wherein the peptide competes for binding to human EphA2 with a peptide that has an amino acid sequence including deletion, substitution, and / or addition of one or several amino acids in the amino acid of SEQ ID NO:1: da-MeF-N-L-Hgl-MeF-W1Me-V-W1Me-T-E-C (SEQ ID NO:1) or a pharmaceutically acceptable salt thereof; and (b)(i) a metal chelator configured to bind with a radionuclide; or (ii) a covalent radionuclide. In one aspect, described herein is a conjugate comprising (a) a peptide that has avidity for ephrin type-A receptor 2 (EphA2), wherein the peptide competes for binding to human EphA2 with a peptide that has a structure of Formula (I) as described herein (e.g., Formulas (I-1), (I-2), (I-3) or (I-4)), or a pharmaceutically acceptable salt thereof; and (b)(i) a metal chelator configured to bind with a radionuclide; or (ii) a covalent radionuclide. In some embodiments, the peptide competes for binding to human EphA2 at one or more amino acid residues selected from Asp53, Met55, Asn57, Met59, Met66, Thr101, Arg103, Phe156, Glu157, Arg159, Val161, Val189, and Ala190. In some embodiments, the peptide competes for binding to human EphA2 at one or more amino acid residues selected from Asp53, Phe156, and Glu157. In some embodiments, the peptide competes for binding to human EphA2 at Asp53, Glu157, or both. In some embodiments, the peptide is a cyclic peptide. In some embodiments, the peptide is a monocyclic peptide.

[0154] In some embodiments, the metal chelator is conjugated to the peptide, either directly or indirectly through a linker. In some embodiments, the metal chelator is conjugated to the peptide, either covalently or non-covalently. In some embodiments, the radionuclide is covalently bound to the peptide, either directly or indirectly through a linker.

[0155] A conjugate described herein can have a suitable plasma half-life (T1 / 2). In some embodiments, the plasma half-life of a conjugate is at least 50 minutes, 100 minutes, 150 minutes, 200 minutes, 250 minutes, 300 minutes, 350 minutes, 400 minutes, 450 minutes, or 500 minutes as determined in vitro in human plasma at 37 ⁰C. In some embodiments, the plasma half-life of a conjugate is at least 280 minutes as determined in vitro in human plasma at 37 ⁰C. In some embodiments, the plasma half-life of a conjugate is at least 250 minutes as determined in vitro in human plasma at 37 ⁰C. In some embodiments, the plasma half-life of a conjugate is at most 30 days, 14 days, 7 days, 2 days, 1 day or 500 minutes as determined in vitro in human plasma at 37 ⁰C. In some embodiments, the plasma half-life is at least 50 minutes, 100 minutes, 150 minutes, 200 minutes, 250 minutes, 300 minutes, 350 minutes, 400 minutes, 450 minutes, or 500 minutes as determined in vivo in a human. In some embodiments, the plasma half- life is at least 280 minutes as determined in vivo in a human. In some embodiments, the plasma half-life is at least 250 minutes as determined in vivo in a human. In some embodiments, the plasma half-life of a conjugate is at most 30 days, 14 days, 7 days, 2 days, 1 day or 500 minutes as determined in vivo in a human. In some embodiments, the plasma half-life of a conjugate is at least 50 minutes, 100 minutes, 150 minutes, 200 minutes, 250 minutes, 300 minutes, 350 minutes, 400 minutes, 450 minutes, or 500 minutes as determined in vitro in a mouse plasma at 37 ⁰C. In some embodiments, the plasma half-life of a conjugate is at least 280 minutes as determined in vitro in a mouse plasma at 37 ⁰C. In some embodiments, the plasma half-life of a conjugate is at least 250 minutes as determined in vitro in a mouse plasma at 37 ⁰C. In some embodiments, the plasma half-life of a conjugate is at most 30 days, 14 days, 7 days, 2 days, 1 day or 500 minutes as determined in vitro in mouse plasma at 37 ⁰C. In some embodiments, the plasma half-life is at least 50 minutes, 100 minutes, 150 minutes, 200 minutes, 250 minutes, 300 minutes, 350 minutes, 400 minutes, 450 minutes, or 500 minutes as determined in vivo in a mouse. In some embodiments, the plasma half-life is at least 280 minutes as determined in vivo in a mouse. In some embodiments, the plasma half-life is at least 250 minutes as determined in vivo in a mouse. In some embodiments, the plasma half-life of a conjugate is at most 30 days, 14 days, 7 days, 2 days, 1 day or 500 minutes as determined in vivo in a mouse. Plasma half-life can be determined by any suitable methods known in the art, e.g., the method described in Example C1. In some embodiments, the conjugate has a plasma half-life (T1 / 2) of at least 250 minutes as determined in vitro in human plasma at 37 ⁰C. In some embodiments, plasma half-life is determined by % remaining of test compound after incubation in plasma.

[0156] A conjugate described herein can have a an uptake ratio between a tumor and intestine. In some embodiments, an uptake ratio is determined between the uptake of a radiopharmaceutical conjugate to a tumor and the uptake of a radiopharmaceutical conjugate to a kidney of a subject. In some embodiments, the subject is a human. In some embodiments, is a mammal. In some embodiments, the subject is a rat or mouse (such as in a xenograft model). In some embodiments, an uptake ratio between a tumor uptake and kidney uptake (i.e., tumor uptake / kidney uptake) toward the radiopharmaceutical conjugate is at least 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8 or 2.0 in a human prostate xenograft mouse model.). In some embodiments, the uptake ratio is determined at about 4 hours, 12 hours, 24 hours, or 48 hours after administration of the radiopharmaceutical conjugate to the mouse. In some embodiments, an uptake ratio between a tumor uptake and kidney uptake toward the radiopharmaceutical conjugate is at least 1.2. In some embodiments, an uptake ratio between a tumor uptake and kidney uptake toward the radiopharmaceutical conjugate is at least 1.5. In some embodiments, a tumor uptake of a herein described radiopharmaceutical conjugate is at least 5%, 10%, 20%, 30%, 40 %, 50%, 60%, 70%, 80%, 90%, or 100% higher than a kidney uptake of the radiopharmaceutical conjugate in a same subject.

[0157] In some embodiments, the uptake of the radiopharmaceutical conjugate is determined at about 4 hours, 12 hours, 24 hours, or 48 hours after administration of the radiopharmaceutical conjugate to the subject. In some embodiments, the uptake of the radiopharmaceutical conjugate is determined at about 4 hours after administration. In some embodiments, the uptake of the radiopharmaceutical conjugate is determined at about 12 hours after administration. In some embodiments, the uptake of the radiopharmaceutical conjugate is determined at about 24 hours. In some embodiments, the uptake of the radiopharmaceutical conjugate is determined at about 48 hours after administration.

[0158] In some embodiments, a conjugate described herein is designed to have a prescribed elimination profile. The elimination profile can be designed by adjusting the sequence and length of the peptide, the property of the linker, the type of radionuclide, etc. In some embodiments, the conjugate has an elimination half-life of about 30 minutes to 120 hours. In some embodiments, the conjugate has an elimination half-life of about 1 to 120 hours. In some embodiments, the conjugate has an elimination half-life of at least 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 7 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours. In some embodiments, the conjugate has an elimination half-life of at most 120 hour, 80 hours, 70 hours, 60 hours, 50 hours, 40 hours, 30 hours, 24 hours, 12 hours, 10 hours, or 5 hours. In some embodiments, the conjugate has an elimination half-life of about 2 to 24 hours. In some embodiments, the conjugate has an elimination half-life of about 3 to 9 hours. In some embodiments, the conjugate has an elimination half-life of about 2 to 12 hours. In some embodiments, the conjugate has an elimination half-life of about 2 to 8 hours. In some embodiments, the conjugate has an elimination half-life of about 2 to 5 hours. In some embodiments, the conjugate has an elimination half-life of about 3 to 4 hours. In some embodiments, the elimination half-life is determined in rats. In some embodiments, the elimination half-life is determined in humans.

[0159] A herein described conjugate can have an elimination half-life in a tumor and non-tumor tissue of the subject. The elimination half-life in a tumor can be the same as or different from (either longer or shorter than) the elimination half-life in a non-tumor issue. In some embodiments, the elimination half- life of the conjugate in a tumor is about 3 hours to 14 days, about 2 to 10 days, about 7 to 10 days, or about 4 to 7 days. In some embodiments, the elimination half-life of the conjugate in a tumor is more than 14 days. In some embodiments, the elimination half-life of the conjugate in a non-tumor tissue is about 1 hour to 14 days, about 12 hours to 2 days, about 1 day to 3 days, about 2 to 10 days, about 7 to 10 days, or about 4 to 7 days. In some embodiments, the elimination half-life of the conjugate in a tumor is at least 1.1, 1.2, 1.3, 1.4, 1.5, 2.0, 2.5, 3.0, 4.0, or 5.0 fold of the elimination half-life of the conjugate in a non-tumor tissue of the subject.

[0160] As used herein, the “elimination half-life” can refer to the time it takes from the maximum concentration after administration to half maximum concentration. In some embodiments, the elimination half-life is determined after intravenous administration. In some embodiments, the elimination half-life is measured as biological half-life, which is the half-life of the cold pharmaceutical in the living system. In some embodiments, the elimination half-life is measured as effective half-life, which is the half-life of a radiopharmaceutical in a living system taking into account the half-life of the radionuclide.

[0161] In some cases, the elimination profile of the conjugate can be adjusted by a reversible binding between the conjugate and a plasma protein such as albumin. A suitable affinity between the conjugate and the plasma protein can utilize the plasma protein as a reservoir for the conjugates, attaching and preserving the conjugates at high concentration and releasing the conjugates at a lower concentration, thereby improving elimination profile. In some embodiments, a dissociation constant (Kd) between the conjugate and human serum albumin is at most 500 μM, as determined at room temperature in human serum condition. In some embodiments, the Kd is from about 0.1 nM to about 1000 μM. In some embodiments, the Kd is at most 100 μM. In some embodiments, the Kd is at most 15 μM. In some embodiments, the Kd is from about 1 nM to about 10 μM. In some embodiments, the Kd is from about 10 nM to about 10 μM. In some embodiments, the Kd is from about 50 nM to about 1 μM. In some embodiments, the Kd is from about 100 nM to about 10 μM.

[0162] In some embodiments, a conjugate of the present disclosure is selected from Tables 2A-Lu, 2A- Lu177, 2A-Ac255, 2B, 2BLu, 2B-Lu177, 2B-Ac255, and 2C. In some embodiments, a conjugate of the present disclosure is selected from Tables 2A-Ac255, and 2B-Ac255. In some embodiments, a conjugate of the present disclosure comprises a peptide of Table 1, a chelator selected from FIGs 4-22, and a radionuclide of Table 7 labeled “chelator”. In some embodiments, a conjugate of the present disclosure comprises a conjugate of FIG.1-3. In some embodiments, a conjugate of the present disclosure comprises a peptide of Table 1 and a radionuclide of Table 7 labeled “covalent”. In some embodiments, a conjugate of the present disclosure comprises a peptide of Table 1, a linker, and a radionuclide of Tables 7 marked “covalent”. In some embodiments, a conjugate of the present disclosure comprises a conjugate of FIG.27-29. EphA2

[0163] EPH receptor A2 (ephrin type-A receptor 2) is a protein that in humans is encoded by the EPHA2 gene. EphA2 may be upregulated in multiple cancers, often correlating with disease progression, metastasis and poor prognosis e.g., in solid tumors such as breast, lung, gastric, pancreatic, prostate, liver and glioblastoma.

[0164] Eph receptor tyrosine kinases (Ephs) belong to a large group of receptor tyrosine kinases (RTKs), kinases that phosphorylate proteins on tyrosine residues. Ephs and their membrane bound ephrin ligands (ephrins) can control cell positioning and tissue organization. Functional and biochemical Eph responses can occur at higher ligand oligomerization states.

[0165] Among other patterning functions, various Ephs and ephrins have been shown to play a role in vascular development. Knockout of EphB4 and ephrin-B2 can result in a lack of the ability to remodel capillary beds into blood vessels and embryonic lethality. Persistent expression of some Eph receptors and ephrins has also been observed in newly-formed, adult micro-vessels (Brantley-Sieders et al. (2004) Curr Pharm Des 10, 3431-42). The de-regulated re-emergence of some ephrins and their receptors in adults may contribute to tumor invasion, metastasis and neo-angiogenesis. Furthermore, some Eph family members may be over-expressed on tumor cells from a variety of human tumors (Booth et al. (2002) Nat Med 8, 1360-1).

[0166] Human EphA2 can have a sequence according to the following Seq ID NO: 276 (Isoform 1, P29317-1) :

[0167] Human EphA2 can have a sequence according to the following Seq ID NO: 277 (Isoform 2, P29317-2) :

[0168] As used herein, the expression “has avidity for EphA2” or “binds to EphA2” indicates having the activity of binding to EphA2. Binding site of the peptide of the present disclosure on the EphA2 is not limited, the peptide can bind to anywhere on the EphA2 protein. Binding to EphA2 may be measured by any method for measuring known intermolecular binding. In a non-limiting manner, for example, this may be determined by competitive binding assays such as surface plasmon resonance (SPR) assays, scatter analysis and / or radioimmunoassays (RIA), enzyme immunoassays (EIA), and sandwich and competitive assays, and in any suitable manner which is known, including different variants of the examples given that are known in the technical field.

[0169] In some embodiments, a peptide or a radiopharmaceutical conjugate comprising the peptide binds to EphA2. In some embodiments, the peptide or conjugate has EphA2 antagonistic activity. In some embodiments, the peptide or conjugate binds to human EphA2 (hEphA2) and has hEphA2 antagonistic activity.

[0170] As used herein, the term “EphA2” refers to any form of EphA2 and a variant thereof for retaining at least a part of the activity of EphA2. The EphA2 includes all the native sequences of EphA2 in mammals such as, for example, humans, dogs, cats, horses, and cows, unless otherwise specifically described as human EphA2 (hEphA2). One exemplification of EphA2 is hEphA2 (Gene ID:1969), which is human EphA2 and is a protein having an amino acid sequence (SEQ ID NO: 276, Isoform 1, P29317- 1). Peptide Ligand

[0171] In one aspect, a conjugate described herein comprises a peptide (e.g., a binding peptide) that has avidity for ephrin type-A receptor 2 (EphA2). The EphA2 can be a mammalian EphA2. The EphA2 can be a human EphA2. The EphA2 can be a wild-type or mutated EphA2. In some embodiments, the conjugate comprises two or more peptides, which can be the same or different. The peptide can be linear or cyclic. In some embodiments, the peptide is monocyclic. The peptide can comprise any suitable number of amino acid residues. In some embodiments, the peptide comprises from 5 to 50, 6 to 40, 7 to 30, 8 to 25, 12 to 25, or 9 to 20 amino acid residues. In some embodiments, the peptide comprises from 5 to 14 amino acid residues. In some embodiments, the peptide comprises from 7 to 12 amino acid residues. In some embodiments, the peptide comprises from 8 to 12 amino acid residues. In some embodiments, the peptide comprises from 8 to 10 amino acid residues. In some embodiments, the peptide comprises from 7 to 13 amino acid residues. In some embodiments, the peptide comprises from 12 to 15 amino acid residues. In some embodiments, the peptide comprises from 13 to 14 amino acid residues. In some embodiments, the peptide comprises 6 amino acid residues. In some embodiments, the peptide comprises 7 amino acid residues. In some embodiments, the peptide comprises 8 amino acid residues. In some embodiments, the peptide comprises 9 amino acid residues. In some embodiments, the peptide comprises 10 amino acid residues. In some embodiments, the peptide comprises 11 amino acid residues. In some embodiments, the peptide comprises 12 amino acid residues. In some embodiments, the peptide comprises 13 amino acid residues. In some embodiments, the peptide comprises 14 amino acid residues. In some embodiments, the peptide comprises 15 amino acid residues. In some embodiments, the peptide comprises 16 amino acid residues. In some embodiments, the peptide consists of 6 amino acid residues. In some embodiments, the peptide consists of 7 amino acid residues. In some embodiments, the peptide consists of 8 amino acid residues. In some embodiments, the peptide consists of 9 amino acid residues. In some embodiments, the peptide consists of 10 amino acid residues. In some embodiments, the peptide consists of 11 amino acid residues. In some embodiments, the peptide consists of 12 amino acid residues. In some embodiments, the peptide consists of 13 amino acid residues. In some embodiments, the peptide consists of 14 amino acid residues. In some embodiments, the peptide consists of 15 amino acid residues. In some embodiments, the peptide consists of 16 amino acid residues. In some embodiments, the conjugate comprises a monocyclic peptide of 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. A peptide described herein can be a binding peptide that binds to EphA2. In some embodiments, the binding peptide consists of 6 to 20 amino acid residues. In some embodiments, the binding peptide consists of 7 to 12 amino acid residues. In some embodiments, the binding peptide consists of 10 to 12 amino acid residues. In some embodiments, the binding peptide consists of 8 to 12 amino acid residues. In some embodiments, the binding peptide is monocyclic. In some embodiments, the peptide of the present technology is an isolated peptide. In some embodiments, the peptide of the present technology is a purified peptide.

[0172] In one aspect, described herein is a peptide (e.g., a cyclic peptide) that has avidity for ephrin type-A receptor 2 (EphA2), wherein the peptide comprises an amino acid sequence including deletion, substitution, and / or addition of one or several (e.g., 1-6) amino acids in the amino acid of SEQ ID NO:1: da-MeF-N-L-Hgl-MeF-W1Me-V-W1Me-T-E-C (SEQ ID NO:1). or a pharmaceutically acceptable salt thereof.

[0173] In some embodiments, the (cyclic) peptide consists of 10 to 12 amino acid residues.

[0174] In some embodiments, the peptide comprises an amino acid sequence including a total of at most 6 deletion, substitution, and / or addition of one or several amino acids in the amino acid of SEQ ID NO:1. In some embodiments, the peptide comprises an amino acid sequence including a total of at most 5 deletion, substitution, and / or addition of one or several amino acids in the amino acid of SEQ ID NO:1. In some embodiments, the peptide comprises an amino acid sequence including a total of at most 4 deletion, substitution, and / or addition of one or several amino acids in the amino acid of SEQ ID NO:1. In some embodiments, the peptide comprises an amino acid sequence including a total of at most 3 deletion, substitution, and / or addition of one or several amino acids in the amino acid of SEQ ID NO:1. In some embodiments, the peptide comprises an amino acid sequence including a total of at most 2 deletion, substitution, and / or addition of one or several amino acids in the amino acid of SEQ ID NO:1. In some embodiments, the peptide comprises an amino acid sequence including a total of at most 1 deletion, substitution, and / or addition of one or several amino acids in the amino acid of SEQ ID NO:1. In some embodiments, the amino acid substitution is a conservative amino acid substitution. The deletion, addition, or substitution position may be either the end or middle of the peptide. In some embodiments, 1-5 amino acids selected from the group consisting of 3rdN, 4thL, 6thMeF, 10thT and 11thE of SEQ ID NO: 1 is / are deleted, optionally without additional addition and / or substitution. In some embodiments, one to several (e.g., 1, 2, 3, 4 or 5) amino acids are added. In some embodiments, one or more amino acid residues selected from the 2ndMeF, 6thMeF, 8thV and 11thE are substituted. In some embodiments, the peptide comprises an amino acid sequence with deletion of 2 or less amino acids in the amino acid SEQ ID NO: 1, optionally without additional addition and / or substitution. In some embodiments, 1-2 amino acids selected from the group consisting of 10th T and 11th E of SEQ ID NO:1 is / are deleted, optionally without additional addition and / or substitution. In some embodiments, the 8thV is substituted. In some embodiments, the 11thE is substituted.

[0175] For the purpose of the disclosure, one event of “substitution” of an amino acid or an amino sequence is not considered two separate events of one deletion plus one addition. Thus, for the avoidance of doubt, as an example, a sequence change of “up to two deletion, substitution and / or addition” includes one deletion and one substitution, one deletion and one addition (at a different position), one substitution and one addition, one deletion only, one substitution only, one addition only, two deletions, two substitutions, two additions, etc. The deletion, addition, or substitution position may be at one or both ends of the peptide, or in the middle of the peptide.

[0176] In some embodiments, the peptide comprises an amino acid sequence wherein 1-5 amino acids selected the group consisting of third N, 4th L, 5th Hgl, 6th MeF, 10th T and 11th E of SEQ ID NO: 1, is deleted in the peptide. In some embodiments, the peptide comprises an amino acid sequence wherein 1, 2, 3, 4 or 5 amino acids selected the group consisting of third N, 4th L, 5th Hgl, 6th MeF, 10th T and 11th E of SEQ ID NO: 1, is deleted in the peptide. In some embodiments, third N is deleted. In some embodiments, 4th L is deleted. In some embodiments, 5th Hgl is deleted. In some embodiments, 6th MeF is deleted. In some embodiments, 11th E is deleted. In some embodiments, the peptide comprises an amino acid sequence wherein 1-5 amino acids selected from the group consisting of amino acids at the 3rd, 4th, 5th, 6th, 10th, and 11thposition of SEQ ID NO: 1, is deleted in the peptide. In some embodiments, the peptide comprises an amino acid sequence wherein 1, 2, 3, 4 or 5 amino acids selected the group consisting of amino acids at the 3rd, 4th, 5th, 6th, 10th, and 11thposition of SEQ ID NO: 1, is deleted in the peptide. In some embodiments,3rdamino acid is deleted. In some embodiments, the 4thamino acid is deleted. In some embodiments, the 5thamino acid is deleted. In some embodiments, the 6thamino acid is deleted. In some embodiments, the 10thamino acid is deleted. In some embodiments, the 11thamino acid is deleted. In certain embodiments, the peptide has deletions of 1-5 amino acids of SEQ ID NO: 1, and no additional residue addition. In certain embodiments, the peptide has deletions of 1-5 amino acids of SEQ ID NO: 1, and no additional residue substitutions. In certain embodiments, the peptide has deletions of 1- 5 amino acids of SEQ ID NO: 1, and no additional residue addition or substitution. In certain embodiments, the peptide has deletions of 1-5 amino acid residues of SEQ ID NO: 1, and no residue addition. In certain embodiments, the peptide has deletions of 1-5 amino acid residues of SEQ ID NO: 1 and no residue substitution. In certain embodiments, the peptide has deletions of 1-5 amino acid residues of SEQ ID NO: 1, and no residue addition and substitution.

[0177] In one aspect, described herein is a peptide that has avidity for ephrin type-A receptor 2 (EphA2), wherein the peptide has an amino acid sequence according to Formula (I), or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) wherein, X1 is an amino acid; X2 is an amino acid comprising an aromatic ring, an N-methylated amino acid thereof, or a variant thereof; X3 is a hydrophilic amino acid (e.g. N, Q, Cit, K or a variant thereof), glycine (G), Alanine (A) or a variant thereof (e.g., da, 2-Aminoisobutyric acid (Aib)); X4 is a hydrophobic amino acid (e.g., leucine (L)), a hydrophilic amino acid (e.g., citrulline (Cit)), or a variant thereof; X5 is a hydrophilic amino acid, or a variant thereof; X6 is a hydrophilic amino acid, an amino acid comprising an aromatic ring, or an N- methylated amino acid thereof; X7 is an amino acid comprising an aromatic ring (e.g., W, F, or a variant thereof); X8 is a hydrophobic amino acid, a hydrophilic amino acid, an N-methylated amino acid, or a variant thereof; X9 is an amino acid comprising an aromatic ring (e.g., W or a variant thereof); X10 is absent or a hydrophilic amino acid (e.g., Threonine (T) or a variant thereof); X11 is absent or a hydrophilic amino acid; and X12 is cysteine (C) or a variant thereof.

[0178] In some embodiments of Formula (I), both X10 and X11 are present. In some embodiments of Formula (I), both X10 and X11 are absent.

[0179] In one aspect, described herein is a peptide that has avidity for ephrin type-A receptor 2 (EphA2), wherein the peptide has an amino acid sequence according to Formula (I), or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) wherein, X1 is an amino acid; X2 is F, or a variant thereof that replaces the unsubstituted phenyl ring of F with (i) a phenyl ring substituted by 1 or 2 substituents each independently selected from -OH, - CN, amino, halogen, -C1-3haloalkyl, and -C1-3alkyl (e.g., -CH3), or (ii) a 6-membered heteroaryl ring optionally substituted by 1 or 2 substituents each independently selected from –OH, -CN, amino, halogen, -C1-3haloalkyl, and -C1-3alkyl, wherein the F or the variant thereof is optionally N-methylated; X3 is a hydrophilic amino acid (e.g. N, Q, Cit, K or a variant thereof), G, Aib, Hgn, Ala, or a variant thereof (e.g., da); X4 is a hydrophobic amino acid (e.g., an amino acid having 4 or more carbon atoms in a side chain comprising a linear, branched, or cyclic carbon chain), and wherein X4 is optionally N-methylated (e.g., Cit or a variant thereof); X5 is an amino acid (e.g., a hydrophilic amino acid; or an amino acid with a functional side chain (e.g., not glycine)); X6 is an N-methylated amino acid thereof; X7 is a W, Y, or a variant thereof (e.g., an amino acid having either a 6-membered aryl or heteroaryl, or a 9- or 10-membered bi-cyclic aryl or heteroaryl linked to the alpha-carbon through a carbon (e.g., a methylene group)), wherein the 6-, 9-, and 10-membered heteroaryl has 1-3 heteroatoms (e.g., N), and wherein the 6-, 9-, and 10-membered aryl or heteroaryl is optionally substituted (e.g., optionally substituted by 1-4 substituents independently selected from -OH, -CN, amino, halogen, -C1-3haloalkyl, and -C1-3alkyl); X8 is an amino acid with –H on the alpha-amino group (e.g., X8 is not an N-alkylated amino acid); X9 is W or Y or a variant thereof; (e.g., W or a variant thereof); X10 is absent, or a polar amino acid (e.g., T or a variant thereof); X11 is absent or an amino acid (e.g., a hydrophilic amino acid; Dab, Dap, R, E or a variant thereof; or an amino acid with a functional side chain (e.g., not glycine)); and X12 is C or a variant thereof.

[0180] In some embodiments, X2 is F, or a variant thereof that replaces the unsubstituted phenyl ring of F with a phenyl ring substituted by 1 or 2 substituents each independently selected from -OH, -CN, and - C1-3alkyl (e.g., -CH3). In some embodiments, X2 is F, or a variant thereof that replaces the unsubstituted phenyl ring of F with a 6-membered heteroaryl ring optionally substituted by 1 or 2 substituents each independently selected from –OH, -CN, amino, halogen, -C1-3haloalkyl, and -C1-3alkyl. In some embodiments, the F or the variant thereof is optionally N-methylated. In some embodiments, the 6- membered heteroaryl ring is pyridine, pyrimidine, or pyridazine. In some embodiments, the 6-membered heteroaryl ring is pyridine.

[0181] In some embodiments, X7 is a W, Y, or a variant thereof (e.g., an amino acid having either a 6- membered aryl or heteroaryl, or a 9- or 10-membered bi-cyclic aryl or heteroaryl linked to the alpha- carbon through a carbon (e.g., a methylene group)), wherein the 6-, 9-, and 10-membered heteroaryl has one heteroatom (e.g., N), and wherein the 6-, 9-, and 10-membered aryl or heteroaryl is optionally substituted by 1 or 2 substituents independently selected from –CH3, -ethyl, -Cl, and -F).

[0182] In one aspect, described herein is a peptide that has avidity for ephrin type-A receptor 2 (EphA2), wherein the peptide has an amino acid sequence according to Formula (I), or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) wherein, X1 is any amino acid (e.g., D-amino acid); X2 is an amino acid comprising an aromatic ring or a substitution thereof, N-methylated amino acid, or a substitution thereof; X3 is absent, N or a substitution thereof; X4 is absent, any hydrophobic amino acid or a substitution thereof; X5 is absent, a hydrophilic amino acid or a substitution thereof, or an amino acid with a functional side chain (e.g., Dab, Dap, K); X6 is absent, a hydrophilic amino acid or amino acid having aromatic ring, N-methylated amino acid thereof, or a substitution thereof; X7 is W or a substitution thereof; X8 is V, hydrophilic amino acid or a substitution thereof, an N-methylated amino acid, or an amino acid with a functional side chain; X9 is W or a substitution thereof; X10 is absent, T or a substitution thereof; X11 is absent, any hydrophilic amino acid, or an amino acid with a functional side chain; and X12 is C or a substitution thereof.

[0183] In some embodiments, the peptide has an amino acid sequence according to Formula (I), or a pharmaceutically acceptable salt thereof, wherein X1 is any amino acid (e.g., D-amino acid); X2 is an amino acid comprising an aromatic ring or a variant thereof, or N-methylated amino acid thereof; X3 is absent, N or a variant thereof; X4 is absent, any hydrophobic amino acid or a variant thereof; X5 is absent, a hydrophilic amino acid or a variant thereof, or an amino acid with a functional side chain (e.g., Dab, Dap, K); X6 is absent, a hydrophilic amino acid or amino acid having aromatic ring, or N-methylated amino acid thereof; X7 is W or a variant thereof; X8 is V, hydrophilic amino acid or a variant thereof, an N-methylated amino acid, or an amino acid with a functional side chain; X9 is W or a variant thereof; X10 is absent, T or a variant thereof; X11 is absent, any hydrophilic amino acid, or an amino acid with a functional side chain; and X12 is C or a variant thereof.

[0184] In some embodiments, of a peptide of Formula (I), or a pharmaceutically acceptable salt thereof, wherein X1 is any amino acid; X2 is an amino acid comprising an aromatic ring, or N-methylated amino acid thereof; X3 is absent, a hydrophilic amino acid (e.g. N, Q, Cit, K or a variant thereof), G, Aib, Hgn, or Ala or a variant thereof (e.g., da); X4 is absent, a hydrophobic amino acid, or a hydrophilic amino acid (e.g., Cit or a variant thereof); X5 is absent, a hydrophilic amino acid, or an amino acid with a functional side chain; X6 is absent, a hydrophilic amino acid, or an or amino acid having aromatic ring, or N- methylated amino acid thereof; X7 is an amino acid comprising an aromatic ring (e.g., W or a variant thereof); X8 is a hydrophobic amino acid, a hydrophilic amino acid, an N-methylated amino acid, or an amino acid with a functional side chain; X9 is an amino acid comprising an aromatic ring (e.g., W or a variant thereof); X10 is absent, or a polar amino acid (e.g., T or a variant thereof); X11 is absent, a hydrophilic amino acid, or an amino acid with a functional side chain; and X12 is C or a variant thereof.

[0185] In some embodiments, of a peptide of Formula (I), or a pharmaceutically acceptable salt thereof, wherein X1 is an amino acid (e.g., D-amino acid); X2 is an amino acid comprising an aromatic ring, or N-methylated amino acid thereof; X3 is absent, a hydrophilic amino acid (e.g. N, Q, Cit, K or a variant thereof), G, Aib, Hgn, or Ala or a variant thereof (e.g, da); X4 is a hydrophobic amino acid, or a hydrophilic amino acid (e.g., Cit or a variant thereof); X5 is a hydrophilic amino acid (e.g., Dab, Dap, R, E or a variant thereof); X6 is absent, a hydrophilic amino acid, an amino acid having aromatic ring (e.g., W), or N-methylated amino acid thereof; X7 is an amino acid comprising an aromatic ring (e.g., W or a variant thereof); X8 is a hydrophobic amino acid, a hydrophilic amino acid, or an N-methylated amino acid; X9 is an amino acid comprising an aromatic ring (e.g., W or a variant thereof); X10 is absent, or a hydrophilic amino acid (e.g., T or a variant thereof); X11 is absent, or a hydrophilic amino acid; and X12 is C or a variant thereof.

[0186] In some embodiments, of a peptide of Formula (I), or a pharmaceutically acceptable salt thereof, wherein X1 is an amino acid (e.g., D-amino acid); X2 is F or a variant thereof, Y or a variant thereof, or W or a variant thereof, or N- methylated amino acid thereof; X3 is absent, N, Q, Cit or a variant thereof, G, Aib, Hgn, K or a variant thereof, Ala, or da; X4 is absent, G substituted with straight or branched C1-5alkyl, A substituted with C3-7cycloalkyl, or Cit or variant thereof; X5 is absent, a hydrophilic amino acid, or an amino acid with a functional side chain (e.g., Dab, Dap, R, E), wherein the hydrophilic amino acid comprises an L- amino acid comprising -NH2, -C(O)OH, -NHC(NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3; X6 is absent, a hydrophilic amino acid, F or a variant thereof, Y or a variant thereof, W or a variant thereof, or N-methylated amino acid thereof, wherein the hydrophilic amino acid comprises a substituent selected from the group consisting of -C(O)OH, -C(O)NH2, and - NHC(O)CH3; X7 is F or a variant thereof, or W or a variant thereof; X8 is G substituted with one or two straight or branched C1-5alkyl, A substituted with C3-7cycloalkyl, or a hydrophilic amino acid wherein the hydrophilic amino acid comprises an L- amino acid comprising -NH2, one or more -OH, -C(O)OH, -NHC(NH)NH2, -NHC(O)NH2, - C(O)NH2, -NHC(O)CH3; or the hydrophilic amino acid comprises a zwitterion; X9 is F or a variant thereof, or W or a variant thereof; X10 is absent, Q, Hgn, S or variant thereof, T or variant thereof (e.g., T optionally substituted with straight or branched C1-5alkyl), K or a variant thereof, Cit or a variant thereof, or an L- amino acid substituted with -NHC(NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3; X11 is absent, E, Hgn, R or a variant thereof, Cit or a variant thereof, Hgl, K or a variant thereof, D, N, or Q; and X12 is C or a variant thereof.

[0187] In some embodiments, described herein is a cyclic peptide that has avidity for ephrin type-A receptor 2 (EphA2), wherein the peptide consists of a sequence of Formula (I), X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) or a pharmaceutically acceptable salt thereof, wherein each of X1, X2, X3, X4, X5, X6, and X8 is independently an amino acid; X7 is W1Me or a variant thereof; X9 is W1Me or a variant thereof; each of X10 and X11 is independently absent or an amino acid; and X12 is cysteine (C) or a variant thereof.

[0188] In some embodiments of a peptide of Formula (I), or a pharmaceutically acceptable salt thereof, wherein: X7 is W1Me, W1MeCl, W1MeBr, Nal1, Nal2, W1Et, 3Bzf, 3Bzt, F23dC, W1Me7N, or F23dMe; X8 is V, KCOpipzaa, Hse, N, Cit, hCit, KAc, DapAc, OrnAc, T, alT, Aib, Alb, Qglucamine, Hgl, E, Hgn, MeF, 3Py6NH2, W1Me, A, Q, or K; and X9 is W1Me, Nal1, W1Et, Nal21N, 3Bzf, 3Bzt, Nal18N, F23dMe, or F23dC.

[0189] In some embodiments of a peptide of Formula (I), or a pharmaceutically acceptable salt thereof, wherein: X7 is W1Me; X8 is V; and X9 is W1Me.

[0190] In some embodiments of a peptide of Formula (I), or a pharmaceutically acceptable salt thereof, wherein: X1 is da, df3CON, dkCOpipzaa, dahp, dDab-NH2-Ph3-SO2F, dDap-NH2-Ph3-SO2F, dDap-NH2-Ph4-SO2F, dCit, Aib, G, Norvaline, Norleucine, or dhAla; X2 is MeF, Me3Py, MeF3CON, MeF3F, Me4Py, MeY(Me), or N-methylated amino acid thereof; X3 is absent, N, Q, Cit, G, Aib, Hgn, hCit , norCit, LysAc, OrnAc, Ala, or da; X4 is L, Cbg, Chg, Cba, Cha, Ahx, Dahp, Cit, I, V, Norleucine, or Norvaline; X5 is Hgl, Hgn, Dab, Dap, DabAc, DapAc, R, hArg, E, or D; X6 is absent, MeF, MeE, Me3Py, Me4Py, MeF4F, MeF4F, MeF4C, or MeY; X7 is W1Me, W1Me7Cl, W1Me7N, W, F, 7-AzaTrp, W7Me, or W1Et; X8 is V, KCOpipzaa, Cit, Qglucamine, hCit, Aib, Norleucine, or Norvaline; X9 is W1Me, W1Me7Cl, W1Me7N, F23dMe, W1Et, W7Me, W, F, or 7-AzaTrp; X10 is absent, T, Q, S, Hgn, Alpha-methylserine, hSer, hThr, N, OrnAc, LysAc, Cit, or hCit; X11 is absent, E, Hgn, R, hArg, Cit, hCit, Hgl, Orn, D, N, Q, DapAc, OrnAc, DabAc, norCit; and X12 is C, hCys, CdMe, C3RMe, C3SMe, Selenocysteine, dc, or Penicillamine.

[0191] In some embodiments, of a peptide of Formula (I), or a pharmaceutically acceptable salt thereof, X7 is W1Me; and X9 is W1Me

[0192] In some embodiments, the peptide of Formula (I), or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) wherein, X1 is any amino acid; X2 is an amino acid comprising an aromatic ring or a variant thereof, or N-methylated amino acid thereof; X3 is absent, N or a variant thereof; X4 is any hydrophobic amino acid or a variant thereof; X5 is a hydrophilic amino acid or a variant thereof; X6 is absent, a hydrophilic amino acid or amino acid having aromatic ring, or N- methylated amino acid thereof; X7 is W or a variant thereof; X8 is V, hydrophilic amino acid or a variant thereof, or an N-methylated amino acid; X9 is W or a variant thereof; X10 is absent, T or a variant thereof; X11 is absent, any hydrophilic amino acid; and X12 is C or a variant thereof.

[0193] In one aspect, described herein is a radiopharmaceutical conjugate comprising: (a) a cyclic peptide that has avidity for ephrin type-A receptor 2 (EphA2), wherein the peptide has an amino acid sequence of Formula (I), X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) wherein, X1 is any D- or L-amino acid; X2 has a structure , wherein ring A2 is phenyl or a 6-membered heteroaryl (e.g., heteroaryl having 1 or 2 N); RX2is each independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, SF5, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally and independently substituted with one or more RXA; kx2 is 0, 1, 2, or 3; mx2 is 0, 1, 2, 3 or 4; RNX2is H, C1-C6alkyl, or C1-C6haloalkyl; *X1 indicates the point of attachment to X1; and, *X3 indicates the point of attachment to X3; X3 has a structure kx3 is 0, 1, 2, or 3; RNX3is H, C1-C6alkyl, or C1-C6haloalkyl; RX3is H, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; *X2 indicates the point of attachment to X2; and, *X4 indicates the point of attachment to X4; X4 is a hydrophobic amino acid (e.g., amino acid having 4 or more carbon atoms in a side chain comprising a linear, branched, or cyclic carbon chain), and wherein X4 is optionally N- alkylated by a C1-3alkyl group; X5 is a hydrophilic L-amino acid, such as an amino acid having a structure of , wherein: RNX5is H, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, or heteroalkyl is optionally and independently substituted with one or more RXA; RX5is -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, SF5, - SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=NRb)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, or heteroalkyl is optionally and independently substituted with one or more RXA; provided that at least one of RNX5and RX5comprises a moiety selected from -OH, -NH2, and -NH- (e.g., -NH-C(=NH)-NH2, -CO-NH2, -NH2, -COOH, -C(OH)-C0-6alkyl, -NH-CO-C1-6alkyl); *X4 indicates the point of attachment to X4; and, *X6 indicates the point of attachment to X6; wherein RNX6is H, C1-C6alkyl, or C1-C6haloalkyl; RX6is -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, SF5, - SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=NRb)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally and independently substituted with one or more RXA; *X5 indicates the point of attachment to X5; and, *X7 indicates the point of attachment to X7; X7 has a structure , wherein RNX7is H, C1-C6alkyl, or C1-C6haloalkyl; ring A7 is an aryl or heteroaryl; RX7is each independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, SF5, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2-halogen, -S(=O)2NRcRd, - NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally and independently substituted with one or more RXA; kx7 is 0, 1, 2, or 3; mx7 is 0, 1, 2, 3, 4 or 5; *X6 indicates the point of attachment to X6; and, *X8 indicates the point of attachment to X8; X8 is an L-amino acid with -H on the alpha-amino group; X9 has a structure , wherein RNX9is H, C1-C6alkyl, or C1-C6haloalkyl; ring A9 is an aryl or heteroaryl; RX9is each independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, SF5, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally and independently substituted with one or more RXA; kx9 is 0, 1, 2, or 3; mx9 is 0, 1, 2, 3, 4, or 5; *X8 indicates the point of attachment to X8; and, *XC indicates the point of attachment to (i) X10 or (i) when X10 and X11 are absent, X12; X10 is absent or an L-amino acid; X11 is absent or an L-amino acid; provided that when X10 is absent, then X11 is also absent; and X12 is an L-amino acid having a reactive thiol group, such as Cys and Cys variants; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R and RXAis independently halogen, -CN, -OH, -OC1-C6alkyl, SF5, -S(=O)C1-C6alkyl, - S(=O)2C1-C6alkyl, -S(=O)2NH2, -S(=O)2-halogen, -S(=O)2NHC1-C6alkyl, - S(=O)2N(C1-C6alkyl)2, -NH2, -NHC1-C6alkyl, -N(C1-C6alkyl)2, -NRbC(=NRb)NRcRd, - NHC(=O)OC1-C6alkyl, -C(=O) C1-C6alkyl, -C(=O)OH, -C(=O)OC1-C6alkyl, -C(=O)NH2, - C(=O)N(C1-C6alkyl)2, -C(=O)NHC1-C6alkyl, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; (b)(i) a metal chelator configured to bind with a radionuclide; or (ii) a covalent radionuclide; and (c)(i) optionally, a linker that connects the peptide with the metal chelator; or (ii) optionally a linker that connects the peptide with the covalent radionuclide.

[0194] In some embodiments, X3 has a structure , wherein the definitions for the groups are provided herein. In some embodiments, A2 is phenyl. In some embodiments, A2 is 6-membered heteroaryl. In some embodiments, RX2is each independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -SH, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)Ra, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, or heteroalkyl is optionally and independently substituted with one or more RXA. In some embodiments, kx2 is 0. In some embodiments, kx2 is 1. In some embodiments, kx2 is 2. In some embodiments, kx2 is 3. In some embodiments, mx2 is 0. In some embodiments, mx2 is 1. In some embodiments, mx2 is 2. In some embodiments, mx2 is 3. In some embodiments, mx2 is 4. In some embodiments, RNX2is H. In some embodiments, RNX2is methyl.

[0195] In some embodiments, X3 has a structure , wherein the definitions for the groups are provided herein. In some embodiments, kx3 is 0. In some embodiments, kx3 is 1. In some embodiments, kx3 is 2. In some embodiments, kx3 is 3. In some embodiments, RNX3is H. In some embodiments, RNX3is methyl. In some embodiments, RX3is H. In some embodiments, RX3is C1-C6alkyl. In some embodiments, RX3is C1-C3alkyl.

[0196] In some embodiments, X5 has a structure of wherein the definitions for the groups are provided herein. In some embodiments, RNX5is H. In some embodiments, RNX5is methyl. In some embodiments, RX5is -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -SH, -NRcRd, - -NRbC(=O)Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, or heteroalkyl is optionally and independently substituted with one or more RXA. In some embodiments, at least one of RNX5and RX5comprises a moiety selected from -NH-C(=NH)-NH2, -CO- NH2, -NH2, -COOH, -C(OH)-C0-6alkyl, -NH-CO-C1-6alkyl. In some embodiments, at least one of RNX5and RX5comprises a moiety selected from -CO-NH2.

[0197] In some embodiments, X6 has a structure , wherein the definitions for the groups are provided herein. In some embodiments, RNX6is H. In some embodiments, RNX6is methyl. In some embodiments, RX6is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, or heteroalkyl is optionally and independently substituted with one or more RXA. In some embodiments, RX6is C1-C6alkyl, which is optionally substituted.

[0198] In some embodiments, X7 has a structure , wherein the definitions for the groups are provided herein. In some embodiments, ring A7 is a 6-membered aryl or heteroaryl. In some embodiments, ring A7 is a 9- or 10-membered bicyclic aryl or heteroaryl. In some embodiments, ring A7 is bicyclic heteroaryl, which is optionally substituted. In some embodiments, the 6-, 9- or 10-membered heteroaryl has one heteroatom selected from N, O, and S. In some embodiments, ring A7 is optionally substituted 5-6, 6-6, or 6-5 fused heteroaryl. In some embodiments, ring A7 is optionally substituted 5-6 or 6-5 fused heteroaryl. In some embodiments, RNX7is H. In some embodiments, each of RX7is independently halogen, -CN, -NO2, -OH, -ORa, amino, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments, RX7is each independently halogen, -CN, -NO2, -OH, -ORa, - OC(=O)Ra, -SH, -NRcRd, - -NRbC(=O)Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, or heteroalkyl is optionally and independently substituted with one or more RXA. In some embodiments, each RX7is independently selected from -CH3, -ethyl, -Cl, and -F, and mx7 is 0, 1, or 2. In some embodiments, mx7 is 0. In some embodiments, mx7 is 1. In some embodiments, mx7 is 2. In some embodiments, mx7 is 3-4. In some embodiments, kx7 is 0. In some embodiments, kx7 is 1. In some embodiments, kx7 is 2. In some embodiments, kx7 is 3.

[0199] In some embodiments, X7 is W1Me, Nal1, Nal2, W1Et, Nal21N, 3Bzf, 3Bzt, Nal15N, Nal14N, Nal24N, Nal28N, F23dMe, F23dC, W1Me7N, or W1Me7Cl. In some embodiments, X7 is W1Me, F23dMe or W1Me7Cl.

[0200] In some embodiments, X9 has a structure definitions for the groups are provided herein. In some embodiments, X9 is , wherein each RX9is independently selected from -OH, CN, NH2, C1-C3alkyl, -Cl, -F, -Br, -CONH2, and -SO2F.

[0201] In some embodiments, ring A9 is bicyclic heteroaryl, which is optionally substituted. In some embodiments, ring A9 is optionally substituted 5-6, 6-6, or 6-5 fused heteroaryl. In some embodiments, ring A9 is optionally substituted 5-6 or 6-5 fused heteroaryl. In some embodiments, , , , . In some embodiments, . In some embodiments, mx9 is 0. In some embodiments, mx9 is 1. In some embodiments, mx9 is 2.

[0202] In some embodiments, each of RX9is independently halogen, -CN, -NO2, -OH, -ORa, - OC(=O)Ra, -SH, , -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)Ra, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl. In some embodiments, each of RX9is independently halogen, -CN, -NO2, -OH, -ORa, amino, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments, RNX9is H. In some embodiments, RNX9is methyl. In some embodiments, kx9 is 0. In some embodiments, kx9 is 1. In some embodiments, kx9 is 2. In some embodiments, kx9 is 3. In some embodiments, mx9 is 0. In some embodiments, mx9 is 1. In some embodiments, mx9 is 2. In some embodiments, mx9 is 3.

[0203] In some embodiments, X9 is W1Me, W, Nal1, W1Et, Nal21N, 3Bzf, 3Bzt, Nal14N, Nal18N, F23dMe, F23dC, or W1Et. In some embodiments, X9 is W1Me or F23dMe.

[0204] In some embodiments, ring A2 is a 6-membered heteroaryl containing 1 or 2 N.

[0205] In some embodiments, RX5is C1-C6hydroxyalkyl, C1-C6aminoalkyl, -C0-6alkylene-NH-C(=NH)- NH2, -C0-6 alkylene-CO-NH2, -C0-6 alkylene-COOH, or -NH-CO-C1-6 alkyl.

[0206] In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (III-1), (III-2), (III-1-RI), and (III-2-RI), X1 is any amino acid (e.g., D-amino acid). In some embodiments, X1 is any one of the canonical amino acids. In some embodiments, X1 is an unnatural amino acid. In some embodiments, X1 is N-alkylated amino acid. In some embodiments, X1 is alanine (A). In some embodiments, X1 is D-alanine. In some embodiments, X1 is df3CON. In some embodiments, X1 is dkCOpipzaa. In some embodiments, X1 is dahp. In some embodiments, X1 is F. In some embodiments, X1 is an amino acid selected from Tables 5A to 5F. In some embodiments, the metal chelator or linker is attached to X1. In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (III-1), (III-2), (III-1-RI), and (III-2-RI), X1 is any amino acid. In some embodiments, X1 is an amino acid (e.g., a D-amino acid). In some embodiments, X1 is da, df3CON, dkCOpipzaa, dahp, dDab-NH2-Ph3-SO2F, dDap-NH2-Ph3-SO2F, dDap-NH2-Ph4-SO2F, dCit, Aib, G, Norvaline, Norleucine, or dhAla. X1 is da. X1 is df3CON. X1 is dkCOpipzaa. X1 is dahp. X1 is dDab-NH2-Ph3-SO2F. X1 is dDap-NH2-Ph3-SO2F. X1 is dCit. X1 is Aib. X1 is G. X1 is Norvaline. X1 is Norleucine. X1 is dhAla. In some embodiments, X1 is F. In some embodiments, X1 is chloroacetylated. In some embodiments, X1 is bromoacetylated. In some embodiments, X1 comprises a chloroacetyl group. In some embodiments, X1 comprises a bromoacetyl group. In some embodiments, in the cyclic peptide, the chloroacetyl or bromoacetyl group has been reacted and is no longer present in X1.

[0207] In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (III-1), (III-2), (III-1-RI), and (III-2-RI), X2 is a canonical amino acid. In some embodiments, X2 is an unnatural amino acid. In some embodiments, X2 is an aromatic amino acid or a variant thereof. In some embodiments, X2 is V. In some embodiments, X2 is an N-methylated amino acid or a variant thereof. In some embodiments, X2 is an N-alkylated amino acid or a variant thereof. In some embodiments, X2 is an amino acid comprising an aryl group. In some embodiments, X2 is an amino acid comprising an optionally substituted phenyl group. In some embodiments, X2 is an amino acid comprising an optionally substituted naphthyl group. In some embodiments, X2 is an amino acid comprising a heteroaryl group. In some embodiments, X2 is an amino acid comprising an optionally substituted monocyclic heteroaryl group. In some embodiments, X2 is an amino acid comprising an optionally substituted bicyclic heteroaryl group. In some embodiments, the aryl or heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from –CH3, -ethyl, -Cl, and -F. In some embodiments, the aryl or heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from -OH, oxo, halogen, CN, amino, C1-C6alkyl, C1-C6alkoxyl, and C1-C6haloalkyl. In some embodiments, X2 is F, or a variant thereof that replaces the unsubstituted phenyl ring of F with (i) a phenyl ring substituted by 1 or 2 substituents each independently selected from -OH, -CN, -C1-3alkyl, or (ii) a 6-membered heteroaryl ring optionally substituted by 1 or 2 substituents each independently selected from –OH, -CN, -C1-3alkyl, wherein the F or the variant thereof is optionally N-methylated. In some embodiments, X2 is Me3Py. In some embodiments, X2 is In some embodiments, X2 is MeF. In some embodiments, X2 is MeF3H. In some embodiments, X2 is MeF3CN. In some embodiments, X2 is MeF3H. In some embodiments, X2 is Me4Py2NH2. In some embodiments, X2 is 4Py2NH2. In some embodiments, X2 is 4Py. In some embodiments, X2 is Me3Py. In some embodiments, X2 is an amino acid substituted with an aryl or heteroaryl. In some embodiments, X2 is histidine (H). In some embodiments, X2 is phenylalanine, tryptophan, tyrosine, or a variant thereof. In some embodiments, X2 is phenylalanine or a variant thereof. In some embodiments, X2 is tryptophan or a variant thereof. In some embodiments, X2 is W1Me. In some embodiments, X2 is tyrosine or a variant thereof. In some embodiments, X2 is absent. In some embodiments, the metal chelator or linker is attached to X2. In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (Ia), (Ib), (Ic), (III-2), (III-1-RI), and (III-2-RI), X2 is an amino acid comprising an aromatic ring, or N-methylated amino acid thereof. In some embodiments, X2 is N- methylated amino acid. In some embodiments, X2 is an amino acid comprising an aromatic ring. In some embodiments, X2 is an N-methylated amino acid comprising an aromatic ring. In some embodiments, X2 is F or a variant thereof, Y or a variant thereof, or W or a variant thereof, or N-methylated amino acid thereof. In some embodiments, X2 is F or a variant thereof. In some embodiments, X2 is N-methyl F or a variant thereof. In some embodiments, X2 is Y or a variant thereof. In some embodiments, X2 is N- methyl Y or a variant thereof. In some embodiments, X2 is W or a variant thereof. In some embodiments, X2 is N-methyl W or a variant thereof. In some embodiments, X2 is MeF, Me3Py, MeF3CON, MeF3F, Me4Py, or MeY(Me). In some embodiments, X2 is MeF. In some embodiments, X2 is Me3Py. In some embodiments, X2 is MeF3CON. In some embodiments, X2 is MeF3F. In some embodiments, X2 is Me4Py. In some embodiments, X2 is MeY. In some embodiments, X2 is MeY(Me).

[0208] In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (III-1), (III-2), (III-1- RI), and (III-2-RI), X3 is a canonical amino acid. In some embodiments, X3 is an unnatural amino acid. In some embodiments, X3 is N-alkylated amino acid. In some embodiments, X3 is asparagine (N). In some embodiments, X3 is a substitute of asparagine. In some embodiments, X3 is absent. In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (Ia), (III-2), (III-1-RI), and (III-2-RI), X3 is absent. In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (Ia), (III-2), (III-1-RI), and (III-2-RI), X3 is a hydrophilic amino acid (e.g. N, Hgn, Q, Cit, K or a variant thereof), glycine (G), Alanine (A) or a variant thereof (e.g., da, 2-Aminoisobutyric acid (Aib). In some embodiments, X3 is a hydrophilic amino acid. In some embodiments, X3 is an amino acid comprising - OH, -NH2, -C(O)OH, -NHC(=NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3group. In some embodiments, X3 has an electrically charged side chain. In some embodiments, X3 has a positively charged side chain. In some embodiments, X3 has a negatively charged side chain. In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (Ia), (III-2), (III-1-RI), and (III-2-RI), X3 is an amino acid comprising an electrically charged side chain (e.g., K or a variant thereof), an amino acid comprising a polar uncharged side chain (e.g,. Q, Cit, N, or a variant thereof), or G, A or variant thereof. In some embodiments, X3 is an amino acid comprising an electrically charged side chain. In some embodiments, X3 is an amino acid comprising a polar uncharged side chain. In some embodiments, X3 has zwitterionic (e.g., KCOpipzaa) side chain. In some embodiments, X3 is zwitterionic. In some embodiments, X3 comprises a -OH, -COOH, -NH- or NH2moiety. In some embodiments, X3 comprises -OH, -C(O)OH, -NHC(=NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3.In some embodiments, X3 comprises a side chain of C1-C6hydroxyalkyl, C1-C6aminoalkyl, -C0-6alkylene-NH-C(=NH)-NH2, -C0-6alkylene-CO-NH2, -C0-6 alkylene-COOH, or -NH-CO-C1-6 alkyl. In some embodiments, X3 is absent, a hydrophilic amino acid (e.g. N, Q, Hgn, Cit, K or a variant thereof), G, Ala, or a variant thereof (e.g., da, Aib,). In some embodiments, X3 is N, Q, K, G, S, T, E, Aib, Hcit, Cit, Hgn, KCOpipzaa, Har, Nmm, Ndm, Ala, Hgl, 3Py6NH2, or a variant thereof including D-amino acid such as da and variations such as Qglucamine. In some embodiments X3 is absent, N, Q, Cit or a variant thereof, G, Aib, Hgn, K or a variant thereof, or Ala or a variant thereof (e.g., da). In some embodiments, X3 is absent, N, Q, Cit, G, Aib, Hgn, hCit , norCit, LysAc, OrnAc, Ala, or da. In some embodiments, X3 is N or a variant thereof. In some embodiments, X3 is N. In some embodiments, X3 is Q or a variant thereof. In some embodiments, X3 is Q. In some embodiments, X3 is Cit or a variant thereof. In some embodiments, X3 is Cit, hCit, or norCit. In some embodiments, X3 is Cit. in some embodiments, X3 is hCit. In some embodiments, X3 is norCit. In some embodiments, X3 is K or a substitution there of. In some embodiments, X3 is K, LysAc, or OrnAc. In some embodiments. X3 is K. In some embodiments, X3 is LysAc. In some embodiments, X3 is OrnAc. In some embodiments, X3 is G or a variant thereof. In some embodiments, X3 is G. In some embodiments, X3 is Hgn. In some embodiments, X3 is Aib. In some embodiments, X3 is Ala or a variant thereof. In some embodiments, X3 is Ala or da. In some embodiments, X3 is Ala. In some embodiments, X3 is da. In some embodiments, X3 is absent. In some embodiments, the metal chelator or linker is attached to X3. In some embodiments, the covalently bound radionuclide or linker is attached to X3. In some embodiments, X1 is directly bound to X3.

[0209] In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (III-1), (III-2), (III- 1-RI), and (III-2-RI), X4 is a hydrophobic amino acid or a variant thereof. In some embodiments, X4 is an unnatural amino acid. In some embodiments, X4 is a canonical amino acid. In some embodiments, X4 is leucine. In some embodiments, X4 comprises 4 or more carbon atoms in a side chain comprising a linear, branched, or cyclic carbon chain. In some embodiments, X4 comprises 4 or more contiguous carbon atoms in a side chain. In some embodiments, X4 comprises an ethylene, propylene, or butylene group in a side chain. In some embodiments, X4 is Cbg. In some embodiments, X4 is absent. In some embodiments, X4 is selected from glycine (G), methionine (M), alanine (A), valine (V), leucine (L), isoleucine (I), proline (P), phenylalanine (F), cysteine (C), substitutes thereof. In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (III-1), (III-2), (III-1-RI), and (III-2-RI), X4 is an amino acid comprising a hydrophobic side chain (e.g., L), an amino acid comprising a polar uncharged side chain (e.g., Cit or a variant thereof). In some embodiments, X4 is an amino acid comprising a hydrophobic side chain. In some embodiments, X4 is an amino acid comprising a polar uncharged side chain. In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (III-1), (III-2), (III- 1-RI), and (III-2-RI), X4 is absent, a hydrophobic amino acid, or a hydrophilic amino acid (e.g., Cit or a variant thereof). In some embodiments, X4 is absent, G substituted with straight or branched C1-5alkyl, A substituted with C3-7cycloalkyl, or Cit or variant thereof. In some embodiments, X4 is absent, L, Cbg, Chg, Cba, Cha, Ahx, Dahp, citrulline (Cit), I, V, Norleucine, or Norvaline. In some embodiments, X4 is absent. In some embodiments, X4 is a hydrophobic amino acid. In some embodiments, X4 is Leu, Hcit, Cbg, Chg, or Cba. In some embodiments, X4 is Leu, Cbg, Chg or Cba. In some embodiments, X4 is G substituted with straight or branched C1-5 alkyl. In some embodiments, X4 is G substituted with methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, or isopentyl. In some embodiments, X4 A substituted with C3-7cycloalkyl. In some embodiments, X4 is A substituted with cyclopropyl. In some embodiments, X4 is A substituted with cyclobutyl. In some embodiments, X4 is A substituted with cyclopentyl. In some embodiments, X4 is A substituted with cyclohexyl. In some embodiments, X4 is A substituted with cycloheptyl. In some embodiments, X4 is L, Cbg, Chg, Cba, Cha, Ahx, Dahp, I, V, Norleucine, or Norvaline. In some embodiments, X4 is L. In some embodiments, X4 is Cbg. In some embodiments, X4 is Chg. In some embodiments, X4 is Cba. In some embodiments, X4 is Cha. In some embodiments, X4 is Ahx. In some embodiments, X4 is Dahp. In some embodiments, X4 is I. In some embodiments, X4 is V. In some embodiments, X4 is Norleucine. In some embodiments, X4 is Norvaline. In some embodiments, X4 is a hydrophilic amino acid. In some embodiments, X4 is Cit or a variant thereof. In some embodiments, X4 is Cit. In some embodiments, X4 is optionally N-methylated. In some embodiments, the metal chelator or linker is attached to X4. In some embodiments, X1 is directly bound to X4. In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (III-1), (III-2), (III-1-RI), and (III- 2-RI), X4 is a hydrophilic amino acid. In some embodiments, X4 is an amino acid comprising -OH, - NH2, -C(O)OH, -NHC(=NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3group. In some embodiments, X4 has an electrically charged side chain. In some embodiments, X4 has a positively charged side chain. In some embodiments, X4 has a negatively charged side chain. In some embodiments, X4 is zwitterionic. In some embodiments, X4 comprises a -OH, -COOH, -NH- or NH2moiety. In some embodiments, X4 comprises -OH, -C(O)OH, -NHC(=NH)NH2, -NHC(O)NH2, - C(O)NH2, or -NHC(O)CH3.In some embodiments, X4 comprises a side chain of C1-C6hydroxyalkyl, C1-C6aminoalkyl, -C0-6alkylene-NH-C(=NH)-NH2, -C0-6alkylene-CO-NH2, -C0-6alkylene-COOH, or - NH-CO-C1-6alkyl. In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (III-1), (III-2), (III-1-RI), and (III-2-RI), X4 is a hydrophobic amino acid. In some embodiments, X4 comprises at least 4 contiguous carbon atoms, either linear or branched. In some embodiments, X4 comprises at least 5 contiguous carbon atoms, either linear or branched. In some embodiments, X4 comprises a propylene moiety in the side chain. In some embodiments, X4 comprises a butylene moiety in the side chain.

[0210] In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (III-1), (III-2), (III- 1-RI), and (III-2-RI), X5 is a hydrophilic amino acid or a variant thereof. In some embodiments, X5 is a hydrophilic amino acid. In some embodiments, X5 is an unnatural amino acid. In some embodiments, X5 is a positively charged amino acid. In some embodiments, X5 is a negatively charged amino acid. In some embodiments, X5 is not charged. In some embodiments, X5 is a canonical amino acid. In some embodiments, X5 is N-alkylated amino acid. In some embodiments, X5 is Ala or a variant thereof. In some embodiments, X5 is N, Q, K, G, S, T, E, Aib, Hcit, Cit, Hgn, KCOpipzaa, Har, Nmm, Ndm, Ala, Hgl, 3Py6NH2, or a variant thereof including D-amino acid such as da and variations such as Qglucamine. In some embodiments, X5 is Hgn, N, Qglucamine, KCOpipzaa, Hgl, Nmm, Ndm, KCOpipzaa, K, S, T, or E. In some embodiments, X5 is Hgn. In some embodiments, X5 is asparagine (N). In some embodiments, X5 is Qglucamine. In some embodiments, X5 is Hgl. In some embodiments, X5 is Nmm. In some embodiments, X5 is Ndm. In some embodiments, X5 is KCOpipzaa. In some embodiments, X5 is Dab. In some embodiments, X5 is S. In some embodiments, X5 is K. In some embodiments, X5 is absent. In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (III-1), (III-2), (III-1-RI), and (III-2-RI), X5 is an amino acid comprising an electrically charged side chain (e.g., E, Hgl, D, or a variant thereof), or an amino acid comprising a polar uncharged side chain (e.g., Q, Cit, Hgn, N, or a variant thereof). In some embodiments, X5 is an amino acid comprising an electrically charged side chain. In some embodiments, X5 is an amino acid comprising a polar uncharged side chain. In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (Ia), (Ib), (III-2), (III-1-RI), and (III-2-RI), X5 is absent, a hydrophilic amino acid, or a variant thereof. In some embodiments, X5 is absent, a hydrophilic amino acid, or an amino acid with a functional side chain (e.g., Dab, Dap, R, E), wherein the hydrophilic amino acid comprises an L- amino acid comprising -NH2, - C(O)OH, -NHC(NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3. In some embodiments, X5 is absent, Hgl, Hgn, Dab, Dap, DabAc, DapAc, R, hArg, E, or D. In some embodiments, X5 is absent. In some embodiments, X5 is a hydrophilic amino acid. In some embodiments, X5 is an amino acid comprising-NH2, -C(O)OH, -NHC(NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3.In some embodiments, X5 is an L-amino acid comprising -NH2, -C(O)OH, -NHC(NH)NH2, -NHC(O)NH2, - C(O)NH2, or -NHC(O)CH3. In some embodiments, X5 is Hgl. In some embodiments, X5 is Hgn. In some embodiments, X5 is Dab. In some embodiments, X5 is Dap. In some embodiments, X5 is DabAc. In some embodiments, X5 is DapAc. In some embodiments, X5 is R or a variant thereof. In some embodiments, X5 is R or hArg. In some embodiments, X5 is R. In some embodiments, X5 is hArg. In some embodiments, X5 is E. In some embodiments, X5 is hCit. In some embodiments, X5 is G. In some embodiments, X5 is D. In some embodiments, the metal chelator or linker is attached to X5. In some embodiments, the covalently bound radionuclide or linker is attached to X5. In some embodiments, X1 is directly bound to X5.

[0211] In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ic), (III-1), (III-2), (III- 1-RI), and (III-2-RI), X6 is any amino acid. In some embodiments, X6 is a canonical amino acid. In some embodiments, X6 is an unnatural amino acid. In some embodiments, X6 is hydrophilic amino acid or amino acid having aromatic ring, or N-methylated amino acid thereof, or a substitute thereof. In some embodiments, X6 is an amino acid having aromatic ring or a substitute thereof. In some embodiments, X6 is an amino acid comprising an aryl group. In some embodiments, X6 is an amino acid comprising an optionally substituted phenyl group. In some embodiments, X6 is an amino acid comprising an optionally substituted naphthyl group. In some embodiments, X6 is an amino acid comprising a heteroaryl group. In some embodiments, X6 is an amino acid comprising an optionally substituted monocyclic heteroaryl group. In some embodiments, X6 is an amino acid comprising an optionally substituted bicyclic heteroaryl group. In some embodiments, the aryl or heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from –CH3, -ethyl, -Cl, and -F. In some embodiments, the aryl or heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from -OH, oxo, halogen, CN, amino, C1-C6 alkyl, C1-C6 alkoxyl, and C1-C6 haloalkyl. In some embodiments, X6 is N- methylated amino acid. In some embodiments, X6 is hydrophilic amino acid or a substitute thereof. In some embodiments, X6 is an amino acid having aromatic ring or a substitute thereof. In some embodiments, X6 is an N-methylated amino acid or a substitute thereof. In some embodiments, X6 is MeE. In some embodiments, X6 is N. In some embodiments, X6 is MeN. In some embodiments, X6 is Me3Py. In some embodiments, X6 is MeF. In some embodiments, X6 is Qglucamine. In some embodiments, X6 is MeF4C. In some embodiments, X6 is absent. In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ic), (III-1), (III-2), (III-1-RI), and (III-2-RI), X6 is an amino acid comprising an electrically charged side chain (e.g., E, Hgl, D, or a variant thereof), or an amino acid comprising a polar uncharged side chain (e.g., Q, Cit, Hgn, N, or variant). In some embodiments, X6 is an amino acid comprising an electrically charged side chain. In some embodiments, X6 is an amino acid comprising a polar uncharged side chain. In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (Ia), (Ic), (III-2), (III-1-RI), and (III-2-RI), X6 is absent, a hydrophilic amino acid, an amino acid comprising an aromatic ring, or N-methylated amino acid thereof. In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (III-1), (III-2), (III-1-RI), and (III-2-RI), X6 is a hydrophilic amino acid. In some embodiments, X6 is an amino acid comprising -OH, -NH2, -C(O)OH, - NHC(=NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3group. In some embodiments, X6 has an electrically charged side chain. In some embodiments, X6 has a positively charged side chain. In some embodiments, X6 has a negatively charged side chain. In some embodiments, X6 is zwitterionic. In some embodiments, X6 comprises a -OH, -COOH, -NH- or NH2moiety. In some embodiments, X6 comprises -OH, -C(O)OH, -NHC(=NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3.In some embodiments, X6 comprises a side chain of C1-C6hydroxyalkyl, C1-C6aminoalkyl, -C0-6alkylene-NH-C(=NH)-NH2, -C0-6alkylene-CO-NH2, -C0-6alkylene-COOH, or -NH-CO-C1-6alkyl. In some embodiments, X6 is absent, a hydrophilic amino acid, F or a variant thereof, Y or a variant thereof, W or a variant thereof, or N- methylated amino acid thereof, wherein the hydrophilic amino acid comprises a substituent selected from the group consisting of -C(O)OH, -C(O)NH2, and -NHC(O)CH3. In some embodiments, X6 is absent, MeF, MeE, Me3Py, Me4Py, MeF4F, MeF4C, or MeY. In some embodiments, X6 is MeE, MeN, Me3Py, MeF, MeF4C, or N. In some embodiments, X6 is absent. In some embodiments, X6 is a hydrophilic amino acid. In some embodiments, X6 is an amino acid comprising-NH2, -C(O)OH, -NHC(NH)NH2, - NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3. In some embodiments, X6 is E or N-methylated amino acid thereof. In some embodiments, X6 is E. In some embodiments, X6 is MeE. In some embodiments, X6 is an amino acid comprising an aromatic ring or N-methylated amino acid thereof. In some embodiments, X6 is an amino acid comprising an optionally substituted phenyl. In some embodiments, X6 is an amino acid comprising an optionally substituted heteroaryl. In some embodiments, X6 is F or a variant thereof, or N-methylated amino acid thereof. In some embodiments, X6 is F, MeF, Me3Py, Me4Py, MeF4F, or MeF4C. In some embodiments, X6 is F. In some embodiments, X6 is MeF. In some embodiments, X6 is Me3Py. In some embodiments, X6 is Me4Py. In some embodiments, X6 is MeF4F. In some embodiments, X6 is MeF4C. In some embodiments, X6 is Y or a variant thereof, or N-methylated amino acid thereof. In some embodiments, X6 is Y or MeY. In some embodiments, X6 is Y. In some embodiments, X6 is MeY. In some embodiments, the metal chelator or linker is attached to X6. In some embodiments, the covalently bound radionuclide or linker is attached to X6. In some embodiments, X1 is directly bound to X6.

[0212] In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (III-1), (III-2), (III-1-RI), and (III-2-RI), X7 is W or a variant thereof. In some embodiments, X7 is a canonical amino acid. In some embodiments, X7 is an unnatural amino acid. In some embodiments, X7 is N-alkylated amino acid. In some embodiments, X7 is W1Me. In some embodiments, X7 is W1Me7Cl. In some embodiments, X7 is W1Me7N. In some embodiments, X7 is absent. In some embodiments, X7 is an amino acid having aromatic ring or a substitute thereof. In some embodiments, X7 is an amino acid comprising an aryl group. In some embodiments, X7 is an amino acid comprising an optionally substituted phenyl group. In some embodiments, X7 is an amino acid comprising an optionally substituted naphthyl group. In some embodiments, X7 is an amino acid comprising a heteroaryl group. In some embodiments, X7 is an amino acid comprising an optionally substituted monocyclic heteroaryl group. In some embodiments, X7 is an amino acid comprising an optionally substituted bicyclic heteroaryl group. In some embodiments, the aryl or heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from –CH3, -ethyl, -Cl, and -F. In some embodiments, the aryl or heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from -OH, oxo, halogen, CN, amino, C1-C6alkyl, C1-C6alkoxyl, and C1-C6haloalkyl. In some embodiments, X7 is W, Y, or a variant thereof (such as an amino acid having either a 6-membered aryl or heteroaryl, or a 9- or 10- membered bi-cyclic aryl or heteroaryl linked to the alpha-carbon through a carbon (e.g., a methylene group), wherein the 6-, 9-, and 10-membered heteroaryl has one heteroatom (e.g., N), and wherein the 6-, 9-, and 10-membered aryl or heteroaryl is optionally substituted by 1 or 2 substituents independently selected from –CH3, -ethyl, -Cl, and -F). In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (III-1), (III-2), (III-1-RI), and (III-2-RI), X7 is an amino acid comprising an aromatic ring. In some embodiments, X7 is an amino acid comprising an aromatic ring (e.g., W or a variant thereof). In some embodiments, X7 is F or a variant thereof, or W or a variant thereof. In some embodiments, X7 is W1Me, W1Me7Cl, W1Me7N, W, F, 7-AzaTrp, W7Me, or W1Et. In some embodiments, X7 is F or a variant thereof. In some embodiments, X7 is F. In some embodiments, X7 is W or a variant thereof. In some embodiments, X7 is Nal1, Nal2, W1Et, Nal21N, 3Bzf, 3Bzt, Nal15N, Nal14N, Nal24N, Nal28N, F23dC, W1Me, W1Me7Cl, or W1Me7N. In some embodiments, X7 is W1Me, W1Me7Cl, W1Me7N, W, 7-AzaTrp, W7Me, or W1Et. In some embodiments, X7 is W1Me, W1Me7Cl, or F23dMe. In some embodiments, X7 is W1Me, W1Me7Cl, or W1Me7N. In some embodiments, X7 is W1Me. In some embodiments, X7 is W1Me7Cl. In some embodiments, X7 is W1Me7N. In some embodiments, X7 is W. In some embodiments, X7 is 7-AzaTrp. In some embodiments, X7 is W7Me. In some embodiments, the metal chelator or linker is attached to X7. In some embodiments, the covalently bound radionuclide or linker is attached to X7. In some embodiments, X1 is directly bound to X7.

[0213] In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (III-1), (III-2), (III-1-RI), and (III-2-RI), X8 is any amino acid. In some embodiments, X8 is any one of the canonical amino acids. In some embodiments, X8 is an unnatural amino acid. In some embodiments, X8 is V, hydrophilic amino acid, an N-methylated amino acid, or a substitute thereof. In some embodiments, X8 is V. In some embodiments, X8 is phenylalanine, tryptophan, tyrosine, or a variant thereof. In some embodiments, X8 is phenylalanine or a variant thereof. In some embodiments, X8 is tryptophan or a variant thereof. In some embodiments, X8 is W1Me. In some embodiments, X8 is tyrosine or a variant thereof. In some embodiments, X8 is N-methylated amino acid or a substitute thereof. In some embodiments, X8 is N-alkylated amino acid or a substitute thereof. In some embodiments, X8 is KCOpipzaa. In some embodiments, X8 is K. In some embodiments, X8 is valine (V). In some embodiments, X8 is Qglucamine. In some embodiments, X8 is Cit. In some embodiments, X8 is hCit. In some embodiments, X8 is absent. In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (III-1), (III-2), (III-1-RI), and (III-2-RI), X8 is a hydrophobic amino acid, a hydrophilic amino acid, an N-methylated amino acid, or an amino acid with a functional side chain. In some embodiments; X8 is G substituted with one or two straight or branched C1-5alkyl, A substituted with C3-7cycloalkyl, or a hydrophilic amino acid wherein the hydrophilic amino acid comprises an L-amino acid comprising -NH2, one or more -OH, -C(O)OH, -NHC(NH)NH2, -NHC(O)NH2, -C(O)NH2, - NHC(O)CH3; or the hydrophilic amino acid comprises a zwitterion. In some embodiments, X8 is V, A, E, N, K, Qglucamine, KCOpipzaa,Q, Hse, N, Cit, Hcit, Kac, DapAc, OrnAc, T, alT, Aib, Alb, or 3Py6NH2. In some embodiments, X8 is A, E, N, K, Qglucamine, KCOpipzaa,Q, Hse, N, Cit, Hcit, Kac, DapAc, OrnAc, T, alT, Aib, Alb, or 3Py6NH2. In some embodiments, X8 is KCOpipzaa, N, Cit, Qglucamine, hCit, K, KAc, Aib, Alb, DapAc, OrnAc, A, T, alT, Norleucine, Norvaline, Hgl, E, Hgn, Q, I, or L. In certain embodiments, X8 is KCOpipzaa, V, Qglucamine, Cit, Hcit, K, or 3Py6NH2. In certain embodiments, X8 is KCOpipzaa, Qglucamine, Cit, Hcit, K, or 3Py6NH2. In some embodiments, X8 is V, KCOpipzaa, Cit, Qglucamine, hCit, Aib, Alb, Norleucine, or Norvaline. In some embodiments, X8 is KCOpipzaa, Cit, Qglucamine, hCit, Aib, Alb, Norleucine, or Norvaline. In some embodiments, X8 is KCOpipzaa, N, Cit, hCit, KAc, DapAc, OrnAc, A, T, alT, Aib, Alb, Qglucamine, Hgl, Q, E, Hgn, or K. In some embodiments, X8 is a hydrophobic amino acid. In some embodiments, X8 is G substituted with straight or branched C1-5alkyl. In some embodiments, X8 is G substituted with one or more substituents selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and isopentyl. In some embodiments, X8 A substituted with C3-7cycloalkyl. In some embodiments, X8 is A substituted with cyclopropyl. In some embodiments, X8 is A substituted with cyclobutyl. In some embodiments, X8 is A substituted with cyclopentyl. In some embodiments, X8 is A substituted with cyclohexyl. In some embodiments, X8 is A substituted with cycloheptyl. In some embodiments, X8 is V, Aib, Alb, Norleucine, or Norvaline. In some embodiments, X8 is Aib, Alb, Norleucine, or Norvaline. In some embodiments, X8 is V. In some embodiments, X8 is Aib. In some embodiments, X8 is Alb. In some embodiments, X8 is Norleucine. In some embodiments, X8 is Norvaline. In some embodiments, X8 is a hydrophilic amino acid. In some embodiments, X8 is an amino acid comprising -NH2, one or more -OH, -C(O)OH, -NHC(NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3.In some embodiments, X8 is an L-amino acid comprising -NH2, one or more -OH, -C(O)OH, -NHC(NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3.In some embodiments, X8 is an amino acid comprising a zwitterion. In some embodiments, X8 is Cit or a variant thereof. In some embodiments, X8 is Cit or hCit. In some embodiments, X8 is KCOpipzaa. In some embodiments, X8 is Qglucamine. In some embodiments, the metal chelator or linker is attached to X8. In some embodiments, covalently bound radionuclide or linker is attached to X8. In some embodiments, X1 is directly bound to X8.

[0214] In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (III-1), (III-2), (III-1-RI), and (III-2-RI), X9 is W or a variant thereof. In some embodiments, X9 is a canonical amino acid. In some embodiments, X9 is an unnatural amino acid. In some embodiments, X9 is N-alkylated amino acid. In some embodiments, X9 is W1Me, W1Me7Cl, F23dMe, Nal1, Nal2, W1Et, Nal21N, 3Bzf, 3Bzt, Nal15N, Nal14N, Nal24N, Nal28N, F23dC, or W1Me7N. In some embodiments, X9 is W1Me or F23dMe. In some embodiments, X9 is W1Me. In some embodiments, X9 is W1Me7Cl. In some embodiments, X9 is W1Me7N. In some embodiments, X9 is absent. In some embodiments, X9 is F23dMe. In some embodiments, X9 an amino acid having aromatic ring or a substitute thereof. In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (III-1), (III-2), (III-1-RI), and (III-2-RI), X9 is an amino acid comprising an aromatic ring. In some embodiments, X9 is an amino acid comprising an aryl group. In some embodiments, X9 is an amino acid comprising an optionally substituted phenyl group. In some embodiments, X9 is an amino acid comprising an optionally substituted naphthyl group. In some embodiments, X9 is an amino acid comprising a heteroaryl group. In some embodiments, X9 is an amino acid comprising an optionally substituted monocyclic heteroaryl group. In some embodiments, X9 is an amino acid comprising an optionally substituted bicyclic heteroaryl group. In some embodiments, the aryl or heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from –CH3, -ethyl, -Cl, and -F. In some embodiments, the aryl or heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from -OH, oxo, halogen, CN, amino, C1-C6alkyl, C1-C6alkoxyl, and C1-C6haloalkyl. In some embodiments, X9 is W, Y, or a variant thereof (such as an amino acid having either a 6-membered aryl or heteroaryl, or a 9- or 10- membered bi-cyclic aryl or heteroaryl linked to the alpha-carbon through a carbon (e.g., a methylene group), wherein the 6-, 9-, and 10-membered heteroaryl has one heteroatom (e.g., N), and wherein the 6-, 9-, and 10-membered aryl or heteroaryl is optionally substituted by 1 or 2 substituents independently selected from –CH3, -ethyl, -Cl, and -F). In some embodiments, X9 is an amino acid comprising an aromatic ring (e.g., W or a variant thereof). In some embodiments, X9 is F or a variant thereof, or W or a variant thereof. In some embodiments, X9 is W1Me, W1Me7Cl, W1Me7N, F23dMe, W1Et, W7Me, W, F, or 7-AzaTrp. In some embodiments, X9 is F or a variant thereof. In some embodiments, X9 is F or F23dMe. In some embodiments, X9 is F. In some embodiments, X9 is F23dMe. In some embodiments, X9 is W or a variant thereof. In some embodiments, X9 is W1Me, W1Me7Cl, W1Me7N, W, 7-AzaTrp, W7Me, or W1Et. In some embodiments, X9 is W1Me or F23dMe. In some embodiments, X9 is W1Me. In some embodiments, X9 is W1Me7Cl. In some embodiments, X9 is W1Me7N. In some embodiments, X9 is W. In some embodiments, X9 is 7-AzaTrp. In some embodiments, X9 is W7Me. In some embodiments, X9 is W1Et. In some embodiments, the metal chelator or linker is attached to X9. In some embodiments, the covalently bound radionuclide or linker is attached to X9. In some embodiments, X1 is directly bound to X9.

[0215] In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (III-1-RI), and (III-2-RI), X10 is absent, T or a variant thereof. In some embodiments, X10 is a canonical amino acid. In some embodiments, X10 is an unnatural amino acid. In some embodiments, X10 is threonine (T). In some embodiments, X10 is absent. In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I- 5), (III-1), (III-2), (III-1-RI), and (III-2-RI), X10 is absent, or a polar amino acid (e.g., T or a variant thereof). In some embodiments, X10 is absent, Q, Hgn, S or a variant thereof, T or variant thereof optionally substituted with straight or branched C1-5alkyl, K or a variant thereof, Cit or a variant thereof, or an L- amino acid substituted with-NHC(NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3. In some embodiments, X10 is absent, T, Q, S, Hgn, Alpha-methylserine, hSer, hThr, N, OrnAc, LysAc, Cit, or hCit. In some embodiments, X10 is absent. In some embodiments, X10 is a polar amino acid. In some embodiments, X10 is Q. In some embodiments, X10 is Hgn. In some embodiments, X10 is S or a variant thereof. In some embodiments. X10 is S, Alpha-methylserine, or hSer. In some embodiments, X10 is S. In some embodiments, X10 is Alpha-methylserine. In some embodiments, X10 is hSer. In some embodiments, X10 is T or a variant thereof optionally substituted with straight or branched C1-5alkyl. In some embodiments, X10 is T or hThr. In some embodiments, X10 is T. In some embodiments, X10 is hThr. In some embodiments, X10 is T substituted with methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, or isopentyl. In some embodiments, X10 is N. In some embodiments, X10 is K or a variant thereof. In some embodiments, X10 is K, OrnAc, or LysAc. In some embodiments, X10 is K. In some embodiments, X10 is OrnAc. In some embodiments, X10 is LysAc. In some embodiments, X10 is Cit or a variant thereof. In some embodiments, X10 is Cit or hCit. In some embodiments, X10 is Cit. In some embodiments, X10 is hCit. In some embodiments, the metal chelator or linker is attached to X10. In some embodiments, the covalently bound radionuclide or linker is attached to X10. In some embodiments, X1 is directly bound to X10.

[0216] In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (III-1-RI), and (III-2-RI), X11 is absent, a hydrophilic amino acid, or a substitute thereof. In some embodiments, X11 is serine, threonine, tyrosine, asparagine, glutamine, or a substitute thereof. In some embodiments, X11 is a canonical amino acid. In some embodiments, X11 is an unnatural amino acid. In some embodiments, X11 is Hgn. In some embodiments, X11 is K. In some embodiments, X11 is glutamate. In some embodiments, X11 is hArg. In some embodiments, X11 is hCit. In some embodiments, X11 is Nmm. In some embodiments, X11 is Ndm. In some embodiments, X11 is Har. In some embodiments, X11 is R. In some embodiments, X11 is Har. In some embodiments, X11 is Arg (R). In some embodiments, X11 is Cit. In some embodiments, X11 is asparagine. In some embodiments, X11 is absent. In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (III-1-RI), and (III-2-RI), X11 is absent, a hydrophilic amino acid, or an amino acid with a functional side chain. In some embodiments, X11 is a hydrophilic amino acid. In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (III-1-RI), and (III-2-RI), X11 is an amino acid comprising an electrically charged side chain (e.g., E, Hgl, D, R, hArg, K or a variant thereof), or an amino acid comprising a polar uncharged side chain (e.g., Q, Cit, Hgn, N, or a variant thereof). In some embodiments, X11 is an amino acid comprising an electrically charged side chain. In some embodiments, X11 is an amino acid comprising a polar uncharged side chain. In some embodiments, X11 is an amino acid comprising -OH, -NH2, -C(O)OH, -NHC(=NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3group. In some embodiments, X11 has an electrically charged side chain. In some embodiments, X11 has a positively charged side chain. In some embodiments, X11 has a negatively charged side chain. In some embodiments, X11 is zwitterionic. In some embodiments, X11 comprises a -OH, -COOH, -NH- or NH2moiety. In some embodiments, X11 comprises -OH, -C(O)OH, -NHC(=NH)NH2, -NHC(O)NH2, - C(O)NH2, or -NHC(O)CH3.In some embodiments, X11 comprises a side chain of C1-C6hydroxyalkyl, C1-C6aminoalkyl, -C0-6alkylene-NH-C(=NH)-NH2, -C0-6alkylene-CO-NH2, -C0-6alkylene-COOH, or - NH-CO-C1-6alkyl. In some embodiments, X11 is absent, E, Hgn, R or a variant thereof, Cit or a variant thereof, Hgl, K or a variant thereof, D, N, or Q. In some embodiments, X11 is absent, E, Hgn, R, hArg, Cit, hCit, Hgl, Orn, D, N, Q, DapAc, OrnAc, DabAc, or norCit. In some embodiments, X11 is absent, arginine (R), asparagine (N), aspartate (D), glutamine (Q), lysine (K), or an unnatural hydrophilic amino acid. In some embodiments, X11 is absent, Hgn, R, hArg, Cit, hCit, Hgl, Orn, D, N, Q, DapAc, OrnAc, DabAc, or norCit. In some embodiments, X11 is Hgn, R, hArg, Cit, hCit, Hgl, Orn, D, N, Q, DapAc, OrnAc, DabAc, or norCit. In some embodiments, X11 is Q, K, G, S, T, E, Aib, Hcit, Cit, Hgn, KCOpipzaa, Har, Nmm, Ndm, Ala, Hgl, 3Py6NH2, or a variant thereof including D-amino acid such as da and variations such as Qglucamine. In some embodiments, X11 is Q, K, G, S, T, Aib, Hcit, Cit, Hgn, KCOpipzaa, Har, Nmm, Ndm, Ala, Hgl, 3Py6NH2, or a variant thereof including D-amino acid such as da and variations such as Qglucamine. In some embodiments, X11 is Hgn, N, R, Har, Nmm, Ndm, E, or K. In some embodiments, X11 is Hgn, N, R, Har, Nmm, Ndm, or K. In some embodiments, X11 is absent. In some embodiments, X11 is a hydrophilic amino acid. In some embodiments, X11 is E. In some embodiments, X11 is Hgn. In some embodiments, X11 is R or a variant thereof. In some embodiments, X11 is R or hArg. In some embodiments, X11 is R. In some embodiments, X11 is hARg. In some embodiments, X11 is Cit or a variant thereof. In some embodiments, X11 is Cit, hCit, or norCit. In some embodiments, X11 is Cit. In some embodiments, X11 is hCit. In some embodiments, X11 is norCit. In some embodiments, X11 is Hgl. In some embodiments, X11 is K or a variant thereof. In some embodiments, X11 is K, Orn, OrnAc, DabAc, or DapAc. In some embodiments, X11 is K. In some embodiments, X11 is Orn. In some embodiments, X11 is OrnAc. In some embodiments, X11 is DabAc. In some embodiments, X11 is DapAc. In some embodiments, X11 is D, N or Q. In some embodiments, X11 is D. In some embodiments, X11 is N. In some embodiments, X11 is Q. In some embodiments, the metal chelator or linker is attached to X11. In some embodiments, the covalently bound radionuclide or linker is attached to X11. In some embodiments, X1 is directly bound to X11.

[0217] In some embodiments of Formulas (I), (I-5), (Ia), (Ib), (Ic), (III-2), and (III-2-RI), X12 is C or a variant thereof. In some embodiments, X12 is a canonical amino acid. In some embodiments, X12 is an unnatural amino acid. In some embodiments, X12 is cysteine. In some embodiments, X12 is a substitute of cysteine. In some embodiments, X12 is homocysteine. In some embodiments, X12 is CdMe. In some embodiments, X12 is C3SMe. In some embodiments, X12 is C3RMe. In some embodiments, the metal chelator or linker is attached to X12. In some embodiments of Formulas (I), (I-5), (Ia), (Ib), (Ic), (III-2), and (III-2-RI), X12 is C or a variant thereof. In some embodiments, X12 is X12 is C, hCys, CdMe, C3RMe, C3SMe, Selenocysteine, dc, or Penicillamine. In some embodiments, X12 is C. In some embodiments, X12 is hCys. In some embodiments, X12 is CdMe. In some embodiments, X12 is C3RMe. In some embodiments, X12 is C3SMe. In some embodiments, X12 is Selenocysteine. In some embodiments, X12 is dc. In some embodiments, X12 is Penicillamine. In some embodiments, the metal chelator or linker is attached to X12. In some embodiments, the covalently bound radionuclide or linker is attached to X12. In some embodiments, X1 is directly bound to X12.

[0218] In some embodiments, the peptide of Formula (I) has a structure of Formula (I-1), or a pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of NH2and OH; R2is selected from the group consisting of H or C1-3alkyl; R3is selected from the group consisting of H or C1-3alkyl; wherein the attachment point to the metal chelator or the linker is not shown, and wherein X1-X11 are described in Formula (I).

[0219] In some embodiments, the peptide of Formula (I-1) has a structure of Formula (I-2), or a pharmaceutically acceptable salt thereof,

[0220] In some embodiments, the peptide of Formula (I-1) has a structure of Formula (I-3), or a pharmaceutically acceptable salt thereof,

[0221] In some embodiments, the peptide of Formula (I-1) has a structure of Formula (I-4), or a pharmaceutically acceptable salt thereof,

[0222] In some embodiments of Formula (I-1), (I-2), (I-3) or (I-4), R1is OH. In some embodiments of Formula (I-1), (I-2), (I-3) or (I-4), R1is NH2. In some embodiments of Formula (I-1), (I-2), (I-3) or (I-4), R1is attached to the linker or to the metal chelator. In some embodiments, the linker or the metal chelator is attached to the peptide through the group R1.

[0223] In some embodiments of Formula (I-1), (I-2), (I-3) or (I-4), R2is H. In some embodiments of Formula (I-1), (I-2), (I-3) or (I-4), R2is C1-3alkyl. In some embodiments of Formula (I-1), (I-2), (I-3) or (I-4), R2is methyl.

[0224] In some embodiments of Formula (I-1), (I-2), (I-3) or (I-4), R3is H. In some embodiments of Formula (I-1), (I-2), (I-3) or (I-4), R3is C1-3alkyl. In some embodiments of Formula (I-1), (I-2), (I-3) or (I-4), R3is methyl.

[0225] In some embodiments, the peptide of Formula (I) has a structure of Formula (I-5), or a pharmaceutically acceptable salt thereof, wherein X1-X12 have the definition described above and Lcyc is a ring closing group that covalently connecting X1 with X12.

[0226] In some embodiments, the Lcyc is a group selected from Table 4B. In some embodiments, the Lcyc is formed by reacting the first and the second functional groups in Table 4C.

[0227] In some embodiments, the peptide of Formula (I) or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) wherein, X1 is any amino acid (e.g., D-amino acid); X2 is an amino acid comprising an aromatic ring or a variant thereof, or N-methylated amino acid thereof; X3 is N or a variant thereof; X4 is any hydrophobic amino acid or a variant thereof; X5 is a hydrophilic amino acid or a variant thereof; X6 is a hydrophilic amino acid or amino acid having aromatic ring, or N-methylated amino acid thereof; X7 is W or a variant thereof; X8 is V or hydrophilic amino acid or a variant thereof; X9 is W or a variant thereof; X10 is T or a variant thereof; X11 is any hydrophilic amino acid; and X12 is C or a variant thereof.

[0228] In some embodiments of Formula (I), wherein, X1 is D-amino acid (such as da, df3CON, dahp, or dkCOpipzaa); X2 is N-methylated phenylalanine or a variant thereof (such as Me3Py, MeF, MeF3H, or MeF3CN); X3 is N; X4 is a hydrophobic amino acid or N-methylated amino acid (such as leucine, Cbg, or Chg); X5 is a Hgn, asparagine (N), 2,4-Diaminobutyric Acid (Dab), Qglucamine, KCOpipzaa, Hgl, Nmm, Ndm, or lysine (K); X6 is asparagine (N) or N-methylated glutamic acid (E), N-methylated asparagine, N- methylated phenylalanine (F) or substitutions thereof (such as Qglucamine, MeE, MeN, Me3Py, MeF, MeF4C, or N); X7 is W1Me, W1Me7Cl, or W1Me7N; X8 is KCOpipzaa, V, Qglucamine, Cit, Hcit, or K; X9 is W1Me or F23dMe; X10 is T; X11 is hArg, hCit, Citrulline (Cit), A Hgn, asparagine (N), Arginine (R), Har, Nmm, Ndm, Glutamic Acid (E), lysine (K); and X12 is cysteine.

[0229] In some embodiments, an amino acid of Formula (I) has a sequence of Formula (Ia), or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X12 Formula (Ia).

[0230] In some embodiments, an amino acid of Formula (I) has a sequence of Formula (Ib), or a pharmaceutically acceptable salt thereof, X1-X2-X4-X5-X7-X8-X9-X12 Formula (Ib).

[0231] In some embodiments, an amino acid of Formula (I) has a sequence of Formula (Ic), or a pharmaceutically acceptable salt thereof, X1-X2-X6-X7-X8-X9-X12 Formula (Ic).

[0232] In some embodiments, a herein described peptide has an amino acid sequence according to Formula (Ia), or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X12 Formula (Ia) wherein, X1 is any amino acid (e.g., a D-amino acid); X2 is an amino acid comprising an aromatic ring or a variant thereof, or an N-methylated amino acid thereof; X3 is N or a variant thereof; X4 is any hydrophobic amino or a variant thereof, X5 is a hydrophilic amino acid or a variant thereof; X6 is a hydrophilic amino acid or amino acid having aromatic ring, or an N-methylated amino acid thereof; X7 is W or a variant thereof; X8 is any hydrophilic amino acid or a variant thereof; X9 is W or a variant thereof; and X12 is C or a variant thereof.

[0233] In some embodiments, a herein described peptide has an amino acid sequence according to Formula (Ib), or a pharmaceutically acceptable salt thereof, X1-X2-X4-X5-X7-X8-X9-X12 Formula (Ib) wherein, X1 is any amino acid (e.g., D-amino acid); X2 is an amino acid comprising an aromatic ring or a variant thereof, or N-methylated amino acid thereof; X4 is any hydrophobic amino or a variant thereof, X5 is a hydrophilic amino acid or a variant thereof; X7 is W or a variant thereof; X8 is an N-methylated amino acid; X9 is W or a variant thereof; and X12 is C or a variant thereof.

[0234] In some embodiments, a herein described peptide has an amino acid sequence according to Formula (Ic), or a pharmaceutically acceptable salt thereof, X1-X2-X6-X7-X8-X9-X12 Formula (Ic) wherein, X1 is any amino acid (e.g., D-amino acid); X2 is an amino acid comprising an aromatic ring or a variant thereof, or N-methylated amino acid thereof; X6 is an N-methyl amino acid; X7 is W or a variant thereof; X8 is an N-methyl amino acid; X9 is W or a variant thereof; and X12 is C or a variant thereof.

[0235] In some embodiments, the peptide of Formula (I), (Ia), (Ib), and / or (Ic) are monocyclic. In some embodiments, the amino acid in X1 and the cysteine or the substitution of cysteine are bound.

[0236] In some embodiments, a peptide of the present disclosure binds to a ligand-binding domain (LBD) of human EphA2.

[0237] In some embodiments, a peptide of the present disclosure has good contact with Asp53 and / or Glu157 of the human EphA2, according to SEQ ID NO: 276. In some embodiments, a peptide of the present disclosure interacts with Asp53 and / or Glu157 of the human EphA2, according to SEQ ID NO: 276. In some embodiments, a peptide of the present disclosure interacts with Asp53 and / or Glu157 of the human EphA2, according to SEQ ID NO: 501. The interaction can be the formation of one or more hydrogen bonds, Van der Waals interactions, dipole-dipole interactions, or pi-pi stacking interactions. In some embodiments, a peptide of the present disclosure interacts with human EphA2 at one or more residues selected from Asp53, Met55, Asn57, Met59, Met66, Thr101, Arg103, Phe156, Glu157, Arg159, Val161, Val189, and Ala190.. In some embodiments, a peptide of the present disclosure binds to Asp53 and Glu157 of the human EphA2. In some embodiments, amino acid residue X5 of Formula (I) interact with Glu157 of a human EphA2. In some embodiments, amino acid residue X6 of Formula (I) interacts with Arg159 of a human EphA2. In some embodiments, amino acid residue X7 of Formula (I) interacts with one or more of Phe156, Thr101, Asn57, Val161, Met59, Ala190, and Met66 of a human EphA2. In some embodiments, amino acid residue X9 of Formula (I) interacts with one or more of Phe156, Arg103, and Val189. In some embodiments, amino acid residue X11 of Formula (I) interact with Asp53 of a human EphA2. In some embodiments, amino acid residue X7 of Formula (I) forms a pi-pi stacking interaction with Phe156 of a human EphA2 of the human EphA2. In some embodiments, amino acid residue X9 of Formula (I) forms a pi-pi stacking interaction with Phe156 of a human EphA2. In some embodiments, amino acid residue X2 of Formula (I) interacts with the backbone carbonyl of C70 of human EphA2 protein via intermolecular aromatic H-bond interactions.

[0238] In some embodiments, when a peptide of Formula (I), or a conjugate comprising the peptide, is bound to a human EphA2, amino acid residue X2 of Formula (I) is located less than 15Å from the C70 of the human EphA2. In some embodiments, X2 is located less than 10Å from the C70. In some embodiments, X2 is located less than 6Å from the C70. In some embodiments, X2 is located less than 4Å from the C70.

[0239] In some embodiments, when a peptide of Formula (I), or a conjugate comprising the peptide, is bound to a human EphA2, amino acid residue X7 of Formula (I) is located less than 10Å from the Phe156 of the human EphA2. In some embodiments, X7 is located less than 6Å from the Phe156. In some embodiments, X7 is located less than 4Å from the Phe156.

[0240] In some embodiments, when a peptide of Formula (I), or a conjugate comprising the peptide, is bound to a human EphA2, amino acid residue X7 of Formula (I) is located less than 20Å from the Thr101 of the human EphA2. In some embodiments, X7 is located less than 15Å from the Thr101. In some embodiments, X7 is located less than 10Å from the Thr101. In some embodiments, X7 is located less than 6Å from the Thr101. In some embodiments, X7 is located less than 4Å from the Thr101.

[0241] In some embodiments, when a peptide of Formula (I), or a conjugate comprising the peptide, is bound to a human EphA2, amino acid residue X7 of Formula (I) is located less than 20Å from the Asn57 of the human EphA2. In some embodiments, X7 is located less than 15Å from the Asn57. In some embodiments, X7 is located less than 10Å from the Asn57. In some embodiments, X7 is located less than 6Å from the Asn57. In some embodiments, X7 is located less than 4Å from the Asn57.

[0242] In some embodiments, when a peptide of Formula (I) is, or a conjugate comprising the peptide, bound to a human EphA2, amino acid residue X7 of Formula (I) is located less than 20Å from the Val161 of the human EphA2. In some embodiments, X7 is located less than 15Å from the Val161. In some embodiments, X7 is located less than 10Å from the Val161. In some embodiments, X7 is located less than 6Å from the Val161. In some embodiments, X7 is located less than 4Å from the Val161.

[0243] In some embodiments, when a peptide of Formula (I), or a conjugate comprising the peptide, is bound to a human EphA2, amino acid residue X7 of Formula (I) is located less than 20Å from the Met59 of the human EphA2. In some embodiments, X7 is located less than 15Å from the Met59. In some embodiments, X7 is located less than 10Å from the Met59. In some embodiments, X7 is located less than 6Å from the Met59. In some embodiments, X7 is located less than 4Å from the Met59.

[0244] In some embodiments, when a peptide of Formula (I), or a conjugate comprising the peptide, is bound to a human EphA2, amino acid residue X7 of Formula (I) is located less than 20Å from the Ala190 of the human EphA2. In some embodiments, X7 is located less than 15Å from the Ala190. In some embodiments, X7 is located less than 10Å from the Ala190. In some embodiments, X7 is located less than 6Å from the Ala190. In some embodiments, X7 is located less than 4Å from the Ala190.

[0245] In some embodiments, when a peptide of Formula (I), or a conjugate comprising the peptide, is bound to a human EphA2, amino acid residue X7 of Formula (I) is located less than 20Å from the Met66 of the human EphA2. In some embodiments, X7 is located less than 15Å from the Met66. In some embodiments, X7 is located less than 10Å from the Met66. In some embodiments, X7 is located less than 6Å from the Met66. In some embodiments, X7 is located less than 4Å from the Met66.

[0246] In some embodiments, when a peptide of Formula (I), or a conjugate comprising the peptide, is bound to a human EphA2, amino acid residue X9 of Formula (I) is located less than 10Å from the Phe156 of the human EphA2. In some embodiments, X9 is located less than 6Å from the Phe156. In some embodiments, X9 is located less than 4Å from the Phe156.

[0247] In some embodiments, when a peptide of Formula (I), or a conjugate comprising the peptide, is bound to a human EphA2, amino acid residue X9 of Formula (I) is located less than 15Å from the Asn3 of the human EphA2. In some embodiments, X9 is located less than 10Å from the Asn3. In some embodiments, X9 is located less than 6Å from the Asn3. In some embodiments, X9 is located less than 4Å from the Asn3.

[0248] In some embodiments, when a peptide of Formula (I), or a conjugate comprising the peptide, is bound to a human EphA2, amino acid residue X9 of Formula (I) is located less than 15Å from the Arg103 of the human EphA2. In some embodiments, X9 is located less than 10Å from the Arg103. In some embodiments, X9 is located less than 6Å from the Arg103. In some embodiments, X9 is located less than 4Å from the Arg103.

[0249] In some embodiments, when a peptide of Formula (I), or a conjugate comprising the peptide, is bound to a human EphA2, amino acid residue X9 of Formula (I) is located less than 15Å from the Val189 of the human EphA2. In some embodiments, X9 is located less than 10Å from the Val189. In some embodiments, X9 is located less than 6Å from the Val189. In some embodiments, X9 is located less than 4Å from the Val189.

[0250] In some embodiments, when a peptide of Formula (I), or a conjugate comprising the peptide, is bound to a human EphA2, amino acid residue X8 of Formula (I) is located less than 10Å from the Phe156 of the human EphA2. In some embodiments, X8 is located less than 6Å from the Phe156. In some embodiments, X8 is located less than 4Å from the Phe156.

[0251] In some embodiments, when a peptide of Formula (I), or a conjugate comprising the peptide, is bound to a human EphA2, amino acid residue X2 of Formula (I) is located less than 15Å from the C70 of the human EphA2. In some embodiments, X2 is located less than 10Å from the C70. In some embodiments, X2 is located less than 7Å from the C70. In some embodiments, X2 is located less than 4Å from the C70.

[0252] In some embodiments, when a peptide of Formula (I), or a conjugate comprising the peptide, is bound to a human EphA2, amino acid residue X7 of Formula (I) is located less than 10Å from the Phe156 of the human EphA2. In some embodiments, X7 is located less than 6Å from the Phe156. In some embodiments, X7 is located less than 3Å from the Phe156.

[0253] In some embodiments, when a peptide of Formula (I), or a conjugate comprising the peptide, is bound to a human EphA2, amino acid residue X9 of Formula (I) is located less than 20Å from the Thr101 of the human EphA2. In some embodiments, X9 is located less than 15Å from the Thr101. In some embodiments, X9 is located less than 10Å from the Thr101. In some embodiments, X9 is located less than 6Å from the Thr101. In some embodiments, X9 is located less than 5Å from the Thr101.

[0254] In some embodiments, when a peptide of Formula (I), or a conjugate comprising the peptide, is bound to a human EphA2, amino acid residue X8 of Formula (I) is located less than 20Å from the Asn57 of the human EphA2. In some embodiments, X8 is located less than 15Å from the Asn57. In some embodiments, X8 is located less than 10Å from the Asn57. In some embodiments, X8 is located less than 6Å from the Asn57. In some embodiments, X8 is located less than 4Å from the Asn57.

[0255] In some embodiments, when a peptide of Formula (I) is, or a conjugate comprising the peptide, bound to a human EphA2, amino acid residue X7 of Formula (I) is located less than 20Å from the Val161 of the human EphA2. In some embodiments, X7 is located less than 15Å from the Val161. In some embodiments, X7 is located less than 11Å from the Val161. In some embodiments, X7 is located less than 6Å from the Val161. In some embodiments, X7 is located less than 5Å from the Val161.

[0256] In some embodiments, when a peptide of Formula (I), or a conjugate comprising the peptide, is bound to a human EphA2, amino acid residue X7 of Formula (I) is located less than 20Å from the Met59 of the human EphA2. In some embodiments, X7 is located less than 15Å from the Met59. In some embodiments, X7 is located less than 11Å from the Met59. In some embodiments, X7 is located less than 6Å from the Met59. In some embodiments, X7 is located less than 4Å from the Met59.

[0257] In some embodiments, when a peptide of Formula (I), or a conjugate comprising the peptide, is bound to a human EphA2, amino acid residue X7 of Formula (I) is located less than 20Å from the Ala190 of the human EphA2. In some embodiments, X7 is located less than 15Å from the Ala190. In some embodiments, X7 is located less than 11Å from the Ala190. In some embodiments, X7 is located less than 6Å from the Ala190. In some embodiments, X7 is located less than 4Å from the Ala190.

[0258] In some embodiments, when a peptide of Formula (I), or a conjugate comprising the peptide, is bound to a human EphA2, amino acid residue X7 of Formula (I) is located less than 20Å from the Met66 of the human EphA2. In some embodiments, X7 is located less than 15Å from the Met66. In some embodiments, X7 is located less than 10Å from the Met66. In some embodiments, X7 is located less than 6Å from the Met66. In some embodiments, X7 is located less than 4Å from the Met66.

[0259] In some embodiments, when a peptide of Formula (I), or a conjugate comprising the peptide, is bound to a human EphA2, amino acid residue X2 of Formula (I) is located less than 15Å from the Arg103 of the human EphA2. In some embodiments, X2 is located less than 10Å from the Arg103. In some embodiments, X2 is located less than 6Å from the Arg103. In some embodiments, X2 is located less than 4Å from the Arg103.

[0260] In some embodiments, when a peptide of Formula (I), or a conjugate comprising the peptide, is bound to a human EphA2, amino acid residue X9 of Formula (I) is located less than 15Å from the Val189 of the human EphA2. In some embodiments, X9 is located less than 10Å from the Val189. In some embodiments, X9 is located less than 6Å from the Val189. In some embodiments, X9 is located less than 4Å from the Val189.

[0261] In some embodiments, a conjugate of the present disclosure has a structure of Formula (III-1), Formula (III-1) wherein –Linker– represents the linker.

[0262] In some embodiments, a conjugate comprising a cyclic peptide of formula (I) has a structure of wherein X1-X12 have the definition described above and Lcyc is a ring closing group that covalently connecting X1 with X12; and –Linker– represents the linker.

[0263] In some embodiments, a conjugate of the present disclosure has a structure of Formula (III-1-RI), wherein X1-X12 have the definition described above; –Linker– represents the linker; and R* represents the covalently bound radionuclide.

[0264] In some embodiments, a conjugate comprising a cyclic peptide of formula (I) has a structure of wherein X1-X12 have the definition described above and Lcyc is a ring closing group that covalently connecting X1 with X12; –Linker– represents the linker; and R* represents the covalently bound radionuclide.

[0265] In some embodiments, the Lcyc is a group selected from Table 4B. In some embodiments, the Lcyc is formed by reacting the first and the second functional groups in Table 4C. In some embodiments, the Lcyc is -C(=O)-CH2-. In some embodiments, the Lcyc is -C(=O)-CH2-, which is formed by reacting with a chloroacetylated (or bromoacetylated) amino acid with a cysteine. In some embodiments, the Lcyc is -C(=O)-CH2-S-, which is formed by reacting with a chloroacetylated (or bromoacetylated) amino acid with an amino acid comprising a SH group.

[0266] In some embodiments, a peptide disclosed herein or a pharmaceutically accepted salt thereof has a cyclic structure having a chloroacetylated amino acid in the first residue X1 and a cysteine residue or a variant thereof, and wherein the chloroacetylated amino acid in X1 and the cysteine residue or a variant thereof are bound. In some embodiments, a peptide disclosed herein or a pharmaceutically accepted salt thereof has a cyclic structure having a chloroacetylated amino acid in the first residue X1 and a cysteine residue or a variant thereof, and wherein the chloroacetylated amino acid in X1 and the cysteine residue or a variant thereof form a covalent bond. In some embodiments, a peptide disclosed herein or a pharmaceutically accepted salt thereof has a cyclic structure having a bromoacetylated amino acid in the first residue X1 and a cysteine residue or a variant thereof, and wherein the bromoacetylated amino acid in X1 and the cysteine residue or a variant thereof form a covalent bond.

[0267] In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NOs: 1-122, 159-163, and 165-171, and the peptide has a cyclic structure having a cysteine residue or a variant thereof at 12th residue (X12). In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NOs: 1-122, 159-163, and 165-171, and the peptide has a cyclic structure having a cysteine residue or a variant thereof at 12th residue (X12), and wherein the chloroacetylated amino acid and the cysteine residue or a variant thereof at 12th residue form a covalent bond. In some embodiments, the chloroacetyl group can be replaced with a bromoacetyl group.

[0268] In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NOs: 123-149 and 164, and the peptide has a cyclic structure having a cysteine residue or a variant thereof at 10th residue (X10). In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NOs: 123-149 and 164, and the peptide has a cyclic structure having a cysteine residue or a variant thereof at 10th residue (X10), and wherein the chloroacetylated amino acid and the cysteine residue or a variant thereof at 10th residue form a covalent bond. In some embodiments, the chloroacetyl group can be replaced with a bromoacetyl group.

[0269] In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NOs: 150-157, and the peptide has a cyclic structure having a cysteine residue or a variant thereof at 8th residue (X8). In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NOs: 150-157, and the peptide has a cyclic structure having a chloroacetylated amino acid and a cysteine residue or a variant thereof at 8th residue (X8), and wherein the chloroacetylated amino acid and the cysteine residue or a variant thereof at 8th residue form a covalent bond. In some embodiments, the chloroacetyl group can be replaced with a bromoacetyl group.

[0270] In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NO: 158, and the peptide has a cyclic structure having a cysteine residue or a variant thereof at 7th residue (X7). In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NO: 158, and the peptide has a cyclic structure having a chloroacetylated amino acid and a cysteine residue or a variant thereof at 7th residue (X7), and wherein the chloroacetylated amino acid and the cysteine residue or a variant thereof at 7th residue form a covalent bond. In some embodiments, the chloroacetyl group can be replaced with a bromoacetyl group.

[0271] In some embodiments, a peptide disclosed herein or a pharmaceutically salt thereof has a cyclic structure having the first amino acid covalently linked to the last amino acid.

[0272] In some embodiments, the peptide or the pharmaceutically accepted salt thereof has a cyclic structure having a chloroacetylated amino acid in X1 and a cysteine or substituted cysteine residue, and wherein the chloroacetylated amino acid in X1 and the cysteine or substituted cysteine are bound. In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NOs: 1-171. In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NOs: 1-171, and the peptide has a cyclic structure. In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NOs: 1-171, and the peptide has a cyclic structure having a chloroacetylated amino acid and a cysteine or substituted cysteine residue at C-terminus, and wherein the chloroacetylated amino acid and the cysteine or substituted cysteine at C-terminus are bound. In some embodiments, the peptide has a cyclic structure having a chloroacetylated amino acid and; (i) a cysteine or substituted cysteine residue at 12th residue, and wherein the chloroacetylated amino acid and the cysteine or substituted cysteine at 12th residue are bound; or (ii) a cysteine or substituted cysteine residue at 10th residue, and wherein the chloroacetylated amino acid and the cysteine or substituted cysteine at 10th residue are bound. In some embodiments, the chloroacetyl group can be replaced with a bromoacetyl group.

[0273] For example, a cyclic peptide of formula (I) can have a structure as illustrated below For example, a cyclic peptide of formula (I) can have a structure as illustrated below .

[0003]

[0274] In some embodiments, a conjugate comprising a cyclic peptide of formula (I) has a structure of .

[0275] In some embodiments, a conjugate of the present disclosure has a structure of wherein represents the linker.

[0276] In some embodiments, a conjugate comprising a cyclic peptide of formula (I) has a structure of

[0277] In some embodiments, a conjugate of the present disclosure has a structure of wherein represents the linker.

[0278] In some embodiments, the peptide or the salt thereof comprises an amino acid sequence that is at least 95% identical to a sequence selected from SEQ ID NOs: (1) X1-X12 of SEQ ID NOs:1-122, 159- 163, and 165-171, (2) X1-X10 of SEQ ID NOs:123-149 and 164, (3) X1-X8 of SEQ ID NOs:150-157, and (4) X1-X7 of SEQ ID No: 158. In some embodiments, the peptide or the salt thereof comprises an amino acid sequence that is at least 90% identical to a sequence selected from SEQ ID NOs: (1) X1-X12 of SEQ ID NOs:1-122, 159-163, and 165-171, (2) X1-X10 of SEQ ID NOs:123-149 and 164, (3) X1-X8 of SEQ ID NOs:150-157, and (4) X1-X7 of SEQ ID No: 158. In some embodiments, the peptide or the salt thereof comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, or 98% identical to a sequence selected from SEQ ID NOs: (1) X1-X12 of SEQ ID NOs:1-122, 159-163, and 165-171, (2) X1- X10 of SEQ ID NOs:123-149 and 164, (3) X1-X8 of SEQ ID NOs:150-157, and (4) X1-X7 of SEQ ID No: 158. In some embodiments, the peptide or the salt thereof consists of an amino acid sequence selected from SEQ ID NOs: (1) X1-X12 of SEQ ID NOs:1-122, 159-163, and 165-171, (2) X1-X10 of SEQ ID NOs:123-149 and 164, (3) X1-X8 of SEQ ID NOs:150-157, and (4) X1-X7 of SEQ ID No: 158. In some embodiments, the peptide or the salt thereof comprises an amino acid sequence that has at most 1, 2, 3, 4, or 5 amino acid residues that are different compared to a sequence selected from SEQ ID NOs: (1) X1-X12 of SEQ ID NOs:1-122, 159-163, and 165-171, (2) X1-X10 of SEQ ID NOs:123-149 and 164, (3) X1-X8 of SEQ ID NOs:150-157, and (4) X1-X7 of SEQ ID No: 158. In some embodiments, the peptide or the salt thereof comprises an amino acid sequence that has at most 1, 2, 3, 4, or 5 additions, deletions and / or substitutions (including conservative substitutions) to a sequence selected from SEQ ID NOs: (1) X1-X12 of SEQ ID NOs:1-122, 159-163, and 165-171, (2) X1-X10 of SEQ ID NOs:123-149 and 164, (3) X1-X8 of SEQ ID NOs:150-157, and (4) X1-X7 of SEQ ID No: 158. In some embodiments, the peptide or the salt thereof comprises an amino acid sequence that has at most 1 addition, deletion, or substitutions (including conservative substitutions) to a sequence selected from SEQ ID NOs: (1) X1- X12 of SEQ ID NOs:1-122, 159-163, and 165-171, (2) X1-X10 of SEQ ID NOs:123-149 and 164, (3) X1-X8 of SEQ ID NOs:150-157, and (4) X1-X7 of SEQ ID No: 158. In some embodiments, the peptide is not SEQ ID NO: 1. In some embodiments, a radiopharmaceutical conjugate described herein comprises a peptide of SEQ ID Nos: 1-275 or 278-449. In some embodiments, the radiopharmaceutical conjugate is not SEQ ID NO: 282.

[0279] Exemplary peptides of the present disclosure include the peptides described in Table 1. In some embodiments, the peptides of Table 1 have a -C(=O)-halogen group attached to the N-terminus. In some embodiments, the peptides of Table 1 have a -C(=O)-CH2-halogen group attached to the N-terminus. In some embodiments, the peptides of Table 1 have a -C(=O)-halogen group attached at residue position 1 (e.g., X1). In some embodiments, the peptides of Table 1 have a -C(=O)-CH2-halogen group attached at residue position 1 (e.g., X1). In some embodiments, the peptides of Table 1 have a -C(=O)-Cl group attached to the N-terminus. In some embodiments, the peptides of Table 1 have a -C(=O)-CH2-Cl group attached to the N-terminus. In some embodiments, the peptides of Table 1 have a -C(=O)-Cl group attached at residue position 1 (e.g., X1). In some embodiments, the peptides of Table 1 have a -C(=O)- CH2-Cl group attached at residue position 1 (e.g., X1). In some embodiments, the peptides of Table 1 have a -C(=O)-Br group attached at residue position 1 (e.g., X1). In some embodiments, the peptides of Table 1 have a -C(=O)-CH2-Br group attached at residue position 1 (e.g., X1).

[0280] In some embodiments, the radiopharmaceutical conjugates of the disclosure have a -C(=O)- halogen group attached to the N-terminus. In some embodiments, the radiopharmaceutical conjugates of the disclosure have a -C(=O)-CH2-halogen group attached to the N-terminus. In some embodiments, the radiopharmaceutical conjugates of the disclosure have a -C(=O)-halogen group attached at residue position 1 (e.g., X1). In some embodiments, the radiopharmaceutical conjugates of the disclosure have a - C(=O)-CH2-halogen group attached at residue position 1 (e.g., X1). In some embodiments, the radiopharmaceutical conjugates of the disclosure have a -C(=O)-Cl group attached to the N-terminus. In some embodiments, the radiopharmaceutical conjugates of the disclosure have a -C(=O)-CH2-Cl group attached to the N-terminus. In some embodiments, the radiopharmaceutical conjugates of the disclosure have a -C(=O)-Cl group attached at residue position 1 (e.g., X1). In some embodiments, the radiopharmaceutical conjugates of the disclosure have a -C(=O)-CH2-Cl group attached at residue position 1 (e.g., X1). In some embodiments, the radiopharmaceutical conjugates of the disclosure have a - C(=O)-Br group attached at residue position 1 (e.g., X1). In some embodiments, the radiopharmaceutical conjugates of the disclosure have a -C(=O)-CH2-Br group attached at residue position 1 (e.g., X1). In some embodiments, the peptides in the radiopharmaceutical conjugates of the disclosure are monocyclic.

[0281] In some embodiments, the peptides of the radiopharmaceutical conjugates described herein are monocyclic peptides, wherein the -C(=O)-Cl at residue position 1 (e.g., X1) forms a bond with the cysteine at residue position 12 (e.g., X12). In some embodiments, the peptides of the radiopharmaceutical conjugates described herein are monocyclic peptides, wherein the -C(=O)-CH2-Cl at residue position 1 (e.g., X1) forms a bond with the cysteine at residue position 12 (e.g., X12). In some embodiments, the peptides in the radiopharmaceutical conjugates described herein are monocyclic peptides with 12 amino acid residues forming the ring.

[0282] Exemplary peptides of the present disclosure include the peptides described in Table 1. In some embodiments, the peptides of Table 1 have an -C(=O)-halogen group attached to the N-terminus. In some embodiments, the peptides of Table 1 have an -C(=O)-halogen group attached at residue position 1 (e.g., X1). In some embodiments, the peptides of Table 1 have an -C(=O)-Cl group attached to the N- terminus. In some embodiments, the peptides of Table 1 have an -C(=O)-Cl group attached at residue position 1 (e.g., X1). In some embodiments, the peptides of Table 1 have an -C(=O)-Br group attached at residue position 1 (e.g., X1).

[0283] In some embodiments, a herein described conjugate is selected from conjugates described in Table 2A-Lu, Table 2A-Lu177 or Table 2A-Ac255. In some embodiments, a herein described conjugate is selected from conjugates described in Table 2B, Table 2B-Lu, Table 2B-Lu177 or Table 2B-Ac255. In some embodiments, a herein described conjugate is selected from conjugates described in Table 2C.

[0284] In some embodiments, provided herein are conjugates having the same peptide sequence and linker as the conjugates described in Table 2A-Lu, Table 2A-Lu177, Table 2A-Ac255, Table 2B, Table 2B-Lu, Table 2B-Lu177, Table 2B-Ac255, or Table 2C, except that the ring closing linkage between the amino acid residue of position 1 and the cysteine (e.g., at position 10 or 12) are covalently bound by a different group. For example, the amino acid residue of position 1 can comprise a group selected from maleimides, halides, disulfides, electron-deficient alkynes, thioesters, and alkenes, which forms a covalent bond with the cysteine.

[0285] In some embodiments, the peptides of conjugates of Table 2A-Lu, Table 2A-Lu177, and Table 2A-Ac255 are monocyclic peptides, wherein the -C(=O)-Cl at residue position 1 forms a bond with the cysteine at residue position 12. In some embodiments, the -C(=O)-CH2-Cl at residue position 1 forms a bond with the cysteine at residue position 12. In some embodiments, the peptides in the conjugates of Table 2A-Lu, Table 2A-Lu177, and Table 2A-Ac255are monocyclic peptides with 12 amino acid residues forming the ring. In some embodiments, the peptides of conjugates of Table 2B, Table 2B-Lu, Table 2B-Lu177, and Table 2B-Ac255 are monocyclic peptides, wherein the -C(=O)-Cl at residue position 1 forms a bond with the cysteine at residue position 10. In some embodiments, the -C(=O)-CH2- Cl at residue position 1 forms a bond with the cysteine at residue position 10. In some embodiments, the peptides in the conjugates of Table 2B, Table 2B-Lu, Table 2B-Lu177, and Table 2B-Ac255 are monocyclic peptides with 10 amino acid residues forming the ring.

[0286] In one aspect, described herein is a peptide that has avidity for ephrin type-A receptor 2 (EphA2), wherein the peptide competes for binding to human EphA2 with a peptide that has an amino acid sequence including deletion, substitution, and / or addition of one or several amino acids in the amino acid of SEQ ID NO:1: da-MeF-N-L-Hgl-MeF-W1Me-V-W1Me-T-E-C (SEQ ID NO:1) or a pharmaceutically acceptable salt thereof .

[0287] In one aspect, described herein is a peptide that has avidity for ephrin type-A receptor 2 (EphA2), wherein the peptide competes for binding to human EphA2 with a peptide that has a structure of Formula (I) as described herein (e.g., Formula (I-1) and Formula (I-2), or a pharmaceutically acceptable salt thereof.

[0288] In some embodiments, the peptide competes for binding to human EphA2 at one or more amino acid residues selected from Asp53, Met55, Asn57, Met59, Met66, Thr101, Arg103, Phe156, Glu157, Arg159, Val161, Val189, and Ala190. In some embodiments, the peptide competes for binding to human EphA2 at one or more amino acid residues selected from Asp53, Phe156, and Glu157. In some embodiments, the peptide competes for binding to human EphA2 at Asp53, Glu157, or both.

[0289] The structures of exemplary unnatural amino acids that are present in Table 1 can be found in Table 3.

[0290] As described in Tables 1, 2A, 2B, 2C, or other tables, abbreviations have the following meanings:

[0291] Lower case d means D-amino acids, e.g., dF refers to d-phenylalanine;

[0292] Me refers to a methyl group, e.g., MeG represents N-Methyl-Glycine;

[0293] Ala or A refer to alanine;

[0294] Arg or R refer to arginine;

[0295] Asn or N refer to asparagine;

[0296] Asp or D refer to aspartic acid;

[0297] Cys or C refer to cysteine;

[0298] Gln or Q refer to glutamine;

[0299] Gly or G refer to glycine;

[0300] His or H refer to histidine;

[0301] Ile or I refer to isoleucine;

[0302] Leu or L refer to leucine;

[0303] Lys or K refer to lysine;

[0304] Met or M refer to methionine;

[0305] Phe or F refer to phenylalanine;

[0306] Pro or P refer to proline;

[0307] Ser or S refer to serine;

[0308] Thr or T refer to threonine;

[0309] Trp or W refer to tryptophan;

[0310] Tyr or Y refer to tyrosine;

[0311] Val or V refer to valine;

[0312] Ahp refers to 2-aminoheptanoic acid;

[0313] Nal1 refers to 1-naphthylalanine;

[0314] Chg refers to cyclohexylglycine;

[0315] F3C refers to 3-chlorophenylalanine;

[0316] mBph refers to 3-phenylphenylalanine;

[0317] Cba refers to cyclobutylalanine;

[0318] Hph refers to homophenylalanine;

[0319] W6C refers to 6-chlorotryptaphan;

[0320] Har refers to homoarginine (i.e., hArg).

[0004] Table 1. Exemplary peptides sequences with avidity to EphA2 “Term” refers to the functional group at the C-terminus.

[0005]

[0006]

[0007]

[0008]

[0009]

[0010]

[0011]

[0012]

[0013] able 2A-Lu. Exemplary conjugates of the present disclosure containing a chelated cold Lutetium (Lu-175) (12mer cyclic peptides). “Term” refers to the functional group at the C-terminus.

[0014]

[0015]

[0016]

[0017]

[0018]

[0019]

[0020]

[0021] able 2A-Lul77. Exemplary conjugates of the present disclosure containing a chelated Lutetium-177 (12mer cyclic peptides).

[0022]

[0321] As an example, PDC_EphA2-00001418-C406 of Table 2A-Lul77 has the same structure as PDC_EphA2-00001418-C306 of Table 2A-Lu, except that ul77 is present in PDC_EphA2-00001418-C406 and Lul75 is present in PDC_EphA2-00001418-C306.

[0023]

[0024]

[0025] able 2A-Ac225. Exemplary conjugates of the present disclosure containing a chelated Actinium-225 (12mer cyclic peptides).

[0026]

[0322] As an example, PDC_EphA2-00001418-C506of Table 2A-Ac255 has the same structure as PDC_EphA2-00001418-C306 of Table 2A-Lu, except that c225 is present in PDC_EphA2-00001418-C506 and Lul75 is present in PDC_EphA2-00001418-C306.

[0027]

[0028]

[0029]

[0030] Table 2B. Exemplary conjugates of the present disclosure (10-mer peptides)

[0031] “Term” refers to the functional group at the C-terminus.

[0032] Table 2B-Lu. Exemplary conjugates of the present disclosure (10-mer peptides) including chelated Lu Table 2B-Lu177. Exemplary conjugates of the present disclosure (10-mer peptides) including chelated lutetium-177 Table 2B-Ac225. Exemplary conjugates of the present disclosure (10-mer peptides) including chelated actinium-225

[0033] m2 2 2 2 2 2 2 reH H H H H H H TN-N-N-N-N-N-N- - - - A T- )AT- )AT- ) rug g gs.sg g g go 5 H H H H H luH H cnsiid mtret- 4 L L L L L L L nesCere3 N N N N N N N phtethat p yPy y y y3P P P PyPyPf u e3e3e3e3e3 3os or e ee2 M M M M M M M tgalgaujnnoi otccnu1adadadadadadadyrfalephtQ : EDIO 0 1 2 3 4 5 6 N7 7 7 7 7 7 7moetS 3 3 3 3 3 3 3xsEr.ef-2-C erA2-2-2-2-2-2h-A-A-A2e”p 6h3h4h-3 Ah-3 Ah-6 Ah-6lE 91 pE90 pE90 pE90 p90 p91 p91b mrae_7C0040_8C0 40_8C0 40_8C0 2E0_8C0 0E1_7C0 2E0_7C0 01TT“DP002CD0P002CD0P002CD0P002CD0P002CD0P002CD0P002C

[0034]

[0035]

[0036] Table 3. Structures of exemplary unnatural amino acids that can be incorporated into a peptide described herein

[0037]

[0323] Structures and names of exemplary unnatural amino acids of the present disclosure are further provided below: Alb (S)-2-amino-3-ureidopropanoic acid (CAS No.1483-07-4) da or Da (2R)‐2-aminopropanoic acid; dkCOpipzaa (2R)Ʈ2-amino-6-{[4-(carboxymethyl)piperazine-1-carbonyl]amino}hexanoic df3CON (2R)Ʈ2-amino-3-(3-carbamoylphenyl)propanoic acid (CAS No.1217637-40-5) MeF (2S)Ʈ2-(methylamino)-3-phenylpropanoic acid; Me3Py (2S)Ʈ2-(methylamino)-3-(pyridin-3-yl)propanoic acid (CAS No.1979173-93-7) Nal1 1-naphthylalanine; 4Py (2S)Ʈ2-amino-3-(pyridin-4-yl)propanoic acid (CAS No.169555-95-7) MeHph (2S)Ʈ2-(methylamino)-4-phenylbutanoic acid (CAS No.1065076-30-3); W7N (2S)Ʈ2-amino-3-{1H-pyrrolo[2,3-b]pyridin-3-yl}propanoic acid (CAS No.737007-45-3) QPh (2S)Ʈ2-amino-4-(phenylcarbamoyl)butanoic acid (CAS No.198134-12-2); MeF3CN (2S)Ʈ3-(3-cyanophenyl)-2-(methylamino)propanoic acid (CAS No.2642331-80-2) MeF3H (2S)Ʈ3-(3-hydroxyphenyl)-2-(methylamino)propanoic acid ; alT (2S,3S)Ʈ2-amino-3-hydroxybutanoic acid; W1Me (2S)Ʈ2-amino-3-(1-methyl-1H-indol-3-yl)propanoic acid (CAS No.1334509-86-2) tma (R)-2-amino-4,4-dimethylpentanoic acid ; Cbg (S) - 2-amino-2-cyclobutylacetic acid (CAS No.1391630-31-1) ; Chg (2S)Ʈ2-amino-2-cyclohexylacetic acid (CAS No.161321-36-4 Cba (2S)Ʈ2-amino-3-cyclobutylpropanoic acid (CAS No.478183-62-9) ; KCOpipzaa (2S)Ʈ2-amino-6-{[4-(carboxymethyl)piperazine-1-carbonyl]amino}hexanoic acid Hgn (2S)Ʈ2-amino-5-carbamoylpentanoic acid (CAS No.1263046-43-0) Nmm (2S)Ʈ2-amino-3-(methylcarbamoyl)propanoic acid (CAS No.149204-93-3) Ndm (2S)Ʈ2Ʈamino-3-(dimethylcarbamoyl)propanoic acid (CAS No.138585-02-1) Hcit or hCit (2S)Ʈ2-amino-6-(carbamoylamino)hexanoic acid (CAS No.201485-17-8) Qglucamine (2S)Ʈ2-amino-4-{[(2S,3R,4R,5R)-2,3,4,5,6 pentahydroxyhexyl] carbamoyl}butanoic acid mBph 3-phenylphenylalanine; MeE (2S)Ʈ2-(methylamino)pentanedioic acid; MeN (2S)Ʈ3-carbamoyl-2-(methylamino)propanoic acid; MeF4C (2S)Ʈ3-(4Ʈchlorophenyl)-2-(methylamino)propanoic acid (CAS No.1217779-77-5); Hph (2S)Ʈ2-amino-4-phenylbutanoic acid; W1Me7N (2S)Ʈ2Ʈamino-3-{1-methyl-1H-pyrrolo[2,3-b]pyridinƮ3Ʈyl}propanoic acid (CAS No.1813528-10-7) W1Me7Cl (2S)Ʈ2-amino-3-(7-chloro-1-methyl-1H-indol-3-yl)propanoic acid W6C 6-chlorotryptophan 3Py6NH2 (2S)‐2‐amino‐3‐(6‐aminopyridin‐3‐yl)propanoic acid Cit (2S)‐2‐amino‐5‐(carbamoylamino)pentanoic acid F23dMe (2S)‐2‐amino‐3‐(2,3‐dimethylphenyl)propanoic acid (CAS No.1270295-08-3) F3C 3-chlorophenylalanine; Har (2S)‐2-amino-6-carbamimidamidohexanoic acid (CAS No.776277-76-0); bA 3-aminopropanoic acid; KAc (2S)‐2-amino-6-acetamidohexanoic acid (CAS No.159766-56-0); dkAc (2R)‐2-amino-6-acetamidohexanoic acid (CAS No.320410-22-8) CdMe (R)-2-amino-3-mercapto-3-methylbutanoic acid; C3SMe (2R,3S)-2-amino-3-mercaptobutanoic acid; C3RMe (2R,3R)-2-amino-3-mercaptobutanoic acid; 4Py2NH2 (S)-2-amino-3-(2-aminopyridin-4-yl)propanoic acid; and Hgl (S)-2-aminohexanedioic acid.

[0324] In some embodiments, a peptide described herein has a binding affinity to a human EphA2 of at most 1, 5, 10, 50, 100, 200, 500, 1000, 5000 or 10,000 nM as determined by Kd in surface plasmon resonance (SPR) analysis. In some embodiments, a peptide described herein has a binding affinity to a human EphA2 of at most 100nM as determined by Kd in surface plasmon resonance (SPR) analysis. In some embodiments, a peptide described herein has a binding affinity to a human EphA2 of at most 1 nM as determined by Kd in surface plasmon resonance (SPR) analysis. In some embodiments, a peptide described herein has a binding affinity to a human EphA2 of at most 2 nM as determined by Kd in surface plasmon resonance (SPR) analysis. In some embodiments, a peptide described herein has a binding affinity to a human EphA2 of at most 5 nM as determined by Kd in surface plasmon resonance (SPR) analysis. In some embodiments, a peptide described herein has a binding affinity to a human EphA2 of at most 10 nM as determined by Kd in surface plasmon resonance (SPR) analysis.

[0325] In some embodiments, a conjugate described herein has a binding affinity to a human EphA2 of at most 1, 5, 10, 50, 100, 200, 500, 1000, 5000 or 10,000 nM as determined by Kd in surface plasmon resonance (SPR) analysis. In some embodiments, a conjugate described herein has a binding affinity to a human EphA2 of at most 100nM as determined by Kd in surface plasmon resonance (SPR) analysis. In some embodiments, a conjugate described herein has a binding affinity to a human EphA2 of at most 1 nM as determined by Kd in surface plasmon resonance (SPR) analysis. In some embodiments, a conjugate described herein has a binding affinity to a human EphA2 of at most 2 nM as determined by Kd in surface plasmon resonance (SPR) analysis. In some embodiments, a conjugate described herein has a binding affinity to a human EphA2 of at most 5 nM as determined by Kd in surface plasmon resonance (SPR) analysis. In some embodiments, a conjugate described herein has a binding affinity to a human EphA2 of at most 10 nM as determined by Kd in surface plasmon resonance (SPR) analysis. In one aspect, the binding affinity of the peptide or radiopharmaceutical conjugate of the present disclosure is at most 100 nM as determined by Kd in surface plasmon resonance (SPR) analysis. In some implementations, the Kd of the peptide or radiopharmaceutical conjugate of the present disclosure is 100 nM ore less, 50 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.9 nM or less, 0.5 nM or less, 0.4 nM or less, 0.3 nM or less, 0.2 nM or less, 0.1 nM or less, 0.09 nM or less, 0.08 nM or less, 0.07 nM or less, 0.06 nM or less, 0.05 nM or less, 0.04 nM or less, 0.03 nM or less, 0.02 nM or less, 0.01 nM or less.

[0326] The molecular weight of the described peptide can vary. In some embodiments, the peptide has a molecular weight of about 0.1 to about 25 kDa. In some embodiments, the peptide has a molecular weight of about 0.2 to about 20 kDa, about 0.5 to about 15 kDa, about 0.75 to about 10 kDa, about 0.5 to about 10 kDa, about 0.5 to about 5 kDa, about 0.5 to about 2.5 kDa, about 0.5 to about 2 kDa, about 0.5 to about 1.5 kDa, about 0.5 to about 1 kDa, about 1 to about 10 kDa, about 1 to about 5 kDa, about 1 to about 2.5 kDa, about 1 to about 2 kDa, about 1 to about 1.5 kDa, about 1 to about 1.25 kDa, or about 0.5 to about 1.25 kDa. In some embodiments, the peptide has a molecular weight of about 0.5 to 5 kDa. In some embodiments, the peptide has a molecular weight of about 0.5 to 2 kDa. In some embodiments, the peptide has a molecular weight of about 0.75 to 1.75 kDa. In some embodiments, the peptide has a molecular weight of about 1 to 1.5 kDa. In some embodiments, the peptide is monocyclic.

[0327] A peptide described herein can be cyclized (i.e., macrocyclized). Cyclization can be achieved less ideally via a single disulfide bond, or more ideally via a peptide bond, alkyl bond, alkenyl bond, ester bond, thioester bond, ether bond, thioether bond, phosphate ether bond, azo bond, C—S—C bond, C— N—C bond, C═N—C bond, C═N—O bond, amide bond, lactam bridge, carbamoyl bond, urea bond, thiourea bond, amine bond, thioamide bond, or the like, but not limited to them. In some embodiments, the peptide is a cyclic peptide that is cyclized by a peptide bond, alkyl bond, alkenyl bond, ester bond, thioester bond, ether bond, thioether bond, phosphate ether bond, azo bond, C—N—C bond, C═N—C bond, C═N—O bond, amide bond, lactam bridge, carbamoyl bond, urea bond, thiourea bond, amine bond, or thioamide bond. In some embodiments, the cyclic peptide is cyclized by a thioether bond. In some embodiments, the cyclic peptide is cyclized via an oxime cyclization reaction. A cyclization of a peptide sometimes stabilizes the peptide structure and thereby enhance affinity for a target. The cyclization can occur between the N- and C-terminus, or it can occur between a terminal amino acid and a non-terminal amino acid. In some embodiments, the cyclization occurs between two non-terminal amino acids. In some embodiments, the peptide is cyclized via oxime cyclization. In some embodiments, the peptide is cyclized between cysteine and haloacyl. In some embodiments, the peptide comprises a haloacetyl group (e.g., chloroacetyl or bromoacetyl) at the N-terminus. In some embodiments, the peptide comprises a haloacetyl group (e.g., chloroacetyl or bromoacetyl) at the C-terminus. In some embodiments, the peptide comprises a Cys at the C-terminus. In some embodiments, the peptide comprises a Cys at the N-terminus. In some embodiments, the cyclization occurs via a thioether bond between Cys and a haloacetyl group. In some embodiments, the cyclization occurs between the N- terminus and the C-terminus of the peptide.

[0328] As amino acids for macrocyclization, for example, an amino acid having the following functional group A and an amino acid having a corresponding functional group B can be used (see Table 4A). Either the functional group A or the functional group B may be placed on the N-terminal side. The amino acid having the functional group A and the amino acid having the functional group B can each be an N- terminal amino acid or C-terminal amino acid or a non-terminal amino acid. In some embodiments, an amino acid having the functional group A is placed at the N-terminus. In some embodiments, an amino acid having the functional group A is placed at the C-terminus. In some embodiments, an amino acid having the functional group A is placed at a non-terminal amino acid. In some embodiments, an amino acid having the functional group B is placed at the N-terminus. In some embodiments, an amino acid having the functional group B is placed at the C-terminus. In some embodiments, an amino acid having the functional group B is placed at a non-terminal amino acid. Table 4A. Functional groups for cyclization

[0038]

[0329] In some embodiments, as the amino acid (I-A), for example, a chloroacetylated amino acid can be used. Examples of the chloroacetylated amino acids include N-chloroacetyl-L-alanine, N- chloroacetyl-L-phenylalanine, N-chloroacetyl-L-tyrosine, N-chloroacetyl-L-tryptophan, N-3-(2- chloroacetamido)benzoyl-L-phenylalanine, N-3-(2-chloroacetamido)benzoyl-L-tyrosine, N-3-(2- chloroacetamido)benzoyl-L-tryptophan, β-N-chloroacetyl-L-diaminopropanoic acid, γ-N-chloroacetyl-L- diaminobutyric acid, σ-N-chloroacetyl-L-ornithine, ε-N-chloroacetyl-L-lysine, N-3- chloromethylbenzoyl-L-tyrosine, and N-3-chloromethylbenzoyl-L-tryptophane and D-amino acid derivatives corresponding thereto (for example, N-Chloroacetyl-D-alanine, N-Chloroacetyl-D- phenylalanine, N-Chloroacetyl-D-tyrosine, and N-Chloroacetyl-D-tryptophan).

[0330] Examples of the amino acid (I-B) include, but are not limited to, cysteine, homocysteine, mercaptonorvaline, mercaptonorleucine, 2-amino-7-mercaptoheptanoic acid, 2-amino-8- mercaptooctanoic acid, and amino acids obtained by protecting the SH group of these amino acids and then eliminating the protecting group, and D-amino acid derivatives corresponding thereto.

[0331] The cyclization method can be carried out, for example, according to the method described in Kawakami, T. et al., Nature Chemical Biology 5, 888-890 (2009); Yamagishi, Y. et al., ChemBioChem 10, 1469-1472 (2009); Sako, Y. et al., Journal of American Chemical Society 130, 7932-7934 (2008); or WO2008 / 117833.

[0332] In some embodiments, for example, the amino acid (II-A) is selected from propargylglycine, homopropargylglycine, 2-amino-6-heptynoic acid, 2-amino-7-octynoic acid, and 2-amino-8-nonynoic acid can be used. In addition, 4-pentynoylated or 5-hexynoylated amino acids can also be used. Examples of the 4-pentynoylated amino acids include N-(4-pentenoyl)-L-alanine, N-(4-pentenoyl)-L- phenylalanine, N-(4-pentenoyl)-L-tyrosine, N-(4-pentenoyl)-L-tryptophan, N-3-(4- pentynoylamido)benzoyl-L-phenylalanine, N-3-(4-pentynoylamido)benzoyl-L-tyrosine, N-3-(4- pentynoylamido)benzoyl-L-tryptophan, β-N-(4-pentenoyl)-L-diaminopropanoic acid, γ-N-(4-pentenoyl)- L-diaminobutyric acid, σ-N-(4-pentenoyl)-L-ornithine, and ε-N-(4-pentenoyl)-L-lysine, and D-amino acid derivatives corresponding thereto.

[0333] In some embodiments, for example, the amino acid (II-B) is selected from azidoalanine, 2- amino-4-azidobutanoic acid, azidoptonorvaline, azidonorleucine, 2-amino-7-azidoheptanoic acid, and 2- amino-8-azidooctanoic acid can be used. In addition, azidoacetylated or 3-azidopentanoylated amino acids can also be used. Examples of the azidoacetylated amino acids include N-azidoacetyl-L-alanine, N- azidoacetyl-L-phenylalanine, N-azidoacetyl-L-tyrosine, N-azidoacetyl-L-tryptophan, N-3-(4- pentynoylamido)benzoyl-L-phenylalanine, N-3-(4-pentynoylamido)benzoyl-L-tyrosine, N-3-(4- pentynoylamido)benzoyl-L-tryptophan, β-N-azidoacetyl-L-diaminopropanoic acid, γ-N-azidoacetyl-L- diaminobutyric acid, α-N-azidoacetyl-L-ornithine, and ε-N-azidoacetyl-L-lysine, and D-amino acid derivatives corresponding thereto.

[0334] The cyclization method can be performed, for example, according to the method described in Sako, Y. et al., Journal of American Chemical Society 130, 7932-7934 (2008) or WO2008 / 117833.

[0335] Examples of amino acid (III-A) include, but are not limited to, N-(4-aminomethyl-benzoyl)- phenylalanine (AMBF) and 4-3-aminomethyltyrosine.

[0336] Examples of the amino acid (III-B) include, but are not limited to, 5-hydroxytryptophan (WoH). The cyclization method can be performed, for example, according to the method described in Yamagishi, Y. et al., ChemBioChem 10, 1469-1472 (2009) or WO2008 / 117833.

[0337] Examples of the amino acid (IV-A) include, but are not limited to, 2-amino-6-chloro-hexynoic acid, 2-amino-7-chloro-heptynoic acid, and 2-amino-8-chloro-octynoic acid.

[0338] Examples of the amino acid (IV-B) include, but are not limited to, cysteine, homocysteine, mercaptonorvaline, mercaptonorleucine, 2-amino-7-mercaptoheptanoic acid, and 2-amino-8- mercaptooctanoic acid, amino acids obtained by protecting the SH group of these amino acids and then eliminating the protecting group, and D-amino acid derivatives corresponding thereto. The cyclization method can be performed, for example, according to the method described in WO2012 / 074129.

[0339] Examples of the amino acid (V-A) include, but are not limited to, N-3-chloromethylbenzoyl-L- phenylalanine, N-3-chloromethylbenzoyl-L-tyrosine, and N-3-chloromethylbenzoyl-L-tryptophane.

[0340] Examples of the amino acid (V-B) include, but are not limited to, cysteine, homocysteine, mercaptonorvaline, mercaptonorleucine, 2-amino-7-mercaptoheptanoic acid, and 2-amino-8- mercaptooctanoic acid, and amino acids obtained by protecting the SH group of these amino acids and then eliminating the protecting group, and D-amino acid derivatives corresponding thereto.

[0341] The amino acids I-A to V-A and I-B to V-B can be introduced into the peptide in a known manner by chemical synthesis or translation and synthesis described herein. In some embodiments, the cyclization reaction comprises forming a thioether bond using an amino acid comprising a sulfanyl group, e.g., cysteine, homocysteine, mercaptonorvaline, mercaptovaline, mercaptonorleucine, 2-amino-7- mercaptoheptanoic acid, and 2-amino-8-mercaptooctanoic acid.

[0342] A peptide described herein can comprise one or more negatively charged amino acids and / or one or more positively charged amino acids. Positively charged amino acids include, for example, lysine, arginine, histidine, and amino acids that contain additional amine groups. Positively charged amino acids can comprise a heteroaryl substitution such as pyridine, imidazole, pyrazole, or triazole that has one or more ring nitrogen atoms. Negatively charged amino acids include, for example, amino acids that contain an additional carboxylic acid group such as glutamic acid or the like.

[0343] In some embodiments, a cyclic peptide of Formula (I), Formula (I-1), Formula (I-2), Formula (Ia), Formula (Ib), or Formula (Ic) has a net charge of -3 to +1. In some embodiments, the cyclic peptide has a net charge of -3. In some embodiments, the cyclic peptide has a net charge of -2. In some embodiments, the cyclic peptide has a net charge of -1. In some embodiments, the cyclic peptide has a net charge of 0. In some embodiments, the cyclic peptide has a net charge of +1. In some embodiments, a cyclic peptide of Formula (I), Formula (I-1), Formula (I-2), Formula (Ia), Formula (Ib), or Formula (Ic) has a net charge of at most -4. In some embodiments, the cyclic peptide has a net charge of -4. In some embodiments, a cyclic peptide of Formula (I), Formula (I-1), Formula (I-2), Formula (Ia), Formula (Ib), or Formula (Ic) has a net charge of at least +2. In some embodiments, the cyclic peptide has a net charge of +2. In some embodiments, the cyclic peptide has a net charge of +3. The net charge can be determined by aggregating the charge of each of the X1 to X12 amino acids (or each of the amino acid in the peptide). For example, aspartic acid (D) and glutamic acid (E) each has a charge of -1, lysine (K), arginine (R) and histidine (H) each has a charge of +1, and the rest of the canonical amino acids each has a charge of 0.

[0344] In some embodiments, a cyclic peptide of formula (I) has a net charge of -3 to +1. In some embodiments, the cyclic peptide has a net charge of -3. In some embodiments, the cyclic peptide has a net charge of -2. In some embodiments, the cyclic peptide has a net charge of -1. In some embodiments, the cyclic peptide has a net charge of 0. In some embodiments, the cyclic peptide has a net charge of +1. The net charge can be determined by aggregating the charge of each of the amino acids of the cyclic peptide.

[0345] In some embodiments, a cyclic peptide described herein (e.g., a cyclic peptide of Formula (I), Formula (I-1), Formula (I-2), Formula (Ia), Formula (Ib), or Formula (Ic)) is configured to bind to EphA2 with a prescribed affinity, for example, measured as Plasma Protein Albumin Binding (PPB) percentage. The % bound can be determined by HSA-HPLC method (measurement of drug protein binding by immobilized human serum albumin-HPLC). PPB can be determined in vitro by HPLC (e.g., Example B3) or by other suitable means known in the art. In some embodiments, 1% to 99% of the cyclic peptide binds to Human Serum Albumin (HSA) in vitro as determined by HPLC, according to the conditions described in Example B3. In some embodiments, about 2% to about 99%, about 5% to about 99%, about 10% to about 99%, about 20% to about 99%, about 30% to about 99%, about 40% to about 99%, about 50% to about 99%, about 60% to about 99%, about 70% to about 99%, or about 80% to about 99% of the cyclic peptide binds to HSA in vitro as determined by HPLC. In some embodiments, about 10% to about 95% of the cyclic peptide binds to HSA in vitro (i.e., PPB of about 10% to about 95%). In some embodiments, about 20% to about 90% of the cyclic peptide binds to HSA in vitro. In some embodiments, about 20% to about 60% of the cyclic peptide binds to HSA in vitro. In some embodiments, about 40% to about 95% of the cyclic peptide binds to HSA in vitro. In some embodiments, about 40% to about 80% of the cyclic peptide binds to HSA in vitro. In some embodiments, about 40% to about 60% of the cyclic peptide binds to HSA in vitro. In some embodiments, about 60% to about 99% of the cyclic peptide binds to HSA in vitro. In some embodiments, about 60% to about 95% of the cyclic peptide binds to HSA in vitro. In some embodiments, about 60% to about 80% of the cyclic peptide binds to HSA in vitro. In some embodiments, about 60% to about 70% of the cyclic peptide binds to HSA in vitro. In some embodiments, about 40% to about 50% of the cyclic peptide binds to HSA in vitro. In some embodiments, about 50% to about 60% of the cyclic peptide binds to HSA in vitro. In some embodiments, about 70% to about 80% of the cyclic peptide binds to HSA in vitro. In some embodiments, about 80% to about 99% of the cyclic peptide binds to HSA in vitro. In some embodiments, about 80% to about 85% of the cyclic peptide binds to HSA in vitro.

[0346] In some embodiments, a conjugate described herein (e.g., a conjugate comprising a cyclic peptide of Formula (I), Formula (I-1), Formula (I-2), Formula (Ia), Formula (Ib), or Formula (Ic)) is configured to bind to a plasma protein with a prescribed affinity, for example, measured as Plasma Protein Albumin Binding (PPB) percentage. PPB can be determined in vitro by HPLC (e.g., Example B3) or by other suitable means known in the art. In some embodiments, 1% to 99% of the conjugate binds to Human Serum Albumin (HSA) in vitro as determined by HPLC, according to the conditions described in Example B3. In some embodiments, about 2% to about 99%, about 5% to about 99%, about 10% to about 99%, about 20% to about 99%, about 30% to about 99%, about 40% to about 99%, about 50% to about 99%, about 60% to about 99%, about 70% to about 99%, or about 80% to about 99% of the conjugate binds to HSA in vitro as determined by HPLC. In some embodiments, about 10% to about 95% of the conjugate binds to HSA in vitro (i.e., PPB of about 10% to about 95%). In some embodiments, about 20% to about 90% of the conjugate binds to HSA in vitro. In some embodiments, about 20% to about 60% of the conjugate binds to HSA in vitro. In some embodiments, about 40% to about 95% of the conjugate binds to HSA in vitro. In some embodiments, about 40% to about 80% of the conjugate binds to HSA in vitro. In some embodiments, about 40% to about 60% of the conjugate binds to HSA in vitro. In some embodiments, about 60% to about 99% of the conjugate binds to HSA in vitro. In some embodiments, about 60% to about 95% of the conjugate binds to HSA in vitro. In some embodiments, about 60% to about 80% of the conjugate binds to HSA in vitro. In some embodiments, about 60% to about 70% of the conjugate binds to HSA in vitro. In some embodiments, about 40% to about 50% of the conjugate binds to HSA in vitro. In some embodiments, about 50% to about 60% of the conjugate binds to HSA in vitro. In some embodiments, about 70% to about 80% of the conjugate binds to HSA in vitro. In some embodiments, about 80% to about 99% of the conjugate binds to HSA in vitro. In some embodiments, about 80% to about 85% of the conjugate binds to HSA in vitro.

[0347] In some embodiments, a cyclic peptide of Formula (I), Formula (I-1), Formula (I-2), Formula (Ia), Formula (Ib), or Formula (Ic) does not contain any S-S bond.

[0348] In some embodiments, a peptide of the present disclosure can be cyclized by forming a group as illustrated in Table 4B. Table 4B. Ring Closing Groups (m and n are independently 0 or an integer from 1 to 6.)

[0349] In some embodiments, m is 0 and n is 0. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6.

[0350] In some embodiments, a peptide of the present disclosure, e.g., peptides of Formulas (I), (Ia), (Ib) and (Ic), can be cyclized by reacting a first functional group with a second functional group, see Table 4C. In some embodiments, the first functional group is located at the N-terminus. In some embodiments, the first functional group is located at a non-terminal amino acid. In some embodiments, the second functional group is located at the C-terminus. In some embodiments, the second functional group is located at a non-terminal amino acid. Table 4C. Formation of Ring Closing Groups

[0351] In some embodiments, a conjugate comprising any one of peptide of Table 1 may further comprise amino acid residues at the N and / or C terminus of the peptide, which is not part of the cyclic structure. In some embodiments, the conjugate further comprises a metal chelator and optionally a linker. In some embodiments, the conjugate further comprises a radionuclide such as Ac-225 or Lutetium-177. In some embodiments, the conjugate further comprises a covalent radionuclide, and optionally a linker connecting the peptide and the covalent radionuclide. In some embodiments, the conjugate further comprises a covalent radionuclide such as18F,74As,76Br,123I,124I,125I,131I, or211At.

[0352] A peptide described herein can be a peptide mimetic. For example, the peptide can comprise non-peptide bonds and it can comprise one or more unnatural amino acids. Unless stated otherwise, each of the amino acid in a peptide described herein (except the natural amino acid glycine) can independently be in its D or L form. Both D and L forms are encompassed by the present disclosure.

[0353] In the present disclosure, the term amino acid embraces derivatives of amino acids. The derivatives include, for example, amino acids obtained by modifying a natural amino acid constituting a protein produced by cellular DNA-encoded biological matter. Examples of such non-natural amino acids include hydroxyproline and hydroxylysine, which are amino acids having a hydroxyl group introduced therein, and diaminopropionic acid, which is an amino acid having an amino group introduced therein.

[0354] A peptide described herein can comprise an N-substituted amino acid. In some embodiments, the N-substituted amino acid is a derivative of tryptophan, phenylalanine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, or valine. In some embodiments, the N-substitution is an N-alkyl, such as N- methyl and N-ethyl. In some embodiments, the N-substitution is N-methyl. In some embodiments, the N- substitution is an N-aryl, such as N-phenyl or N-biphenyl. In some embodiments, the N-substitution is an N-heteroaryl such as N-pyridyl. In some embodiments, the N-substituted amino acid is at the N-terminus of the peptide. In some embodiments, the N-substituted amino acid is a non-terminal amino acid.

[0355] In some embodiments, peptides described herein comprise one or more amino acids in Tables 5A to 5F. Table 5A. Exemplary Amino Acids at N or C-terminus Table 5B. Exemplary Amino Acids That Crosslink With A Peptide Table 5C. D-amino Acids Table 5D. Exemplary N-alkylamino Acids

[0356] Exemplary alkyl groups for Table 5D include methyl, ethyl, and propyl groups. Table 5E. Exemplary Peptoid Blocks Table 5F. Exemplary Unnatural Amino Acids

[0357] Amino acids used in the disclosed peptides can be substituted with similar amino acids. In some embodiments, an amino acid can be substituted with another amino acid with similar hydrophobicity. In some embodiments, an amino acid can be substituted with another amino acid with similar hydrophilicity. In some embodiments, an amino acid can be substituted with another amino acid with similar size. In some embodiments, an amino acid can be substituted with another amino acid with similar charge. In some embodiment, an amino acid can be substituted with another amino acid with a similar functional group. In some embodiments, an amino acid can be substituted with another amino acid with the same functional group.

[0358] In some embodiments, an amino acid described herein can be replaced with a variant thereof. Examples of an amino acid substitution or variant include derivatives having an amine, amide, ester, or carboxyl group as the C-terminus and / or N-terminus thereof. Additional examples of amino acid / peptide variants include those obtained by modification such as phosphorylation, alkylation (e.g., methylation), acetylation, adenylylation, ADP-ribosylation, or glycosylation and fused protein obtained by fusion with another peptide or protein. These variants can be prepared by those skilled in the art in a known manner or a method based thereon. An amino acid variant further encompasses the amino acids that have the same functional groups but with different lengths of the side chain (e.g., LysAc vs. OrnAc and cysteine vs. homocysteine). An amino acid variant further encompasses amino acids with a different aromatic moiety compared to the canonical amino acid (e.g., the indole in tryptophan vs the 7-azaindole in 7- AzaTrp; the phenyl in phenylalanine vs the pyridine in 4Py). An amino acid variant further encompasses amino acids with optional substituents, i.e., optionally substituted amino acid. In some embodiments, the optionally substituted amino acid is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano, amino, amide, nitro, ureido, C1-C6alkyl, C1-C6alkoxy, C6-C10aryl, C3-C6 cycloalkyl, 6-10 membered heterocycloalkyl, and 6-10 membered heteroaryl. In some embodiments, the optionally substituted amino acid is optionally substituted with one or more substituents independently selected from halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, oxo, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), - S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some embodiments, substituents may include any substituents described herein, for example: halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazino (=N-NH2), SF5, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N (Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2), and -Rb-S(O)tN(Ra)2(where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, and heterocycle, any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazine (=N- NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2); wherein each Rais independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, and heterocycle, wherein each Ra, valence permitting, may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazine (=N- NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)O Ra, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2); and wherein each Rbis independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each Rcis a straight or branched alkylene, alkenylene or alkynylene chain.

[0359] In some embodiments, a variant of an amino acid is selected from amino acids having one, two or three substituents based on the amino acid, and wherein the substituents are independently selected from halogen, -CN, -NH2, -NH(C1-C3alkyl), -N(C1-C3alkyl)2, oxo, -OH, -CO2H, -CO2-C1-C3alkyl, - C(=O)NH2, -C(=O)NH(C1-C3alkyl), -C(=O)N(C1-C3alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C3alkyl), - S(=O)2N(C1-C3alkyl)2, C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, C6-C10aryl, C3-C6cycloalkyl, 6-10 membered heterocycloalkyl, and 6-10 membered heteroaryl.

[0360] In some embodiments, the variant is selected from amino acids having one or two substituents based on the amino acid, and wherein the substituents are independently selected from halogen, -CN, - NH2, -NH(C1-C3alkyl), -N(C1-C3alkyl)2, oxo, -OH, -CO2H, -CO2-C1-C3alkyl, -C(=O)NH2, -C(=O)NH(C1- C3alkyl), -C(=O)N(C1-C3alkyl)2, and C1-C6alkyl. In some embodiments, the variant is selected from amino acids having one or two substituents based on the amino acid, and wherein the substituents are independently selected from halogen, -CN, -NH2, -NH(C1-C3alkyl), -N(C1-C3alkyl)2, and C1-C6alkyl. In some embodiments, the variant is selected from amino acids having one or two substituents based on the amino acid, and wherein the substituents are independently selected from C1-C6alkyl.

[0361] In some embodiments, a variant of an amino acid is selected from amino acids that have the similar hydrophilicity or hydrophobicity compared to the amino acid. Thus, in some embodiments, a positively charged amino acid can be a variant of another positively charged amino acid. In some embodiments, a negatively charged amino acid can be a variant of another negatively charged amino acid. In some embodiments, a zwitterionic amino acid can be a variant of another zwitterionic amino acid.

[0362] In some embodiments, a hydrophilic amino acid has an electrically charged side chain. In some embodiments, a hydrophilic amino acid has a positive charge. In some embodiments, a hydrophilic amino acid has a negative charge. In some embodiments, a hydrophilic amino acid is zwitterionic (e.g., KCOpipzaa). In some embodiments, a hydrophilic amino acid comprises a -OH, COOH, -NH- or NH2moiety. In some embodiments, a hydrophilic amino acid comprises -OH, -C(O)OH, -NHC(=NH)NH2, - NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3.In some embodiments, a hydrophilic amino acid comprises a side chain of C1-C6hydroxyalkyl, C1-C6aminoalkyl, -C0-6alkylene-NH-C(=NH)-NH2, -C0-6alkylene-CO- NH2, -C0-6alkylene-COOH, or -NH-CO-C1-6alkyl.

[0363] In some embodiments, a hydrophobic amino acid is not charged. In some embodiments, a hydrophobic amino acid contains at least 2 contiguous carbon atoms. In some embodiments, a hydrophobic amino acid comprises at least 3 contiguous carbon atoms, either linear or branched. In some embodiments, a hydrophobic amino acid comprises at least 4 contiguous carbon atoms, either linear or branched. In some embodiments, a hydrophobic amino acid comprises at least 5 contiguous carbon atoms, either linear or branched. In some embodiments, a hydrophobic amino acid comprises an ethylene moiety in the side chain. In some embodiments, a hydrophobic amino acid comprises a propylene moiety in the side chain. In some embodiments, a hydrophobic amino acid comprises a butylene moiety in the side chain. In some embodiments, a hydrophobic amino acid comprises phenyl moiety. In some embodiments, a hydrophobic amino acid comprises a heteroaryl moiety. In some embodiments, a hydrophobic amino acid is Trp, Tyr, Phe, or derivatives thereof.

[0364] In some embodiments, a variant of an amino acid is selected from amino acids that have the same functional group as the amino acid, and wherein the variant has a different length of a side chain compared to the amino acid. In some embodiments, a variant of an amino acid is selected from amino acids that have the same functional group as the amino acid, and wherein the variant has a different carbon chain length of a side chain compared to the amino acid (e.g., leucine vs. (S)-2-amino-5- methylhexanoic acid, or 2-(methylamino)pentanedioic acid vs.2-(methylamino)hexanedioic acid). In some embodiments, a variant of an amino acid is selected from amino acids that have the same charge compared to the amino acid. In some embodiments, a variant of an amino acid is selected from amino acids that have the same polarity compared to the amino acid. In some embodiments, an amino acid comprising an aromatic group can be a variant of another amino acid having an aromatic group. In some embodiments, an amino acid comprising a phenyl can be a variant of another amino acid having a phenyl. In some embodiments, an amino acid comprising a heteroaryl can be a variant of another amino acid having a heteroaryl. In some embodiments, an amino acid comprising a heteroaryl can be a variant of another amino acid having a phenyl group. Amino acids having an aromatic group include, but are not limited to, F, W, Me3Py, MeF, MeF3H, MeFCN, MeF4F, MeF3F, MeFCON, F23dMe, df3CON, W1Me, W1Me7Cl, W1Me7N, W1Et, 7-AzaTrp, W1Me7Br, W1Me7Ome, W1Me6O7Cl, d4PyCON, W7Me, dDab-NH2-Ph3-SO2F, dDap-NH2-Ph3-SO2F, dDap-NH2-Ph4-SO2F, MeF4C, 4Py, 3Py6NH2, 4Py2NH2, and Me4Py. Accordingly, a variant of an amino acid comprising a heteroaryl ring encompasses amino acids comprising a different heteroaryl. In some embodiments, F or a variant thereof encompasses amino acids where the phenyl ring is replaced with a heteroaryl (e.g., pyridine). In some embodiments, an amino acid comprising a cycloalkyl group can be a variant of another amino acid having a cycloalkyl group. In some embodiments, an amino acid comprising a heterocycloalkyl group can be a variant of another amino acid having a heterocycloalkyl group.

[0365] In some embodiments, a variant of an amino acid is selected from amino acids that have similar polarity and / or charge with the amino acid. For example, in some embodiments, a polar, uncharged amino acid can be a variant of another polar, uncharged amino acid (e.g., Hgn, Q, S, T, Qglucamine).

[0366] In some embodiments, a variant of an amino acid has the same number of hydrogen donor as the amino acid. In some embodiments, a variant of an amino acid has the same number of hydrogen acceptor as the amino acid.

[0367] In some embodiments, the variant has a molecular weight that does not vary for more than 14, 28, 30, 45 or 60 g / mol compared to the amino acid. In some embodiments, the variant has a molecular weight that does not vary for more than 14 g / mol compared to the amino acid. In some embodiments, the variant has a molecular weight that does not vary for more than 50 g / mol compared to the amino acid. In some embodiments, the variant has a molecular weight that does not vary for more than 28 g / mol compared to the amino acid.

[0368] An amino acid variant further encompasses amino acids wherein a functional group is substituted with another functional group having similar properties, e.g., a cysteine can be substituted with a homocysteine. In some embodiments, an aryl functional group can be substituted with an aryl or heteroaryl group. In some embodiments, a heteroaryl functional group can be substituted with an aryl or heteroaryl group. In some embodiments, an amino functional group can be substituted with a NH(alkyl) group.

[0369] As used herein, the expression “conservative amino acid substitution” refers to a substitution of functionally equivalent or similar amino acids. A conservative amino acid substitution in a peptide brings about a static change to the amino acid sequence of the peptide. For example, one or two or more amino acids having similar polarity act functionally equivalent to each other and bring about a static change in the amino acid sequence of the peptide. In general, a substitution within a certain group may be considered conservative regarding structure and function. However, as is clear to a person having ordinary skill in the art, the role played by a defined amino acid residue may be determined by its implication in the three-dimensional structure of the molecule containing the amino acid. For example, a cysteine residue in an oxidized-type (disulfide) form may have a lower polarity than that of a reduced- type (thiol) form. The long aliphatic part of the arginine side chain may constitute structurally and functionally important features. Furthermore, the side chain (tryptophan, tyrosine, phenylalanine) including an aromatic ring may contribute to ion-aromatic interaction or cation-pi interaction. In such a case, even if the amino acids having these side chains are substituted for amino acids belonging to the acidic or non-polar groups, they may be structurally and functionally conservative. There is a possibility that residues such as proline, glycine, cysteine (disulfide foam) have a direct effect on the three- dimensional structure of the main chain and often may not be substituted without structural distortion.

[0370] Conservative amino acid substitution, as shown below, includes specific substitution based on the similarity of side chains (for example, substitutions are described in Lehninger, Biochemistry, Revised 2nd Edition, published in 1975, pp.73 to 75: L. Lehninger, Biochemistry, 2nd edition, pp.73 to 75, Worth Publisher, New York (1975)), incorporated herein by reference, and typical substitution.

[0371] Hydrophobic amino acids include amino acids that exhibit hydrophobicity, including alanine (also referred to as “Ala” or simply “A”), glycine (also referred to as “Gly” or simply “G”), valine (also referred to as “Val” or simply “V”), leucine (also referred to as “Leu” or simply “L”), isoleucine (also referred to as “Ile” or simply “I”), proline (also referred to as “Pro” or simply “P”), phenylalanine (also referred to as “Phe” or simply “F”), tryptophan (also referred to as Trp” or simply “W”), tyrosine (also referred to as “Tyr” or simply “Y”), and methionine (also referred to as “Met” or simply “M”).

[0372] Exemplary hydrophobic amino acids may be further divided into the following groups: x Aliphatic amino acids: Amino acids having a fatty acid or hydrogen in the side chain, including e.g., Ala, Gly, Val, Ile, and Leu. x Aliphatic / branched-chain amino acids: Amino acids having a branched fatty acid in the side chain, including e.g., Val, Ile, and Leu. x Aromatic amino acids: Amino acids having an aromatic ring in the side chain, including e.g., Trp, Tyr, and Phe.

[0373] In some embodiments, a hydrophobic amino acid has 4 or more carbon atoms in a side chain (a linear, branched, or cyclic carbon side chain), e.g., Leu, Hcit, Cbg, Chg, or Cba, each of which is optionally N-methylated. In some embodiments, a hydrophobic amino acid has 4-5, 4-6 or 4-7 carbon atoms in a side chain.

[0374] Hydrophilic amino acids include amino acids that exhibit hydrophilicity, including e.g., serine (also referred to as “Ser” or simply “S”), threonine (also referred to as “Thr” or simply “T”), cysteine (also referred to as “Cys” or simply “C”), asparagine (also referred to as “Asn” or simply “N”), glutamine (also referred to as “Gln” or simply “Q”), aspartic acid (also referred to as “Asp” or simply “D”), glutamic acid (also referred to as “Glu” or simply “E”), Elysine (also referred to as “Lys” or simply “K”), arginine (also referred to as “Arg” or simply “R”), and histidine (also referred to as “His” or “H”).

[0375] Exemplary hydrophilic amino acids may be further divided into the following groups: x Acidic amino acids: Amino acids whose side chains exhibit acidity, including Asp and Glu. x Basic amino acids: Amino acids whose side chains exhibit basicity, including Lys, Arg, and His. x Neutral amino acids: Amino acids whose side chains exhibit neutrality, including Ser, Thr, Asn, Gln, and Cys.

[0376] Exemplary hydrophilic amino acids include, for example, N, Q, K, G, S, T, E, Aib, Hcit, Cit, Hgn, KCOpipzaa, Har, Nmm, Ndm, Ala, Hgl, 3Py6NH2, or a variant thereof (including D-amino acid such as da and variations such as Qglucamine, which has gulucamine composition added to the NH2terminus of its side chain).

[0377] In some embodiments, a peptide described herein comprises an amino acid that affects the direction of the main chain, e.g., Gly and Pro. In some embodiments, a peptide described herein comprises a sulfur-containing amino acid, e.g., Cys and Met. In some embodiments, a peptide described herein comprises an amino acid that comprises an aromatic ring, which can be optionally substituted. Amino acids comprising an aromatic ring include, e.g., F (Phe; phenylalanine), Y (Tyr: tyrosine), W (Trp; tryptophan).

[0378] In some embodiments, W or a variant thereof can be W, an amino acid having a heteroatom in the indole ring of W in the side chain, an amino acid in which the hydrogen of NH in the indole ring of W is substituted, or an amino acids having a substituent in the benzene ring of W, or the like.

[0379] In some embodiments, F or a variant thereof can be F (phenylalanine), an amino acid wherein (i) the phenyl ring of F is substituted with 1 or 2 substituents each independently selected from -OH, -CN, - C1-3alkyl, such as -CH3: (ii) a 6-membered heteroaryl ring optionally substituted by 1 or 2 substituents each independently selected from –OH, -CN, - C1-3alkyl (such as -CH3); or (iii-1) having a heteroatom in the phenyl ring of F in the side chain; (iii-2) a derivative amino acid of F in which a 6-membered heteroaryl ring in the side chain is substituted; or the like. In some aspect, F or a variant thereof is optionally N-methylated.

[0380] In some embodiments, W, Y or a variant thereof can be W, Y, an amino acid having either a 6- membered aryl or heteroaryl, or a 9- or 10-membered bi-cyclic aryl or heteroaryl linked to the alpha- carbon through a carbon (e.g., a methylene group). In some embodiments, the 6-, 9-, and 10-membered heteroaryl has one heteroatom (e.g., N), and wherein the 6-, 9-, and 10-membered aryl or heteroaryl is optionally substituted with 1 or 2 substituents independently selected from –methyl, -ethyl, -Cl, and -F. In certain embodiments, W or Y or a variant thereof is W1Me, W1Me7Cl, or F23dMe, Nal1, Nal2, W1Et, Nal21N, 3Bzf, 3Bzt, Nal15N, Nal14N, Nal24N, Nal28N, F23dC, or W1Me7N. In some embodiments, a variant of W is W1Me. In some embodiments, a variant of W is W1Me7Cl. In some embodiments, a variant of Y is F23dMe.

[0381] Examples of the amino acids include natural protein L-amino acids, unnatural amino acids, and chemically synthesized compounds having properties known in the art as characteristics of an amino acid. Examples of the unnatural amino acids include, but not limited to, α,α-disubstituted amino acids (such as α-methylalanine), N-alkyl-α-amino acids, D-amino acids, β-amino acids, and α-hydroxy acids, each having a backbone structure different from that of natural amino acids; amino acids (such as norleucine and homohistidine) having a side-chain structure different from that of natural amino acids; amino acids (such as “homo” amino acids, homophenylalanine, and homohistidine) having extra methylene in the side chain thereof; and amino acids (such as cysteic acid) obtained by substituting a carboxylic acid functional amino group in the side chain thereof by a sulfonic acid group.

[0382] In some embodiments, an amino acid described herein is N-alkylated. In some embodiments, an amino acid described herein is not N-alkylated (e.g., an amino acid with -H on the alpha-amino group). In certain embodiments, such amino acid is A, E, N, K, Qglucamine, KCOpipzaa, Q, Hse, Cit, Hcit, KAc, DapAc, OrnAc, T, alT, Aib, or 3Py6NH2, more preferably, V, Qglucamine, Cit, Hcit, K, or 3Py6NH2.

[0383] The peptides described herein can comprise one or more unnatural amino acids. Unnatural amino acids include, but are not limited to, (1) amino acids corresponding to an amino acid residue on a polypeptide subjected to modification after expression (ex. phosphorylated tyrosine, acetylated lysine, or farnesylated cysteine), (2) amino acids that cannot be used in expression on a ribosome but occur naturally, and (3) artificial amino acids that do not occur naturally (unnatural amino acids). Non-limiting examples of unnatural amino acids include: p-acetyl-L-phenylalanine, p-iodo-L-phenylalanine, p- methoxyphenylalanine, O-methyl-L-tyrosine, p-propargyloxyphenylalanine, p-propargyl-phenylalanine, L-3-(2-naphthyl)alanine, 3-methyl-phenylalanine, O-4-allyl-L-tyrosine, 4-propyl-L-tyrosine, tri-O-acetyl- GlcNAcp-serine, L-Dopa, fluorinated phenylalanine, isopropyl-L-phenylalanine, p-azido-L- phenylalanine, p-acyl-L-phenylalanine, p-benzoyl-L-phenylalanine, Boronophenylalanine, O- propargyltyrosine, L-phosphoserine, phosphonoserine, phosphonotyrosine, p-bromophenylalanine, selenocysteine, p-amino-L- phenylalanine, isopropyl-L-phenylalanine, and azido-lysine (AzK). In some embodiments, the unnatural amino acid is an unnatural analogue of a tyrosine amino acid; an unnatural analogue of a glutamine amino acid; an unnatural analogue of a phenylalanine amino acid; an unnatural analogue of an alanine amino acid; an unnatural analogue of a serine amino acid; an unnatural analogue of a threonine amino acid; an alkyl, aryl, acyl, azido, cyano, halo, hydrazine, hydrazide, hydroxyl, alkenyl, alkynl, ether, thiol, sulfonyl, seleno, ester, thioacid, borate, boronate, phospho, phosphono, phosphine, heterocyclic, enone, imine, aldehyde, hydroxylamine, keto, or amino substituted amino acid; or a combination thereof. In some embodiments, the unnatural amino acid is an amino acid with a photoactivatable cross-linker; a spin-labeled amino acid; a fluorescent amino acid; a metal binding amino acid; a metal-containing amino acid; a radioactive amino acid; a photocaged and / or photoisomerizable amino acid; a biotin or biotin-analogue containing amino acid; a keto containing amino acid; an amino acid comprising polyethylene glycol or polyether; a heavy atom substituted amino acid; a chemically cleavable or photocleavable amino acid; an amino acid with an elongated side chain; an amino acid containing a toxic group; a sugar substituted amino acid; a carbon-linked sugar-containing amino acid; a redox-active amino acid; an a-hydroxy containing acid; an amino thio acid; an α, α-disubstituted amino acid; a β-amino acid; a cyclic amino acid other than proline or histidine, or an aromatic amino acid other than phenylalanine, tyrosine or tryptophan.

[0384] Unnatural amino acids include, for example, N-alkyl amino acids in which a natural amino acid described above is N-alkylated, e.g., those modified with lower alkyl groups (for example, of C1 to C5, C1 to C3, and C1) in which the nitrogen forming a peptide bond is branched or not branched. Exemplary N-alkyl amino acids include, e.g., N-ethyl amino acid, N-butyl amino acid, and N-methyl amino acid. Also included are amino acids to which a functional group is further added to the side chain of a natural amino acid or substituted for another functional group (for example, an amino acid having a substitution or an addition in a part such as an arylene group, an alkylene group, or the like of the side chain; an amino acid wherein the arylene group or the alkyl group of the side chain has an increased C-number; an amino acid having a substitution in the aromatic ring of the side chain; a heterocyclic or condensed cyclic amino acid; or the like). Exemplary N-alkyl amino acids further include, e.g., N-alkyllysine and N- methyllysine. Exemplary N-alkyl amino acids further include, e.g., N-methyllysine in which an albumin binder is bound.

[0385] In a non-limiting manner, unnatural amino acids include, but are not limited to N-methyl amino acids, da, kCOpipzaa, dahp, df3CON, 4Py, W7N, QPh, alT, W1Me, Cbg, Chg, Cba, Hgl, Hgn, Nmm, Ndm, Hcit, Qglucamine, Hph, W1Me7N, W1Me7Cl, 3Py6NH2, Cit, F23dMe, Har, bA, Kac, dkAc, MeF, Me3Py, MeHph, MeF3CN, MeF3H, MeE, MeN, MeF4C, Nal1, Nal2, W1Et, Nal21N, 3Bzf, 3Bzt, al15N, Nal14N, Nal24N, Nal28N, F23dMe, F23dC, W1Me7N, W1Me7Cl, Hse, DapAc, OrnAc, Alb, and the like. Note that D-amino acids such as da may be classified as D-amino acids, but they may also be classified according to the properties of their side chains, and N-methyl amino acids may be classified as N-alkyl amino acids and may also be classified according to the property of the side chain .

[0386] In some embodiments, the unnatural amino acids incorporated into the peptides include one or more of: 1) a ketone functional group (as found in para or meta acetyl-phenylalanine) that can be specifically reacted with hydrazines, hydroxylamines and their derivatives (Addition of the keto functional group to the genetic code of Escherichia coli. Wang L, Zhang Z, Brock A, Schultz P G. Proc Natl Acad Sci USA.2003 Jan.7; 100(1):56-61; Bioorg Med Chem Lett.2006 Oct.15; 16(20):5356-9. Genetic introduction of a diketone-containing amino acid into proteins. Zeng H, Xie J, Schultz P G), 2) azides (as found in p-azido-phenylalanine) that can be reacted with alkynes via copper catalyzed “click chemistry” or strain promoted (3+2) cycloadditions to form the corresponding triazoles (Addition of p- azido-L-phenylalanine to the genetic code of Escherichia coli. Chin J W, Santoro S W, Martin A B, King D S, Wang L, Schultz P G. J Am Chem Soc.2002 Aug.7; 124(31):9026-7; Adding amino acids with novel reactivity to the genetic code of Saccharomyces cerevisiae. Deiters A, Cropp T A, Mukherji M, Chin J W, Anderson J C, Schultz P G. J Am Chem Soc.2003 Oct.1; 125(39):11782-3), or azides that can be reacted with aryl phosphines, via a Staudinger ligation (Selective Staudinger modification of proteins containing p-azidophenylalanine. Tsao M L, Tian F, Schultz P G. Chembiochem.2005 December; 6(12):2147-9), to form the corresponding amides, 3) alkynes that can be reacted with azides to form the corresponding triazole (In vivo incorporation of an alkyne into proteins in Escherichia coli. Deiters A, Schultz P G. Bioorg Med Chem Lett.2005 Mar.1; 15(5):1521-4), 4) boronic acids (boronates) than can be specifically reacted with compounds containing more than one appropriately spaced hydroxyl group or undergo palladium mediated coupling with halogenated compounds (Angew Chem Int Ed Engl.2008; 47(43):8220-3. A genetically encoded boronate-containing amino acid., Brustad E, Bushey M L, Lee J W, Groff D, Liu W, Schultz P G), and 5) metal chelating amino acids, including those bearing bipyridyls, that can specifically co-ordinate a metal ion (Angew Chem Int Ed Engl.2007; 46(48):9239-42. A genetically encoded bidentate, metal-binding amino acid. Xie J, Liu W, Schultz P G).

[0387] The peptide of the present disclosure embraces various derivatives thereof. Examples of the derivatives include derivatives having an amide, ester, or carboxyl group as the C-terminus and / or N- terminus thereof. Additional examples of the derivatives of the peptide include those obtained by modification such as phosphorylation, methylation, acetylation, adenylylation, ADP-ribosylation, or glycosylation and fused protein obtained by fusion with another peptide or protein. These derivatives can be prepared by those skilled in the art in a known manner or a method based thereon.

[0388] In some embodiments, the peptide described herein comprises a basic amino acid. Examples of the basic amino acid include arginine, lysine, citrulline, ornithine, creatine, histidine, diaminobutanoic acid, and diaminopropionic acid.

[0389] In some embodiments, provided herein is a peptide having 90% or more sequence identity to any of sequences disclosed herein. In some embodiments, the sequence identity is at least 95% or 99%.

[0390] In some embodiments, the peptide is bicyclic or polycyclic. In some embodiments, a conjugate described herein comprises a bicyclic peptide. Exemplary bicyclic peptides include the bicyclic targeting peptides of BT5528, BT1718, and BT8009. Exemplary bicyclic peptides are described in US20180200378, US10441663, US8680022B2, US20180280525, and US20200215199, each of which is hereby incorporated by reference in its entirety. In some cases, when a peptide is cyclized, protease resistance is improved, metabolic stability is improved, and restrictions are also added to conformational change, so that rigidity is increased and membrane permeability and affinity for the target protein is improved.

[0391] In some embodiments, the peptide of the present disclosure has a cyclic structure in which a chloroacetylated amino acid and a cysteine residue present in the peptide are bound. In one aspect, the peptide has a cyclic structure in which an N-terminal amino acid and a cysteine residue present in the peptide are bound. In some embodiments, the peptide has a cyclic structure in which an N-terminal amino acid and the thirteenth cysteine residue present in the peptide are bound. In some embodiments, the peptide has a cyclic structure in which a chloroacetylated N-terminal amino acid and the 12th cysteine residue present in the peptide are bound. “Chloroacetylation” may be replaced with “haloacetylation” using another halogen. Furthermore, “acetylation” may be “acylation” using an acyl group other than an acetyl group.

[0392] In some embodiments, the peptide is a lasso peptide. Lasso peptides can be synthetic or naturally produced by bacteria, and they possess a distinctive threaded lariat fold that offers a 3D array of functionality for engaging biological targets. This lasso structure can enable beneficial properties such as affinity, stability and potent biological activities. Suitable lasso structure can be designed by algorithms. Exemplary lasso peptides are provided in Hegemann, J.D., et al., Lasso Peptides: An Intriguing Class of Bacterial Natural Products, Acc. Chem. Res., 2015, 48, 1909−1919; Tietz, J.I., et al., A new genome-mining tool redefines the lasso peptide biosynthetic landscape, Nature Chem Bio, 2017, 13, 470-478; DiCaprio, A.J., et al., Enzymatic Reconstitution and Biosynthetic Investigation of the Lasso Peptide Fusilassin, J. Am. Chem. Soc., 2019, 141, 290−297; Al Toma, R.S., et al., Site-Directed and Global Incorporation of Orthogonal and Isostructural Noncanonical Amino Acids into the Ribosomal Lasso Peptide Capistruin, ChemBioChem, 2015, 16, 503–509.

[0393] Further exemplary peptides include BMS-753493, Somatostatins, Octreotide, Octreotate, Lanreotide, Pasireotide, JR-11, L-779,976, BIM-23120, Satoreotide, depreotide, 18F- KYNDRLPLYISNP (SEQ ID NO: 274), CaIX-P1, and FAP-2286.

[0394] The peptide of the present disclosure embraces salts thereof. As the salts of the peptide, salts with physiologically acceptable base or acid are used. Examples include addition salts with an inorganic acid (such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, or phosphoric acid), addition salts with an organic acid (such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p- bromophenylsulfonic acid, carboxylic acid, succinic acid, citric acid, benzoic acid, or acetic acid), inorganic bases (such as ammonium hydroxide, alkali or alkaline earth metal hydroxide, carbonate, or bicarbonate), and an amino acid.

[0395] The peptide of the present disclosure can be prepared by a known peptide preparation method, for example, chemical synthesis method such as liquid-phase method, solid-phase method, or hybrid method using a liquid-phase method and a solid-phase method in combination; or gene recombination method.

[0396] In solid-phase method, an esterification reaction can be performed, for example, between the hydroxyl group of a hydroxyl-containing resin and the carboxyl group of a first amino acid (usually, C- terminal amino acid of an intended peptide) having an a-amino group protected with a protecting group. As the esterifying catalyst, a dehydration condensation agent such as 1-mesitylenesulfonyl-3-nitro-1,2,4- triazole (MSNT), dicyclohexylcarbodiimide (DCC), and diisopropylcarbodiimide (DIPCDI) may be used. Next, the protecting group of the a-amino group of the first amino acid is eliminated and at the same time, a second amino acid having all the functional groups protected except the main chain carboxyl group is added to activate the carboxyl group and bind the first and second amino acids to each other. Then, the a-amino group of the second amino acid is deprotected, a third amino acid having all the functional groups protected except the main chain carboxyl group is added, and the carboxyl gro...

Claims

CLAIMS What is claimed is:

1. A radiopharmaceutical conjugate comprising: (a) a cyclic peptide that has avidity for ephrin type-A receptor 2 (EphA2), wherein the peptide comprises an amino acid sequence of Formula (I), or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) wherein, X1 is an amino acid; X2 is an amino acid comprising an aromatic ring, an N-methylated amino acid thereof, or a variant thereof; X3 is a hydrophilic amino acid (e.g. N, Q, Cit, K or a variant thereof), glycine (G), Alanine (A) or a variant thereof (e.g., da, 2-Aminoisobutyric acid (Aib)); X4 is a hydrophobic amino acid (e.g., leucine (L)), a hydrophilic amino acid (e.g., citrulline (Cit)), or a variant thereof; X5 is a hydrophilic amino acid, or a variant thereof; X6 is a hydrophilic amino acid, an amino acid comprising an aromatic ring, or an N- methylated amino acid thereof; X7 is an amino acid comprising an aromatic ring (e.g., W, F, or a variant thereof); X8 is a hydrophobic amino acid, a hydrophilic amino acid, an N-methylated amino acid, or a variant thereof; X9 is an amino acid comprising an aromatic ring (e.g., W or a variant thereof); X10 is absent or a hydrophilic amino acid (e.g., Threonine (T) or a variant thereof); X11 is absent or a hydrophilic amino acid; and X12 is cysteine (C) or a variant thereof; and (b) (i) a metal chelator configured to bind with a radionuclide, wherein the metal chelator is conjugated to the peptide, or (ii) a radionuclide covalently bound to the cyclic peptide.

2. A radiopharmaceutical conjugate comprising: (a) a cyclic peptide that has avidity for ephrin type-A receptor 2 (EphA2), wherein the peptide comprises an amino acid sequence including deletion, substitution, and / or addition of one or several (e.g., 1-6) amino acids in the amino acid sequence of SEQ ID NO:1: da-MeF-N-L-Hgl-MeF-W1Me-V-W1Me-T-E-C (SEQ ID NO:1) or a pharmaceutically acceptable salt thereof, wherein the cyclic peptide consists of 10 or 12 amino acid residues; and (b) (i) a metal chelator configured to bind with a radionuclide, wherein the metal chelator is conjugated to the peptide, or (ii) a radionuclide covalently bound to the cyclic peptide.

3. The radiopharmaceutical conjugate of claim 1 or 2, comprising a metal chelator configured to bind with a radionuclide, wherein the metal chelator is conjugated to the peptide.

4. The radiopharmaceutical conjugate of claim 2, wherein 1-5 amino acids selected from the group consisting of 3rdN, 4thL, 6thMeF, 10thT and 11thE of SEQ ID NO: 1 is / are deleted, optionally without additional addition and / or substitution.

5. The radiopharmaceutical conjugate of claim 2 or 4, wherein one to several (e.g., 1, 2, 3, 4 or 5) amino acids are added.

6. The radiopharmaceutical conjugate of any one of claims 2, 4, or 5, wherein one or more amino acid residues selected from the 2ndMeF, 6thMeF, 8thV and 11thE are substituted.

7. The radiopharmaceutical conjugate of any one of claims 1 or 4 to 6, wherein 1-2 amino acids selected from the group consisting of 10th T and 11th E of SEQ ID NO:1 is / are deleted, optionally without additional addition and / or substitution.

8. The radiopharmaceutical conjugate of any one of claims 2 or 4 to 6, wherein the 8thV is substituted.

9. The radiopharmaceutical conjugate of any one of claims 2 or 4 to 6, wherein the 11thE is substituted.

10. The radiopharmaceutical conjugate of any one of claims 1 to 9, wherein the metal chelator is conjugated to the N-terminus of the peptide.

11. The radiopharmaceutical conjugate of any one of claims 1 to 10, further comprising a radionuclide bound to the metal chelator.

12. The radiopharmaceutical conjugate of claim 11, wherein the radionuclide is an alpha particle- emitting radionuclide.

13. The radiopharmaceutical conjugate of claim 12, wherein the alpha particle-emitting radionuclide is selected from Ac-225, Bi-213, Bi-209, Tb-149, Ra-223, Th-227, Fr-223, Gd-148, Th-229, Pb- 212, and Po-213.

14. The radiopharmaceutical conjugate of claim 12, wherein the alpha particle-emitting radionuclide is Ac-225.

15. The radiopharmaceutical conjugate of claim 11, wherein the radionuclide is a beta particle- emitting radionuclide (e.g., Cu-67, Lu-177, Y-90, Rh-105, Yb-175, Tm-167, Pm-153, Sm-153, or In-111).

16. The radiopharmaceutical conjugate of claim 15, wherein the beta particle-emitting radionuclide is Lu-177.

17. The radiopharmaceutical conjugate of claim 11, wherein the radionuclide is a positron-emitting radionuclide (e.g., Ga-68, Cu-62, Cu-64, Zr-89, or Tb-152).

18. The radiopharmaceutical conjugate of claim 17, wherein the positron-emitting radionuclide is Ga-68 or Cu-64.

19. The radiopharmaceutical conjugate of any one of claims 1 to 18, wherein the metal chelator comprises DOTA, DOTA-GA, pBn-DOTA, pBn-SCN-DOTA, NH2-DOTA, NH2-DOTA-GA,p-NCS-Bn-DOTA-GA, p-NH2-Bn-oxo-DO3A, p-SCN-Bn-oxo-DO3A, NOTA, NODA-GA, NH2-NODA-GA, p-NCS-Bn-NODA-GA, p-NH2-Bn-NOTA, p-SCN-Bn-NOTA, NCS-MP- NODA, NH2-MPAA-NODA, PCTA, p-NH2-Bn-PCTA, p-SCN-Bn-PCTA, p-SCN-Bn-HEHA, H2-MACROPA-NCS, H1-MACROPA, H2-MACROPA-NH2, H4-OCTAPA, tetra-(S, S, S, S)- Me-DOTA, tetra-(S, S, S, S)-Et-DOTA, tetra-(S, S, S, S)-iBu-DOTA, or maleimide-nBu-DOTA.

20. The radiopharmaceutical conjugate of claim 19, wherein the metal chelator has a structure of21. The radiopharmaceutical conjugate of claim 19, wherein the metal chelator has a structure of22. The radiopharmaceutical conjugate of any one of claims 1 to 21, further comprising a linker that covalently connects the peptide with the metal chelator.

23. The radiopharmaceutical conjugate of claim 22, wherein the conjugate has a structure of:wherein represents the linker.

24. The radiopharmaceutical conjugate of claim 22 or 23, wherein the linker is attached to the peptide via a non-terminal amino acid residue of the peptide.

25. The radiopharmaceutical conjugate of claim 24, wherein the linker is attached to the 5thamino acid residue or X5.

26. The radiopharmaceutical conjugate of claim 24, wherein the linker is attached to the 8thamino acid residue or X8.

27. The radiopharmaceutical conjugate of claim 24, wherein the linker is attached to the 11thamino acid residue or X11.

28. The radiopharmaceutical conjugate of any one of claims 24 to 27, wherein linker is attached to a lysine of the peptide.

29. The radiopharmaceutical conjugate of claim 22 or 23, wherein the linker is attached to the peptide via the N terminus of the peptide.

30. The radiopharmaceutical conjugate of claim 22 or 23, wherein the linker is attached to the peptide via the C terminus of the peptide.

31. The radiopharmaceutical conjugate of any one of claims 22 to 30, wherein the linker is a bond.

32. The radiopharmaceutical conjugate of any one of claims 22 to 30, wherein the linker comprises 3 to 30 intervening atoms between the metal chelator and the peptide.

33. The radiopharmaceutical conjugate of any one of claims 22 to 30, wherein the linker comprises 6 to 18 intervening atoms between the metal chelator and the peptide.

34. The radiopharmaceutical conjugate of claim 32 or 33, wherein the intervening atoms comprise 1 to 6 nitrogen and 0 to 4 oxygen.

35. The radiopharmaceutical conjugate of any one of claims 22 to 30 or 32 to 34, wherein the linker comprises one or more amino acid residues.

36. The radiopharmaceutical conjugate of claim 35, wherein the linker comprises an amino acid residue selected from a lysine residue, an alanine residue, a glycine residue, a d-phenylalanine and a phenylalanine residue.

37. The radiopharmaceutical conjugate of any one of claims 22 to 30 or 32 to 36, wherein the linker comprises one or more structures selected from AEEA, AEEP, AEEEP, and AEEEEP.

38. The radiopharmaceutical conjugate of any one of claims 22 to 30, wherein the linker has a structure of Formula (II-1)wherein each L is independently -O-, –NRL-, –N(RL)2-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, =CH-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRL-, - NRLC(=O)O-, -NRLC(=O)NRL-, -NRLC(=S)NRL-, -CRL=N-, -N=CRL, -NRLS(=O)2-, - S(=O)2NRL-, -C(=O)NRLS(=O)2-, -S(=O)2NRLC(=O)-, substituted or unsubstituted C3-C15cycloalkyl, substituted or unsubstituted C1-C12heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C30alkylene, substituted or unsubstituted C2-C30alkenylene, substituted or unsubstituted C2-C30alkynylene, substituted or unsubstituted C1-C30heteroalkylene, -(C1-C30alkylene)-O-, -O-(C1-C30alkylene)-, -(C1-C30alkylene)-NRL-, -NRL-(C1-C30alkylene)-, -(C1-C30alkylene)-N(RL)2-, or -N(RL)2-(C1-C30alkylene)-; and each RLis independently hydrogen, substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted C1-C4heteroalkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C5alkynyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C2-C7heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and n is 1 to 20.

39. The radiopharmaceutical conjugate of claim 38, wherein the linker comprises a structure of Formula (II-1a),wherein each of L1and L3is independently -O-, –NRL-, –N(RL)2-, -OP(=O)(ORL)O-, -S-, - S(=O)-, -S(=O)2-, -CH=CH-, =CH-, -C≡C-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, - C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRL-, -NRLC(=O)O-, -NRLC(=O)NRL-, -NRLS(=O)2-, - S(=O)2NRL-, -C(=O)NRLS(=O)2-, or -S(=O)2NRLC(=O)-; and L2is absent, substituted or unsubstituted C1-C30 alkylene, or substituted or unsubstituted C1-C30 heteroalkylene.

40. The radiopharmaceutical conjugate of claim 39, wherein L1is -NH-.

41. The radiopharmaceutical conjugate of claim 39 or 40, wherein L2is substituted or unsubstituted C1-C30alkylene, or substituted or unsubstituted C1-C30heteroalkylene.

42. The radiopharmaceutical conjugate of claim 39 or 40, wherein L2is substituted or unsubstituted C1-C18alkylene, or substituted or unsubstituted C1-C18heteroalkylene.

43. The radiopharmaceutical conjugate of any one of claims 39 to 42, wherein L2is optionally substituted with one or more substituents selected from -OH, -SH, oxo, amino, C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6haloalkyl, C1-C6aminoalkyl, -C(=O)ORL, -OC(=O)RL, -OC(=O)ORL, - C(=O)N(RL)2, -NRLC(=O)RL, -OC(=O)N(RL)2, and -NRLC(=O)ORL; and the C1-C6alkyl is further optionally substituted with one or more substituents chosen from -OH, -SH, oxo, amino, C6-C10aryl, 6- to 10- membered heteroaryl, -C(=O)ORL, -OC(=O)RL, -OC(=O)ORL, - C(=O)N(RL)2, -NRLC(=O)RL, -OC(=O)N(RL)2, and -NRLC(=O)ORL.

44. The radiopharmaceutical conjugate of any one of claims 39 to 43, wherein L3is -NH-.

45. The radiopharmaceutical conjugate of claim 39, wherein the linker has a structure of ,,, , , 46. The radiopharmaceutical conjugate of claim 39, wherein the linker has a structure of47. The radiopharmaceutical conjugate of any one of claims 1 to 46, wherein the peptide or the pharmaceutically accepted salt thereof has a cyclic structure, wherein the first amino acid (or X1) is covalently linked to the last amino acid (or X12).

48. The radiopharmaceutical conjugate of any one of claims 1 to 46, wherein the peptide or the pharmaceutically accepted salt thereof has a cyclic structure having an amino acid in the first residue X1 and a cysteine residue or a variant thereof, and wherein the amino acid in X1 and the cysteine residue or a variant thereof form a covalent bond.

49. The radiopharmaceutical conjugate of claim 48, wherein the peptide consists of an amino acid sequence selected from SEQ ID NOs: 1-122, 159-163, and 165-171, and the peptide has a cyclic structure having a cysteine residue or a variant thereof at 12th residue, and wherein the amino acid X1 and the cysteine residue or a variant thereof at 12th residue are connected via a covalent bond (e.g., by reacting a chloroacetyl group in the amino acid of X1 with the cysteine residue or a variant thereof).

50. The radiopharmaceutical conjugate of claim 48, wherein the peptide consists of an amino acid sequence selected from SEQ ID NOs: 123-149 and 164, and the peptide has a cyclic structure having a cysteine residue or a variant thereof at 10th residue, and wherein the amino acid X1 and the cysteine residue or a variant thereof at 10th residue are connected via a covalent bond.

51. The radiopharmaceutical conjugate of any one of claims 1 or 10 to 50, wherein X3 is a hydrophilic amino acid.

52. The radiopharmaceutical conjugate of claim 51, wherein X3 is an amino acid comprising an electrically charged side chain (e.g., K or a variant thereof), an amino acid comprising a polar uncharged side chain (e.g., Q, Cit, N, or a variant thereof), G, A, or variant thereof.

53. The radiopharmaceutical conjugate of any one of claims 1 or 10 to 52, wherein X4 is a hydrophobic amino acid.

54. The radiopharmaceutical conjugate of claim 53, wherein X4 is an amino acid comprising a hydrophobic side chain (e.g., L), an amino acid comprising a polar uncharged side chain (e.g., Cit or a variant thereof).

55. The radiopharmaceutical conjugate of any one of claims 1 or 10 to 54, wherein X5 is a hydrophilic amino acid.

56. The radiopharmaceutical conjugate of claim 55, wherein X5 is an amino acid comprising an electrically charged side chain (e.g., E, Hgl, D, or a variant thereof), or an amino acid comprising a polar uncharged side chain (e.g., Q, Cit, Hgn, N, or a variant thereof).

57. The radiopharmaceutical conjugate of any one of claims 1 or 10 to 56, wherein X6 is a hydrophilic amino acid.

58. The radiopharmaceutical conjugate of claim 57, wherein X6 is an amino acid comprising an electrically charged side chain (e.g., E, Hgl, D, or a variant thereof), or an amino acid comprising a polar uncharged side chain (e.g., Q, Cit, Hgn, N, or variant).

59. The radiopharmaceutical conjugate of any one of claims 1 or 10 to 58, wherein X11 is a hydrophilic amino acid.

60. The radiopharmaceutical conjugate of claim 59, wherein X11 is an amino acid comprising an electrically charged side chain (e.g., E, Hgl, D, R, hArg, K or a variant thereof), or an amino acid comprising a polar uncharged side chain (e.g., Q, Cit, Hgn, N, or a variant thereof).

61. The radiopharmaceutical conjugate of claim 59, wherein X11 is arginine (R), asparagine (N), aspartate (D), glutamine (Q), lysine (K), or an unnatural hydrophilic amino acid.

62. The radiopharmaceutical conjugate of any one of claims 1 to 61, wherein the peptide has an amino acid sequence of Formula (I), or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) wherein, X1 is an amino acid; X2 is F, or a variant thereof that replaces the unsubstituted phenyl ring of F with (i) a phenyl ring substituted by 1 or 2 substituents each independently selected from -OH, - CN, and -C1-3alkyl, or (ii) a 6-membered heteroaryl ring optionally substituted by 1 or 2 substituents each independently selected from –OH, -CN, and -C1-3alkyl, wherein the F or the variant thereof is optionally N-methylated; X3 is a hydrophilic amino acid (e.g. N, Q, Cit, K or a variant thereof), G, Aib, Hgn, Ala, or a variant thereof (e.g., da); X4 is a hydrophobic amino acid (e.g., an amino acid having 4 or more carbon atoms in a side chain comprising a linear, branched, or cyclic carbon chain), and wherein X4 is optionally N- methylated (e.g., Cit or a variant thereof); X5 is an amino acid (e.g., a hydrophilic amino acid; Dab, Dap, R, E or a variant thereof; or an amino acid with a functional side chain); X6 is an N-methylated amino acid thereof; X7 is a W, Y, or a variant thereof (e.g., an amino acid having either a 6-membered aryl or heteroaryl, or a 9- or 10-membered bi-cyclic aryl or heteroaryl linked to the alpha-carbon through a carbon (e.g., a methylene group), wherein the 6-, 9-, and 10-membered heteroaryl has one heteroatom (e.g., N), and wherein the 6-, 9-, and 10-membered aryl or heteroaryl is optionally substituted by 1 or 2 substituents independently selected from –CH3, -ethyl, -Cl, and -F); X8 is an amino acid with –H on the alpha-amino group;X9 is W or Y or a variant thereof; (e.g., W or a variant thereof); X10 is absent, or a polar amino acid (e.g., T or a variant thereof); X11 is absent, or an amino acid (e.g., a hydrophilic amino acid; Dab, Dap, R, E or a variant thereof; or an amino acid with a functional side chain); and X12 is C or a variant thereof.

63. The radiopharmaceutical conjugate of claim 62, wherein X8 is KCOpipzaa, N, Cit, Qglucamine, hCit, K, KAc, Aib, Alb, DapAc, OrnAc, A, T, alT, Norleucine, Norvaline, Hgl, E, Hgn, Q, I, or L.

64. The radiopharmaceutical conjugate of claim 62 or 63, wherein X11 is absent, arginine (R), asparagine (N), aspartate (D), glutamine (Q), lysine (K), or an unnatural hydrophilic amino acid.

65. The radiopharmaceutical conjugate of any one of claims 1 to 61, wherein the peptide has an amino acid sequence of Formula (Ia), or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X12 Formula (Ia) wherein, X1 is an amino acid (e.g., D-amino acid); X2 is an amino acid comprising an aromatic ring, an N-methylated amino acid thereof, or a variant thereof; X3 is a hydrophilic amino acid (e.g., N, Q, Cit, K or a variant thereof), G, A, or a variant thereof (e.g., da, Aib); X4 is a hydrophobic amino acid, or a hydrophilic amino acid (e.g., Cit or a variant thereof); X5 is a hydrophilic amino acid (e.g., Dab, Dap, R, E, Q, D, K), or a variant thereof; X6 is a hydrophilic amino acid, an amino acid comprising an aromatic ring (e.g., W, or F, or a variant thereof), or an N-methylated amino acid thereof; X7 is an amino acid comprising an aromatic ring (e.g., W, F, or a variant thereof); X8 is a hydrophobic amino acid, a hydrophilic amino acid, or an N-methylated amino acid; X9 is an amino acid comprising an aromatic ring (e.g., W, F or a variant thereof); and X12 is C or a variant thereof.

66. The radiopharmaceutical conjugate of any one of claims 1 to 61, wherein the peptide has an amino acid sequence according to Formula (I), or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) wherein, X1 is an amino acid (e.g., D-amino acid);X2 is an amino acid comprising an aromatic ring, an N-methylated amino acid thereof, or a variant thereof; X3 is a hydrophilic amino acid (e.g., N, Q, Cit, K or a variant thereof), G, A, or a variant thereof (e.g., da, Aib); X4 is a hydrophobic amino acid, or a hydrophilic amino acid (e.g., Cit or a variant thereof); X5 is a hydrophilic amino acid (e.g., Dab, Dap, R, E, Q, D, K), or a variant thereof; X6 is a hydrophilic amino acid, an amino acid comprising an aromatic ring (e.g., W, or F, or a variant thereof), or an N-methylated amino acid thereof; X7 is an amino acid comprising an aromatic ring (e.g., W, F, or a variant thereof); X8 is a hydrophobic amino acid, a hydrophilic amino acid, or an N-methylated amino acid; X9 is an amino acid comprising an aromatic ring (e.g., W, F or a variant thereof); X10 is a hydrophilic amino acid (e.g., T, S, N, Q, K, Cit, or a variant thereof); X11 is a hydrophilic amino acid; and X12 is C or a variant thereof.

67. The radiopharmaceutical conjugate of claim 66, wherein X8 is KCOpipzaa, N, Cit, Qglucamine, hCit, K, KAc, Aib, Alb, DapAc, OrnAc, A, T, alT, Norleucine, Norvaline, Hgl, E, Hgn, Q, I, or L.

68. The radiopharmaceutical conjugate of claim 66 or 67, wherein X11 is arginine (R), asparagine (N), aspartate (D), glutamine (Q), lysine (K), or an unnatural hydrophilic amino acid.

69. The radiopharmaceutical conjugate of any one of claims 1 to 61, wherein X1 is an amino acid (e.g., D-amino acid); X2 is F, Y, W, a variant thereof (e.g., Hgn), or an N-methylated amino acid thereof; X3 is N, Q, Cit, G, Aib, K, A, or a variant thereof; X4 is G, A, Cit, L, or a variant thereof (e.g., G substituted with straight or branched C1-5alkyl, G substituted with C3-7cycloalkyl, or A substituted with C3-7cycloalkyl); X5 is a hydrophilic L-amino acid, wherein the L-amino acid comprises a functional group selected from -NH2, -C(O)OH, -NHC(NH)NH2, -NHC(O)NH2, -C(O)NH2, and - NHC(O)CH3; X6 is a hydrophilic amino acid, F, Y, W, N-methylated amino acid thereof, or a variant thereof, wherein the hydrophilic amino acid comprises a functional group selected from - C(O)OH, -C(O)NH2, and -NHC(O)CH3; X7 is F, W, or a variant thereof; X8 is G substituted with one or two straight or branched C1-5alkyl, G substituted with C3-7cycloalkyl, A substituted with C3-7cycloalkyl, or a hydrophilic L-amino acid wherein the hydrophilic L-amino acid comprises -NH2, one or more -OH, -C(O)OH, -NHC(NH)NH2, - NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3; or the hydrophilic amino acid comprises a zwitterion;X9 is F, W, or a variant thereof; X10 is absent, Q, S, K, Cit, N, T, or a variant thereof (e.g., Q, S, K, Cit, N, or T optionally substituted with straight or branched C1-5alkyl) or an L- amino acid comprising - NHC(NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3; X11 is absent, E, Q, R, Cit, K, D, or N, or a variant thereof; and X12 is C or a variant thereof.

70. The radiopharmaceutical conjugate of claim 69, wherein X8 is KCOpipzaa, N, Cit, Qglucamine, hCit, K, KAc, Aib, Alb, DapAc, OrnAc, A, T, alT, Norleucine, Norvaline, Hgl, E, Hgn, Q, I, or L.

71. The radiopharmaceutical conjugate of claim 69 or 70, wherein X11 is absent, arginine (R), asparagine (N), aspartate (D), glutamine (Q), lysine (K), or an unnatural hydrophilic amino acid.

72. The radiopharmaceutical conjugate of any one of claims 1 or 10 to 71, wherein a variant of an amino acid is selected from amino acids having one, two or three substituents based on the amino acid, and wherein the substituents are independently selected from halogen, -CN, -NH2, -NH(C1- C3alkyl), -N(C1-C3alkyl)2, oxo, -OH, -CO2H, -CO2-C1-C3alkyl, -C(=O)NH2, -C(=O)NH(C1- C3alkyl), -C(=O)N(C1-C3alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C3alkyl), -S(=O)2N(C1-C3alkyl)2, C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, C6-C10aryl, C3-C6cycloalkyl, 6-10 membered heterocycloalkyl, and 6-10 membered heteroaryl.

73. The radiopharmaceutical conjugate of claim 72, wherein the variant is selected from amino acids having one or two substituents based on the amino acid, and wherein the substituents are independently selected from halogen, -CN, -NH2, -NH(C1-C3alkyl), -N(C1-C3alkyl)2, oxo, -OH, - CO2H, -CO2-C1-C3alkyl, -C(=O)NH2, -C(=O)NH(C1-C3alkyl), -C(=O)N(C1-C3alkyl)2, and C1-C6alkyl.

74. The radiopharmaceutical conjugate of any one of claims 1 or 10 to 71, wherein a variant of an amino acid is selected from amino acids that have the similar hydrophilicity or hydrophobicity compared to the amino acid.

75. The radiopharmaceutical conjugate of any one of claims 1 or 10 to 71, wherein a variant of an amino acid is selected from amino acids that have the same functional group as the amino acid, and wherein the variant has a different length of a side chain compared to the amino acid.

76. The radiopharmaceutical conjugate of any one of claims 1 or 10 to 75, wherein the variant has a molecular weight that does not vary for more than 14, 28, 30, 45 or 60 g / mol compared to the amino acid.

77. The radiopharmaceutical conjugate of any one of claims 1 to 71, wherein the peptide has an amino acid sequence according to Formula (I), or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) wherein,X1 is da, df3CON, dkCOpipzaa, dahp, dDab-NH2-Ph3-SO2F, dDap-NH2-Ph3-SO2F, dDap-NH2-Ph4-SO2F, dCit, Aib, G, Norvaline, Norleucine, d4PyCON, or dhAla; X2 is MeF, Me3Py, MeF3CON, MeF3F, Me4Py, or MeY(Me); X3 is absent, N, Q, Cit, G, Aib, Hgn, hCit , norCit, LysAc, OrnAc, Ala, or da; X4 is L, Cbg, Chg, Cba, Cha, Ahx, Dahp, Cit, I, V, Norleucine, or Norvaline; X5 is Hgl, Hgn, Dab, Dap, DabAc, DapAc, R, hArg, E, or D; X6 is absent, MeF, MeE, Me3Py, Me4Py, MeF4F, MeF4F, MeF4C, or MeY; X7 is W1Me, W1Me7Cl, W1Me7N, W, F, 7-AzaTrp, W7Me, W1Et, W1Me7Br, W1Me7OMe, or W1Me6O7Cl; X8 is V, KCOpipzaa, N, Cit, Qglucamine, hCit, K, KAc, Aib, Alb, DapAc, OrnAc, A, T, alT, Norleucine, Norvaline, Hgl, E, Hgn, Q, I, or L; X9 is W1Me, W1Me7Cl, W1Me7N, F23dMe, W1Et, W7Me, W, F, or 7-AzaTrp; X10 is absent, T, Q, S, Hgn, Alpha-methylserine, hSer, hThr, N, OrnAc, LysAc, Cit, or hCit; X11 is absent, E, Hgn, R, hArg, Cit, hCit, Hgl, Orn, D, N, Q, DapAc, OrnAc, DabAc, or norCit; and X12 is C, hCys, CdMe, C3RMe, C3SMe, Selenocysteine, dc, or Penicillamine.

78. The radiopharmaceutical conjugate of claim 77, wherein X8 is KCOpipzaa, N, Cit, Qglucamine, hCit, K, KAc, Aib, Alb, DapAc, OrnAc, A, T, alT, Norleucine, Norvaline, Hgl, E, Hgn, Q, I, or L.

79. The radiopharmaceutical conjugate of claim 77 or 78, wherein X11 is absent, Hgn, R, hArg, Cit, hCit, Hgl, Orn, D, N, Q, DapAc, OrnAc, DabAc, or norCit.

80. The radiopharmaceutical conjugate of any one of clams 62 to 79, wherein X7 is W1Me or a variant thereof; and X9 is W1Me or a variant thereof.

81. The radiopharmaceutical conjugate of any one of claims 62 to 80, wherein X7 is W1Me, W1MeCl, W1MeBr, Nal1, Nal2, W1Et, 3Bzf, 3Bzt, F23dC, W1Me7N, or F23dMe; X8 is V, KCOpipzaa, N, Cit, hCit, KAc, DapAc, OrnAc, A, T, alT, Aib, Alb, Qglucamine, Hgl, Q, E, Hgn, or K; and X9 is W1Me, Nal1, W1Et, Nal21N, 3Bzf, 3Bzt, Nal18N, F23dMe, or F23dC.

82. The radiopharmaceutical conjugate of claim 81, wherein X8 is KCOpipzaa, N, Cit, hCit, KAc, DapAc, OrnAc, A, T, alT, Aib, Alb, Qglucamine, Hgl, Q, E, Hgn, or K.

83. A radiopharmaceutical conjugate comprising: (a) a cyclic peptide that has avidity for ephrin type-A receptor 2 (EphA2), wherein the peptide consists of a sequence of Formula (I), X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I)or a pharmaceutically acceptable salt thereof, wherein each of X1, X2, X3, X4, X5, X6, and X8 is independently an amino acid; X7 is W1Me or a variant thereof; X9 is W1Me or a variant thereof; each of X10 and X11 is independently absent or an amino acid; and X12 is cysteine (C) or a variant thereof; (b) a metal chelator configured to bind with a radionuclide; and (c) optionally, a linker that connects the peptide with the metal chelator.

84. The radiopharmaceutical conjugate of claim 83, wherein X8 is KCOpipzaa, N, Cit, Qglucamine, hCit, K, KAc, Aib, Alb, DapAc, OrnAc, A, T, alT, Norleucine, Norvaline, Hgl, E, Hgn, Q, I, or L.

85. The radiopharmaceutical conjugate of claim 83 or 84, wherein X11 is absent, arginine (R), asparagine (N), aspartate (D), glutamine (Q), lysine (K), or an unnatural hydrophilic amino acid.

86. A radiopharmaceutical conjugate comprising: (a) a cyclic peptide that has avidity for ephrin type-A receptor 2 (EphA2), wherein the peptide has an amino acid sequence of Formula (I), X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) wherein, X1 is any D- or L-amino acid; X2 has a structure, wherein ring A2 is phenyl or a 6-membered heteroaryl (e.g., heteroaryl having 1 or 2 N); RX2is each independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, SF5, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally and independently substituted with one or more RXA; kx2 is 0, 1, 2, or 3; mx2 is 0, 1, 2, 3 or 4; RNX2is H, C1-C6alkyl, or C1-C6haloalkyl; *X1 indicates the point of attachment to X1; and,*X3 indicates the point of attachment to X3; X3 has a structurekx3 is 0, 1, 2, or 3; RNX3is H, C1-C6alkyl, or C1-C6haloalkyl; RX3is H, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; *X2 indicates the point of attachment to X2; and, *X4 indicates the point of attachment to X4; X4 is a hydrophobic amino acid (e.g., amino acid having 4 or more carbon atoms in a side chain comprising a linear, branched, or cyclic carbon chain), and wherein X4 is optionally N- alkylated by a C1-3alkyl group; X5 is a hydrophilic L-amino acid, such as an amino acid having a structure of, wherein: RNX5is H, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, or heteroalkyl is optionally and independently substituted with one or more RXA; RX5is -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, SF5, - SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=NRb)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, or heteroalkyl is optionally and independently substituted with one or more RXA; provided that at least one of RNX5and RX5comprises a moiety selected from -OH, -NH2, and -NH- (e.g., -NH-C(=NH)-NH2, -CO-NH2, -NH2, -COOH, -C(OH)-C0-6alkyl, -NH-CO-C1-6alkyl); *X4 indicates the point of attachment to X4; and, *X6 indicates the point of attachment to X6;X6 is(e.g., N, F), wherein RNX6is H, C1-C6alkyl, or C1-C6haloalkyl; RX6is -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, SF5, - SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=NRb)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally and independently substituted with one or more RXA; *X5 indicates the point of attachment to X5; and, *X7 indicates the point of attachment to X7; X7 has a structure, wherein RNX7is H, C1-C6alkyl, or C1-C6haloalkyl; ring A7 is an aryl or heteroaryl; RX7is each independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, SF5, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2-halogen, -S(=O)2NRcRd, - NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally and independently substituted with one or more RXA; kx7 is 0, 1, 2, or 3; mx7 is 0, 1, 2, 3, 4 or 5; *X6 indicates the point of attachment to X6; and, *X8 indicates the point of attachment to X8; X8 is an L-amino acid comprising an -H on the alpha-amino group;X9 has a structureRNX9is H, C1-C6alkyl, or C1-C6haloalkyl; ring A9 is an aryl or heteroaryl; RX9is each independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, SF5, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally and independently substituted with one or more RXA; kx9 is 0, 1, 2, or 3; mx9 is 0, 1, 2, 3, 4, or 5; *X8 indicates the point of attachment to X8; and, *XC indicates the point of attachment to (i) X10 or (i) when X10 and X11 are absent, X12; X10 is absent or an L-amino acid; X11 is absent or an L-amino acid; provided that when X10 is absent, then X11 is also absent; and X12 is an L-amino acid having a reactive thiol group, such as Cys and Cys variants; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R and RXAis independently halogen, -CN, -OH, -OC1-C6alkyl, SF5, -S(=O)C1-C6alkyl, - S(=O)2C1-C6alkyl, -S(=O)2NH2, -S(=O)2-halogen, -S(=O)2NHC1-C6alkyl, - S(=O)2N(C1-C6alkyl)2, -NH2, -NHC1-C6alkyl, -N(C1-C6alkyl)2, -NRbC(=NRb)NRcRd, - NHC(=O)OC1-C6alkyl, -C(=O) C1-C6alkyl, -C(=O)OH, -C(=O)OC1-C6alkyl, -C(=O)NH2, - C(=O)N(C1-C6alkyl)2, -C(=O)NHC1-C6alkyl, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; (b) a metal chelator configured to bind with a radionuclide; and (c) optionally, a linker that connects the peptide with the metal chelator.

87. The radiopharmaceutical conjugate of claim 86, wherein ring A7 is a 6-membered aryl or heteroaryl, or a 9- or 10-membered bicyclic aryl or heteroaryl, wherein the 6-, 9- or 10- membered heteroaryl has one heteroatom selected from N, O, and S.

88. The radiopharmaceutical conjugate of claim 86 or 87, wherein RNX7is H.

89. The radiopharmaceutical conjugate of any one of claims 86 to 88, wherein each RX7is independently selected from -CH3, -ethyl, -Cl, and -F, and mx7 is 0, 1, or 2.

90. The radiopharmaceutical conjugate of claim 86, wherein X7 is W1Me, Nal1, Nal2, W1Et, Nal21N, 3Bzf, 3Bzt, Nal15N, Nal14N, Nal24N, Nal28N, F23dMe, F23dC, W1Me7N, or W1Me7Cl.

91. The radiopharmaceutical conjugate of claim 90, wherein X7 is W1Me, F23dMe or W1Me7Cl.

92. The radiopharmaceutical conjugate of any one of claims 86 to 91, wherein X9 is, each RX9is independently selected from -OH, CN, NH2, C1-C3alkyl, -Cl, -F, -Br, -CONH2, and -SO2F.

93. The radiopharmaceutical conjugate of any one of claims 86 to 92, wherein.

94. The radiopharmaceutical conjugate of any one of claims 86 to 93, wherein RX9is each independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -SH, , -SRa, -S(=O)Ra, -S(=O)2Ra, - S(=O)2NRcRd, -NRcRd, -NRbC(=O)Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl.

95. The radiopharmaceutical conjugate of any one of claims 86 to 91, wherein X9 is W1Me, W, Nal1, W1Et, Nal21N, 3Bzf, 3Bzt, Nal14N, Nal18N, F23dMe, F23dC, or W1Et.

96. The radiopharmaceutical conjugate of claim 95, wherein X9 is W1Me or F23dMe.

97. The radiopharmaceutical conjugate of any one of claims 86 to 96, wherein ring A2 is a 6- membered heteroaryl containing 1 or 2 N.

98. The radiopharmaceutical conjugate of any one of claims 86 to 97, wherein RX5is C1-C6hydroxyalkyl, C1-C6aminoalkyl, -C0-6alkylene-NH-C(=NH)-NH2, -C0-6alkylene-CO-NH2, -C0-6alkylene-COOH, or -NH-CO-C1-6alkyl.

99. The radiopharmaceutical conjugate of any one of claims 83 to 86, wherein X7 is W1Me, W1MeCl, W1MeBr, Nal1, Nal2, W1Et, 3Bzf, 3Bzt, F23dC, W1Me7N, or F23dMe; X8 is V, KCOpipzaa, Hse, N, Cit, hCit, KAc, DapAc, OrnAc, T, alT, Aib, Alb, Qglucamine, Hgl, E, Hgn, MeF, 3Py6NH2, W1Me, A, Q, or K; and X9 is W1Me, Nal1, W1Et, Nal21N, 3Bzf, 3Bzt, Nal18N, F23dMe, or F23dC.

100. The radiopharmaceutical conjugate of claim 99, wherein X8 is KCOpipzaa, N, Cit, hCit, KAc, DapAc, OrnAc, A, T, alT, Aib, Alb, Qglucamine, Hgl, Q, E, Hgn, or K.

101. The radiopharmaceutical conjugate of claim 81 or 99, wherein X7 is W1Me; X8 is V; and X9 is W1Me.

102. The radiopharmaceutical conjugate of claim 81 or 99, wherein X7 is W1Me; X8 is KCOpipzaa, N, Cit, hCit, KAc, DapAc, OrnAc, A, T, alT, Aib, Alb, Qglucamine, Hgl, Q, E, Hgn, or K; andX9 is W1Me.

103. The radiopharmaceutical conjugate of any one of claims 1 to 61, wherein the peptide has an amino acid sequence according to Formula (I), or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) wherein, X1 is any amino acid X2 is an amino acid having an aromatic ring or a variant thereof X3 is N, X4 is a hydrophobic amino acid or a variant thereof; X5 is a hydrophilic amino acid or a variant thereof; X6 is a hydrophilic amino acid or amino acid having aromatic ring; X7 is W or a variant thereof; X8 is V or hydrophilic amino acid or a variant thereof, X9 is W or a variant thereof; X10 is T or a variant thereof; X11 is a hydrophilic amino acid; X12 is C or a variant thereof (such as C).

104. The radiopharmaceutical conjugate of claim 103, wherein X8 is KCOpipzaa, N, Cit, Qglucamine, hCit, K, KAc, Aib, Alb, DapAc, OrnAc, A, T, alT, Norleucine, Norvaline, Hgl, E, Hgn, Q, I, or L.

105. The radiopharmaceutical conjugate of claim 103 or 104, wherein X11 is arginine (R), asparagine (N), aspartate (D), glutamine (Q), lysine (K), or an unnatural hydrophilic amino acid.

106. The radiopharmaceutical conjugate of any one of claims 1 to 61, wherein the peptide has an amino acid sequence according to Formula (Ia), or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X12 Formula (Ia) wherein, X1 is any amino acid; X2 is an amino acid having an aromatic ring or a variant thereof; X3 is N or a variant thereof; X4 is a hydrophobic amino or a variant thereof, X5 is a hydrophilic amino acid or a variant thereof; X6 is a hydrophilic amino acid or amino acid having aromatic ring; X7 is W or a variant thereof; X8 is a hydrophilic amino acid or a variant thereof, X9 is W or a variant thereof; and X12 is C or a variant thereof.

107. The radiopharmaceutical conjugate of any one of claims 1 to 106, wherein the peptide has a monocyclic structure.

108. The radiopharmaceutical conjugate of claim 107, wherein the amino acid X1 and the cysteine or a variant thereof are bound.

109. The radiopharmaceutical conjugate of claim 107, wherein the peptide has a structure of Formula (I-1),wherein R1is selected from the group consisting of NH2and OH; R2is selected from the group consisting of H or C1-3alkyl; R3is selected from the group consisting of H or C1-3alkyl; wherein X1 to X11 have the definitions described in Formula (I), and wherein the attachment point to the radionuclide or the linker is not shown.

110. The radiopharmaceutical conjugate of claim 109, or a pharmaceutically acceptable salt thereof, wherein the peptide of Formula (I-1) has a structure of Formula (I-2),Formula (I-2).

111. The radiopharmaceutical conjugate of any one of claims 22 to 110, wherein the conjugate having a structure of Formula (III-1)Formula (III-1) wherein X1 to X11 have the definitions described in Formula (I), and wherein –Linker– represents the linker connecting the peptide and the metal chelator.

112. The radiopharmaceutical conjugate of any one of claims 22 to 110, wherein the conjugate having a structure of Formula (III-2),wherein Lcyc is a ring closing group that covalently connects X1 with X12; –Linker– represents the linker that connects the peptide and the metal chelator; and wherein X1 to X12 have the definitions described in Formula (I).

113. The radiopharmaceutical conjugate of any one of claims 1 to 112, wherein the peptide or the salt thereof comprises an amino acid sequence that is at least 90% identical to a sequence selected from SEQ ID NOs: 1-171.

114. The radiopharmaceutical conjugate of any one of claims 1 to 112, wherein the peptide or the salt thereof consists of an amino acid sequence selected from SEQ ID NOs: 1-171.

115. The radiopharmaceutical conjugate of any one of claims 1 to 114, wherein the radiopharmaceutical conjugate is not SEQ ID NO:

282.

116. The radiopharmaceutical conjugate of any one of claims 1 to 115, wherein the peptide has a binding affinity to a human EphA2 of at most 100nM as determined by Kd in surface plasmon resonance (SPR) analysis.

117. The radiopharmaceutical conjugate of claim 116, wherein the peptide has a binding affinity to a human EphA2 of at most 1 nM as determined by Kd in surface plasmon resonance (SPR) analysis.

118. The radiopharmaceutical conjugate of any one of claims 1 to 117, wherein the conjugate has a binding affinity to a human EphA2 of at most 100nM as determined by Kd in surface plasmon resonance (SPR) analysis.

119. The radiopharmaceutical conjugate of claim 118, wherein the conjugate has a binding affinity to a human EphA2 of at most 1 nM as determined by Kd in surface plasmon resonance (SPR) analysis.

120. The radiopharmaceutical conjugate of any one of claims 1 to 119, wherein the conjugate has a plasma half-life (T1 / 2) of at least 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 minutes as determined in vitro in human plasma at 37 ⁰C.

121. The radiopharmaceutical conjugate of any one of claims 1 to 120, wherein an uptake ratio between a tumor uptake and kidney uptake toward the radiopharmaceutical conjugate is at least 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8 or 2.0 in a human prostate xenograft mouse model.

122. The radiopharmaceutical conjugate of any one of claims 1 to 121, wherein the peptide binds to a ligand-binding domain (LBD) domain of the EphA2.

123. The radiopharmaceutical conjugate of any one of claims 1 to 122, wherein the peptide interacts with a human EphA2 at one or more amino acid residues selected from Asp53, Met55, Asn57, Met59, Met66, Thr101, Arg103, Phe156, Glu157, Arg159, Val161, Val189, and Ala190.

124. The radiopharmaceutical conjugate of any one of claims 1 to 123, wherein the peptide interacts with a human EphA2 at Asp53 and Glu157.

125. The radiopharmaceutical conjugate of any one of claims 1 or 10 to 124, wherein the peptide is a peptide of Formula (I) and wherein, when the peptide is bound to the human EphA2, amino acid residue X7 is located less than 10Å from the Phe156 of the human EphA2.

126. The radiopharmaceutical conjugate of claim 125, wherein amino acid residue X7 is located less than 6Å from the Phe156.

127. The radiopharmaceutical conjugate of any one of claims 1 or 10 to 126, wherein the peptide is a peptide of Formula (I) and wherein, when the peptide is bound to the human EphA2, amino acid residue X9 is located less than 10Å from the Phe156 of the human EphA2.

128. The radiopharmaceutical conjugate of claim 127, wherein amino acid residue X9 is located less than 6Å from the Phe156.

129. The radiopharmaceutical conjugate of any one of claims 1 or 10 to 128, wherein the peptide is a peptide of Formula (I) and wherein, when the peptide is bound to the human EphA2, amino acid residue X8 is located less than 10Å from the Phe156 of the human EphA2.

130. The radiopharmaceutical conjugate of any one of claims 123 to 128, wherein the human EphA2 comprises a sequence of SEQ ID NO: 276 or SEQ ID NO:

277.

131. The radiopharmaceutical conjugate of claim 1, 2 or 83, wherein the conjugate is a compound of Tables 1, 2A, 2B, 2B-Lu, 2B-Lu-177, 2B-Ac-225, or 2C.

132. A radiopharmaceutical conjugate, comprising: (a) a peptide that has avidity for ephrin type-A receptor 2 (EphA2), wherein the peptide competes for binding to a human EphA2 with a peptide that has an amino acid sequence including deletion, substitution, and / or addition of one or several amino acids in the amino acid of SEQ ID NO:1: da-MeF-N-L-Hgl-MeF-W1Me-V-W1Me-T-E-C (SEQ ID NO:1) or a pharmaceutically acceptable salt thereof ; and (b) a metal chelator configured to bind with a radionuclide, wherein the metal chelator is conjugated to the peptide.

133. The radiopharmaceutical conjugate of claim 2 or 132, wherein the 8thV is substituted.

134. The radiopharmaceutical conjugate of any one of claims 2, 132 or 133, wherein the 11thE is substituted.

135. A radiopharmaceutical conjugate, comprising: (a) a peptide that has avidity for ephrin type-A receptor 2 (EphA2), wherein the peptide competes for binding to a human EphA2 with a peptide that has a structure of Formula (I), or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) wherein, X1 is an amino acid;X2 is an amino acid comprising an aromatic ring, an N-methylated amino acid thereof, or a variant thereof; X3 is a hydrophilic amino acid (e.g. N, Q, Cit, K or a variant thereof), glycine (G), Alanine (A) or a variant thereof (e.g., da, 2-Aminoisobutyric acid (Aib)); X4 is a hydrophobic amino acid (e.g., leucine (L)), a hydrophilic amino acid (e.g., citrulline (Cit)), or a variant thereof; X5 is a hydrophilic amino acid, or a variant thereof; X6 is a hydrophilic amino acid, an amino acid comprising an aromatic ring, or an N- methylated amino acid thereof; X7 is an amino acid comprising an aromatic ring (e.g., W, F, or a variant thereof); X8 is a hydrophobic amino acid, a hydrophilic amino acid, an N-methylated amino acid, or a variant thereof; X9 is an amino acid comprising an aromatic ring (e.g., W or a variant thereof); X10 is absent or a hydrophilic amino acid (e.g., Threonine (T) or a variant thereof); X11 is absent or a hydrophilic amino acid; and X12 is cysteine (C) or a variant thereof; and (b) a metal chelator configured to bind with a radionuclide, wherein the metal chelator is conjugated to the peptide.

136. A radiopharmaceutical conjugate comprising: (a) a cyclic peptide that has avidity for ephrin type-A receptor 2 (EphA2), wherein the peptide consists of a sequence of Formula (I), X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) or a pharmaceutically acceptable salt thereof, wherein each of X1, X2, X3, X4, X5, X6, and X8 is independently an amino acid; X7 is W1Me or a variant thereof; X9 is W1Me or a variant thereof; each of X10 and X11 is independently absent or an amino acid; and X12 is cysteine (C) or a variant thereof; (b) a metal chelator configured to bind with a radionuclide; and (c) a linker that connects the peptide with the metal chelator.

137. The radiopharmaceutical conjugate of any one of claims 1, 135 or 136, wherein X8 is KCOpipzaa, N, Cit, Qglucamine, hCit, K, KAc, Aib, Alb, DapAc, OrnAc, A, T, alT, Norleucine, Norvaline, Hgl, E, Hgn, Q, I, or L.

138. The radiopharmaceutical conjugate of any one of claims 1 or 135-137, wherein X11 is absent, arginine (R), asparagine (N), aspartate (D), glutamine (Q), lysine (K), or an unnatural hydrophilic amino acid.

139. The radiopharmaceutical conjugate of any one of claims 1 to 138, wherein the peptide competes for binding to a human EphA2 at one or more amino acid residues selected from Asp53, Met55, Asn57, Met59, Met66, Thr101, Arg103, Phe156, Glu157, Arg159, Val161, Val189, and Ala190.

140. The radiopharmaceutical conjugate of claim 139, wherein the peptide competes for binding to human EphA2 at one or more amino acid residues selected from Asp53, Phe156, and Glu157.

141. The radiopharmaceutical conjugate of any one of claims 132 to 140, wherein the human EphA2 comprises a sequence of SEQ ID NO: 276 or SEQ ID NO:

277.

142. A radiopharmaceutical conjugate, wherein the conjugate is a salt of a conjugate of any one of the preceding claims.

143. A pharmaceutical composition comprising a radiopharmaceutical conjugate of any one of claims 1 to 142, and a pharmaceutically acceptable excipient or carrier.

144. A radiolabeled human EphA2 protein, wherein the EphA2 protein is bound to a radiopharmaceutical conjugate of any one of claims 1 to 142.

145. A method of treating a disease or disorder characterized by overexpression of EphA2, comprising administering to the subject a radiopharmaceutical conjugate of any one of claims 1 to 142, or a pharmaceutical composition of claim 143.

146. The method of claim 145, wherein the disease or disorder is cancer.

147. A method of diagnosing or imaging a cancer in a subject in need thereof, comprising administering to the subject a radiopharmaceutical conjugate of any one of claims 1 to 142, or a pharmaceutical composition of claim 143.

148. A method of treating a cancer in a subject in need thereof, comprising administering to the subject a radiopharmaceutical conjugate of any one of claims 1 to 142, or a pharmaceutical composition of claim 143.

149. The method of claim 148, wherein the cancer is selected from glioblastoma, prostate cancer, lung cancer, breast cancer, gastric cancer, ovarian cancer, bladder cancer, colon cancer, esophageal cancer, multiple myeloma and fibrosarcoma.

150. The method of claim 148, wherein the cancer is non-small cell lung carcinomas (NSCLC).

151. The method of claim 148, wherein the cancer is triple negative breast cancer.

152. The method of claim 148 or 149, wherein the method comprises administering (i) a first radiopharmaceutical conjugate comprising a radionuclide configured for companion diagnostic (such as PET imaging) and (ii) a second radiopharmaceutical conjugate comprising a radionuclide selected from an alpha or beta-particle emitter, wherein the first and the second conjugate have the same structure except for the radionuclide.

153. The method of claim 152, wherein the radionuclide of the first conjugate is selected from Lu-177, In-111, Ga-68, Cu-64, and Zr-89.

154. A kit for use in a method of diagnosing disease or disorder characterized by an over or decreased level of expression of EphA2, wherein the kit comprising a radiopharmaceutical conjugate of any one of claims 1 to 142, or a pharmaceutical composition of claim 143.

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