Radiopharmaceutical compositions targeting hepatic ligand protein A receptor 2 and uses thereof

Abstract

Provided herein are radiopharmaceutical conjugate compositions that target EphA2 and uses thereof. In one aspect, provided herein are conjugates comprising a peptide having affinity for EphA2 and a metal chelating agent configured to bind to a radionuclide. The conjugates described herein may further comprise a linker linking the chelating agent and the peptide. The conjugates described herein may further comprise radionuclides. In another aspect, provided herein are conjugates comprising a peptide having affinity for EphA2 and a covalently bound radionuclide. The conjugates described herein may further comprise a linker linking the radionuclide and the peptide. Further provided herein are methods of treating cancer by administering the conjugates and compositions.

Description

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 Agreement

[0002] The subject matter disclosed herein was made by, on behalf of, or in cooperation with 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), and the claimed invention was made by, on behalf of, or in cooperation with such one or more parties, and the JRA was in effect on or before the effective filing date of the claimed invention. The one or more parties to the JRA consist of PeptiDream, Inc. (Kanagawa, Japan) and RayzeBio, Inc. (San Diego, California, USA). The claimed invention is the result of activities carried out within the scope of the Joint Research Agreement. Sequence Listing

[0003] This application contains a sequence listing that has been electronically submitted in XML format and is hereby incorporated by reference in its entirety. The name of the XML copy created on September 28, 2023 is 59541 - 729_601_SL.xml, and the size is 2,096,382 bytes. Background Art

[0004] In the United States, cancer is the leading cause of death in people under 65 years old and accounted for approximately 21% of all deaths in 2018. For decades, traditional radiation therapies such as external beam radiation therapy have been used as the standard of care for diagnosed cancer patients. While some patients respond to external beam radiation therapy, many others do not. In addition, metastases and circulating tumor cells can spread and remain in the bloodstream or body fluids after standard of care treatment and cause resistance to the therapy. The presence of cancer cells in various parts of the body reduces the therapeutic efficacy of traditional radiation therapy. Therefore, strategies for targeted radiation therapy are being developed, and there is still a need for targeted radiation therapies with desired affinity, stability, and action characteristics. Summary of the Invention

[0005] In one aspect, the present disclosure relates to a radiopharmaceutical conjugate comprising: (a) a cyclic peptide that has an affinity for ephrin type - A receptor 2 (EphA2), wherein the peptide comprises the 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 containing an aromatic ring, its N-methylated amino acid or its variant; X3 is a hydrophilic amino acid (e.g., N, Q, Cit, K or its variant), glycine (G), alanine (A) or its variant (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 its variant; X5 is a hydrophilic amino acid or its variant; X6 is a hydrophilic amino acid, an amino acid containing an aromatic ring, or its N-methylated amino acid; X7 is an amino acid containing an aromatic ring (e.g., W, F or its variant); X8 is a hydrophobic amino acid, a hydrophilic amino acid, its N-methylated amino acid or variant; X9 is an amino acid containing an aromatic ring (e.g., W or its variant); X10 is absent or is a hydrophilic amino acid (e.g., threonine (T) or its variant); X11 is absent or is a hydrophilic amino acid; and X12 is cysteine (C) or its variant; and (b) (i) a metal chelator configured to bind to 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 to 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 having an affinity for ephrin type-A receptor 2 (EphA2), wherein the peptide comprises an amino acid sequence having one or more (e.g., 1-6) amino acid deletions, substitutions and / or additions of the following 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 to 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 to 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 that binds to the metal chelator. In some embodiments, the radionuclide is an alpha-emitting radionuclide. In some embodiments, the alpha-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-emitting radionuclide is Ac-225. In some embodiments, the radionuclide is a beta-emitting radionuclide. In some embodiments, the beta-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-emitting radionuclide is Lu-177. In some embodiments, the radionuclide is a gamma-emitting radionuclide. In some embodiments, the gamma-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 the following structure:

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

[0010] In some embodiments, the radiopharmaceutical conjugate has the following structure: 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 5th amino acid residue or X5. In some embodiments, the linker is attached to the 8th amino acid residue or X8. In some embodiments, the linker is attached to the 11th amino acid residue or X11.

[0012] In some embodiments, the radionuclide is covalently bound to an amino acid containing an aromatic ring. In some embodiments, the radionuclide is 18 F, 74 As, 76 Br, 123 I, 124 I, 125 I, 131I or 211 At. In some embodiments, the radionuclide is 18 F, 125 I, 131 I or 211 At. 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 to the radionuclide. In some embodiments, the linker covalently connects the peptide to the radionuclide.

[0013] In some embodiments, the radiopharmaceutical conjugate has the following structure: 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 5th amino acid residue or X5. In some embodiments, the linker is attached to the 8th amino acid residue or X8. In some embodiments, the linker is attached to the 11th amino acid residue or X11. In some embodiments, the linker comprises a residuation agent. In some embodiments, the residuation agent is selected from In some embodiments, has a structure selected from the following: wherein each of 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 a pharmaceutically acceptable 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 a pharmaceutically acceptable salt thereof has a cyclic structure having an amino acid and a cysteine residue or a variant thereof in the first residue X1, 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 the 12th residue, and wherein the amino acid X1 and the cysteine residue or a variant thereof at the 12th residue form a covalent bond (e.g., by reacting the 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 the 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 the 10th residue, and wherein the amino acid X1 and the cysteine residue or a variant thereof at the 10th residue form a covalent bond.

[0015] In some embodiments, the radiopharmaceutical conjugate comprises a metal chelator configured to bind to 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 the 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, wherein the unsubstituted benzene ring of F is replaced by (i) a benzene ring substituted with 1 or 2 substituents each independently selected from -OH, -CN, and -C 1-3 alkyl, or (ii) optionally substituted with 1 or 2 substituents each independently selected from -OH, -CN, and -C1-3 A 6-membered heteroaryl ring substituted with substituents of an alkyl group, wherein said F or its variant is optionally N-methylated; X3 is a hydrophilic amino acid (e.g., N, Q, Cit, K or its variant), G, Aib, Hgn, Ala or its variant (e.g., da); X4 is a hydrophobic amino acid (e.g., an amino acid having 4 or more carbon atoms in a side chain containing a straight-chain, branched-chain or cyclic carbon chain), and wherein X4 is optionally N-methylated (e.g., Cit or its variant); X5 is an amino acid (e.g., a hydrophilic amino acid; Dab, Dap, R, E or its variant; or an amino acid having a functional side chain); X6 is its N-methylated amino acid; X7 is W, Y or its variant (e.g., an amino acid having a 6-membered aryl or heteroaryl or a 9- or 10-membered bicyclic aryl or heteroaryl connected to the α-carbon through a carbon (e.g., methylene), wherein said 6-, 9- and 10-membered heteroaryls have one heteroatom (e.g., N), and wherein said 6-, 9- and 10-membered aryl or heteroaryl is optionally substituted with 1 or 2 substituents independently selected from: -CH3, -ethyl, -Cl and -F); X8 is an amino acid having -H on the α-amino; X9 is W or Y or its variant (e.g., W or its variant); X10 is absent or is a polar amino acid (e.g., T or its variant); X11 is absent or is an amino acid (e.g., a hydrophilic amino acid; Dab, Dap, R, E or its variant; or an amino acid having a functional side chain); and X12 is C or its variant.

[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., a D-amino acid); X2 is an amino acid containing an aromatic ring, its N-methylated amino acid or its variant; X3 is a hydrophilic amino acid (e.g., N, Q, Cit, K or its variant), G, A or its variant (e.g., da, Aib); X4 is a hydrophobic amino acid or a hydrophilic amino acid (e.g., Cit or its variant); 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 containing an aromatic ring (e.g., W or F or a variant thereof), or an N-methylated amino acid thereof; X7 is an amino acid containing 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 containing 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 containing 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 containing an aromatic ring (e.g., W or F or a variant thereof), or an N-methylated amino acid thereof; X7 is an amino acid containing 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 containing 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 or is 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 or is 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, Q glucosamine, 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 or is T, Q, S, Hgn, α-methylserine, hSer, hThr, N, OrnAc, LysAc, Cit or hCit; X11 is absent or is 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 an affinity 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 is an amino acid; and X12 is cysteine (C) or a variant thereof; (b) (i) A metal chelator that is configured to bind to 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 to the metal chelator; or (ii) optionally, a linker that connects the peptide to the covalent radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a metal chelator that is configured to bind to a radionuclide and optionally a linker that connects the peptide to the metal chelator. In some embodiments, the radiopharmaceutical conjugate comprises a covalent radionuclide and optionally a linker that connects the peptide to 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 to the covalent radionuclide.

[0020] In one aspect, the present disclosure relates to a radiopharmaceutical conjugate comprising: (a) A cyclic peptide that has an affinity 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 the structure of, wherein ring A2 is phenyl or a 6-membered heteroaryl (e.g., a heteroaryl having 1 or 2 Ns); RX2 Each independently is halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, SF5, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b , -NR c R d , -NR b , -NR a , -NR b , -NR b , -NR b , -NR a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein said alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally and independently substituted by one or more R XA substituted; kx2 is 0, 1, 2 or 3; mx2 is 0, 1, 2, 3 or 4; R NX2 is H, C1-C6 alkyl or C1-C6 haloalkyl; *X1 indicates the attachment point to X1; and, *X3 indicates the attachment point to X3; X3 has the structure of, where kx3 is 0, 1, 2 or 3; R NX3 is H, C1-C6 alkyl or C1-C6 haloalkyl; R X3 is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; *X2 indicates the attachment point to X2; and, *X4 indicates the attachment point to X4; X4 is a hydrophobic amino acid (e.g., an amino acid having 4 or more carbon atoms in a side chain comprising a straight-chain, branched-chain or cyclic carbon chain), and wherein X4 is optionally N-methylated by C 1-3 alkyl; X5 is a hydrophilic L-amino acid, such as an amino acid having the structure, wherein: R NX5 is H, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; wherein said alkyl, haloalkyl, hydroxyalkyl, aminoalkyl or heteroalkyl is optionally and independently substituted by one or more R XA substituents; R X5 is -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d 、-SH, SF5, -SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=NR b )NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d 、C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; wherein said alkyl, haloalkyl, hydroxyalkyl, aminoalkyl or heteroalkyl is optionally and independently substituted by one or more RXA Substituted; provided that R NX5 and R X5 at least one of which contains a moiety selected from the following: -OH, -NH2, and -NH- (e.g., -NH-C(=NH)-NH2, -CO-NH2, -NH2, -COOH, -C(OH)-C 0-6 alkyl, -NH-CO-C 1-6 alkyl); *X4 indicates the attachment point to X4; and, *X6 indicates the attachment point to X6; X6 is (e.g., N, F), where R NX6 is H, C1-C6 alkyl, or C1-C6 haloalkyl; R X6 is -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, SF5, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=NR b )NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally and independently substituted by one or more R XA substituted; *X5 indicates the attachment point to X5; and, *X7 indicates the attachment point to X7; X7 has the structure of, wherein R NX7 is H, C1-C6 alkyl or C1-C6 haloalkyl; Ring A7 is aryl or heteroaryl; R X7 are each independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, SF5, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2-halogen, -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally and independently substituted by one or more R XA substituted; kx7 is 0, 1, 2 or 3; mx7 is 0, 1, 2, 3, 4 or 5; *X6 indicates the attachment point to X6; and, *X8 indicates the attachment point to X8; X8 is an L-amino acid containing -H on the α-amino group; X9 has the structure of, where R NX9 is H, C1-C6 alkyl or C1-C6 haloalkyl; Ring A9 is aryl or heteroaryl; R X9 are each independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, SF5, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; where the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally and independently substituted by one or more R XA substituted; kx9 is 0, 1, 2 or 3; mx9 is 0, 1, 2, 3, 4 or 5; *X8 indicates the attachment point to X8; and, *The XC indicates the attachment point to (i) X10 or (i) to X12 when X10 and X11 are absent; X10 is absent or is an L - amino acid; X11 is absent or is 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 R a independently is C1 - C6 alkyl, C1 - C6 haloalkyl, C1 - C6 hydroxyalkyl, C1 - C6 aminoalkyl, C1 - C6 heteroalkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1 - C6 alkyl(cycloalkyl), C1 - C6 alkyl(heterocycloalkyl), C1 - C6 alkyl(aryl) or C1 - C6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted by one or more Rs; Each R b independently is hydrogen, C1 - C6 alkyl, C1 - C6 haloalkyl, C1 - C6 hydroxyalkyl, C1 - C6 aminoalkyl, C1 - C6 heteroalkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1 - C6 alkyl(cycloalkyl), C1 - C6 alkyl(heterocycloalkyl), C1 - C6 alkyl(aryl) or C1 - C6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted by one or more Rs; Each R c and R d independently is hydrogen, C1 - C6 alkyl, C1 - C6 haloalkyl, C1 - C6 hydroxyalkyl, C1 - C6 aminoalkyl, C1 - C6 heteroalkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1 - C6 alkyl(cycloalkyl), C1 - C6 alkyl(heterocycloalkyl), C1 - C6 alkyl(aryl) or C1 - C6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted by one or more Rs; Or R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted by one or more Rs; and Each R and R XAindependently is halogen, -CN, -OH, -OC1-C6 alkyl, SF5, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2-halogen, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NR b C(=NR b )NR c R d , -NHC(=O)OC1-C6 alkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; (b) (i) a metal chelator configured to bind to a radionuclide; or (ii) a covalent radionuclide; and (c) (i) optionally, a linker that links the peptide to the metal chelator; or (ii) optionally, a linker that links the peptide to the covalent radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a metal chelator configured to bind to a radionuclide and optionally a linker that links the peptide to the metal chelator. In some embodiments, the radiopharmaceutical conjugate comprises a covalent radionuclide and optionally a linker that links the peptide to 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 links the peptide to 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 an amino acid having an aromatic ring; X7 is W or a variant thereof; X8 is V or a 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 an amino acid having an 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), where R 1 is selected from NH2 and OH; R 2 is selected from H or C 1-3 alkyl; R 3 is selected from H or C 1-3 alkyl; where X1 to X11 have the definitions described in formula (I), and the attachment points to the radionuclide or the linker are 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 the structure of formula (III-1) wherein X1 to X11 have the definitions as described in formula (I), and wherein -Linker- represents the linker that links the peptide to the metal chelator.

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

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

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

[0030] In some embodiments, the peptide or its salt comprises an amino acid sequence that is at least 90% identical to a sequence selected from SEQ ID NO: 1-171. In some embodiments, the peptide or its salt consists of an amino acid sequence selected from SEQ ID NO: 1-171. In some embodiments, the peptide or its salt is not SEQ ID NO: 1. In some embodiments, the peptide or its salt does not contain 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 human EphA2 at one or more amino acid residues selected from the group consisting of Asp53, Met55, Asn57, Met59, Met66, Thr101, Arg103, Phe156, Glu157, Arg159, Val161, Val189, and Ala190. In some embodiments, the peptide interacts with human EphA2 at Asp53 and Glu157. In some embodiments, the peptide is a peptide of formula (I), and wherein when the peptide binds to the human EphA2, amino acid residue X7 is less than from Phe156 of the human EphA2. In some embodiments, the peptide is a peptide of formula (I), and wherein when the peptide binds to the human EphA2, amino acid residue X9 is less than from Phe156 of the human EphA2. In some embodiments, the peptide is a peptide of formula (I), and wherein when the peptide binds to the human EphA2, amino acid residue X8 is less than from Phe156 of the human EphA2. In some embodiments, the human EphA2 comprises the sequence of SEQ ID NO:276 or SEQ ID NO:277.

[0032] In some embodiments, the conjugate is a compound of Table 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 an affinity for ephrin type-A receptor 2 (EphA2), wherein the peptide competes with a peptide having an amino acid sequence with one or several amino acid deletions, substitutions, and / or additions in the amino acids comprising SEQ ID NO:1 for binding to human EphA2: 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 to 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 to 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 having an affinity for ephrin type-A receptor 2 (EphA2), wherein the peptide competes with a peptide having the structure of formula (I) for binding to human EphA2; 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 containing an aromatic ring, its N-methylated amino acid 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 containing an aromatic ring, or its N-methylated amino acid; X7 is an amino acid containing an aromatic ring (e.g., W, F or a variant thereof); X8 is a hydrophobic amino acid, a hydrophilic amino acid, its N-methylated amino acid or a variant; X9 is an amino acid containing an aromatic ring (e.g., W or a variant thereof); X10 is absent or is a hydrophilic amino acid (e.g., threonine (T) or a variant thereof); X11 is absent or is a hydrophilic amino acid; and X12 is cysteine (C) or a variant thereof; and (b)(i) A metal chelator configured to bind to 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 to 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 having an affinity 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 is an amino acid; and X12 is cysteine (C) or a variant thereof; (b)(i) A metal chelator configured to bind to a radionuclide; or (ii) a covalent radionuclide; and (c)(i) A linker that links the peptide to the metal chelator; or (ii) a linker that links the peptide to the covalent radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a metal chelator configured to bind to a radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a linker that links the peptide to the metal chelator. In some embodiments, the radiopharmaceutical conjugate comprises a covalent radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a linker that links the peptide to 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 radioactively labeled human EphA2 protein, wherein the EphA2 protein binds 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 EphA2 overexpression, the method comprising administering to the subject a radiopharmaceutical conjugate or a pharmaceutical composition thereof as described herein. In some embodiments, the disease or disorder is cancer.

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

[0040] In one aspect, the present disclosure relates to a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a radiopharmaceutical conjugate or a pharmaceutical composition thereof as described herein. 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 cancer (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 formulated for companion diagnostics such as PET imaging and (ii) a second radiopharmaceutical conjugate comprising a radionuclide selected from an α or β particle emitter, wherein the first conjugate 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 from 18 F, 74 As, 76 Br, 123 I, 124 I, and 125 I. In some embodiments, the radionuclide of the second conjugate is selected from 131 I, and 211 At.

[0041] In one aspect, there is disclosed herein 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, the present disclosure provides a method for treating a disease or disorder characterized by EphA2 overexpression, the method comprising administering to a subject a radiopharmaceutical conjugate or a salt thereof as described herein.

[0043] In one aspect, the present disclosure provides a kit for use in a method of diagnosing a disease or disorder characterized by EphA2 overexpression / reduced expression by determining the expression level of EphA2, wherein the kit comprises a radiopharmaceutical conjugate or a salt thereof as described herein.

[0044] In one aspect, the present disclosure provides a composition for use in a method of diagnosing a disease or disorder characterized by EphA2 overexpression / reduced expression, wherein the composition comprises a radiopharmaceutical conjugate or a salt thereof as described herein.

[0045] In one aspect, the present disclosure provides the use of a radiopharmaceutical conjugate or a salt thereof as described herein for use in a method of diagnosing a disease or disorder characterized by EphA2 overexpression / reduced expression. Incorporation by reference

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

[0047] The novel features of the present disclosure are set forth with particularity in the appended claims. The features and advantages of the present disclosure will be better understood from the following detailed description, which sets forth illustrative embodiments and the accompanying drawings (also referred to herein as “figures” and “drawings”) that illustrate the principles of the present disclosure, and in the drawings:

[0048] Figure 1 The structures of exemplary conjugates of the present disclosure (including peptides, linkers, and metal chelators) are shown. Figure 1 SEQ ID NOs 296, 433, 424, 434, 435, 436, and 437 are disclosed in order of appearance.

[0049] Figure 2 The structures of exemplary conjugates of the present disclosure (including peptides, linkers, metal chelators, and cold lutetium) are shown. Figure 2 SEQ ID NOs 292, 330, 283, 328, 334, 360, and 361 are disclosed in order of appearance.

[0050] Figure 3 The structures of exemplary conjugates of the present disclosure (including peptides, linkers, and metal chelators) are shown.

[0051] Figure 4A Shows exemplary metal chelators of the present disclosure, wherein represents the attachment point of the metal chelator to the remaining conjugate. Figure 4B Shows the same metal chelator as Figure 4A , except that a portion of a linker or peptide covalently linked to the metal chelator is shown within the dashed circle .

[0052] Figure 5A Shows exemplary metal chelators of the present disclosure, wherein represents the attachment point of the metal chelator to the remaining conjugate. Figure 5B Shows the same metal chelator as Figure 5A , except that a portion of a linker or peptide covalently linked to the metal chelator is shown within the dashed circle .

[0053] Figure 6A Shows exemplary metal chelators of the present disclosure, wherein represents the attachment point of the metal chelator to the remaining conjugate. Figure 6B Shows the same metal chelator as Figure 6A , except that a portion of a linker or peptide covalently linked to the metal chelator is shown within the dashed circle .

[0054] Figure 7A Shows exemplary metal chelators of the present disclosure, wherein represents the attachment point of the metal chelator to the remaining conjugate. Figure 7B Shows the same metal chelator as Figure 7A , except that a portion of a linker or peptide covalently linked to the metal chelator is shown within the dashed circle .

[0055] Figure 8 Shows the structure of a representative metal chelator.

[0056] Figure 9 Shows the structure of a representative metal chelator.

[0057] Figure 10 Shows the structure of a representative metal chelator.

[0058] Figure 11 Shows the structure of a representative metal chelator.

[0059] Figure 12 Shows the structure of a representative metal chelator.

[0060] Figure 13Shows the structures of representative metal chelators.

[0061] Figure 14 Shows the structures of representative metal chelators.

[0062] Figure 15 Shows the structures of representative metal chelators.

[0063] Figure 16 Shows the structures of representative metal chelators.

[0064] Figure 17 Shows the structures of representative metal chelators.

[0065] Figure 18 Shows the structures of representative metal chelators.

[0066] Figure 19 Shows the structures of representative metal chelators.

[0067] Figure 20 Shows the structures of representative metal chelators.

[0068] Figure 21 Shows the structures of representative metal chelators.

[0069] Figure 22 Shows the structures of representative metal chelators.

[0070] Figure 23 Shows the cell binding and binding EC50 of biotinylated compounds EphA2-biotin-21 and EphA2-biotin-88 tested in HCT116 cells.

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

[0072] Figure 25 Shows the internalization rates of 10 nM and 100 nM of biotinylated compounds EphA2-biotin-21 and EphA2-biotin-88 measured in PC3 cells at the 2-hour time point.

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

[0074] Figure 27 Shows the structure of an exemplary conjugate comprising a covalently bound radionuclide of the present disclosure text. Figure 27 SEQ ID NOs 88, 171, 114, 55, 438 - 440 are disclosed in the order of appearance.

[0075] Figure 28 Shows the structure of an exemplary conjugate comprising a covalently bound radionuclide of the present disclosure text. Figure 28 441 - 443 are disclosed in the order of appearance.

[0076] Figure 29 Shows the structure of an exemplary conjugate (including a peptide, a linker, and a radionuclide) comprising a covalently bound radionuclide of the present disclosure text. Detailed Description

[0077] The following description and examples detail the embodiments of the present disclosure text. It should be understood that the present disclosure text is not limited to the specific embodiments described herein and can thus vary. Those skilled in the art will recognize that various changes and modifications of the present disclosure text are encompassed within the scope of the present disclosure text.

[0078] Although various features of the present disclosure text 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 text may be described in the context of separate embodiments for clarity, the present disclosure text may also be implemented in a single embodiment.

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

[0080] All terms are intended to be understood as understood by those skilled in the art. Unless otherwise defined, 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 present disclosure text pertains.

[0081] The following definitions supplement those in the art and pertain to the present application and are not to be classified in any related or unrelated cases, such as any co-owned patents or applications. Although any methods and materials similar or equivalent to those described herein may be used in the practice for testing the present disclosure text, the preferred materials and methods are described herein. Thus, the terms used herein are for the purpose of describing particular embodiments only and are not intended to be limiting. I. Definitions

[0082] As used in the specification and the appended claims, unless otherwise specified, the following terms have the meanings 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 "a medicament" includes a plurality of such medicaments, and reference to "the cell" includes reference to one or more cells (or cell populations) and equivalents thereof known to those skilled in the art, and so on. When ranges are used herein with respect to physical properties (such as molecular weight) or chemical properties (such as chemical formula), all combinations and sub-combinations of the ranges and specific embodiments therein are intended to be included.

[0084] The term "about" or "approximately" can mean within an acceptable error range of a particular value as determined by one of ordinary skill in the art, which error range depends in part on how the value is measured or determined, i.e., the limitations of the measuring system. For example, according to the practice in the art, "about" can mean within one or more standard deviations. 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, especially with respect to biological systems or processes, the term can mean within an order of magnitude of the value, within 5-fold of the value, or within 2-fold of the value.

[0085] The term "comprising" (and related terms such as "comprise", "comprises", or "having" or "including") should be interpreted in an open, inclusive sense, i.e., "including but not limited to". The term "comprising" (and related terms such as "comprise", "comprises", or "having" or "including") is not intended to exclude in certain other embodiments described herein (such as embodiments of any substance composition, composition, method, or process, etc.) "consisting of the described features" or "consisting essentially of the described features".

[0086] "Amino" refers to the -NH2 group.

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

[0088] "Nitro" means the -NO2 group.

[0089] "Oxo group" means the =O group.

[0090] "Imino group" means the =N-H group.

[0091] "Oximino group" means the =N-OH group.

[0092] "Hydrazino group" means the =N-NH2 group.

[0093] "Hydroxy" or "hydroxyl" means the -OH group.

[0094] "Hydroxyamino" means the -NH-OH group.

[0095] "Acyl group" means a substituted or unsubstituted alkylcarbonyl, a substituted or unsubstituted alkenylcarbonyl, a substituted or unsubstituted alkynylcarbonyl, a substituted or unsubstituted cycloalkylcarbonyl, a substituted or unsubstituted heterocycloalkylcarbonyl, a substituted or unsubstituted arylcarbonyl, a substituted or unsubstituted heteroarylcarbonyl, an amide or an ester, wherein the carbonyl atom of the carbonyl group is the point of attachment. Unless specifically stated otherwise in the specification, the alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkylcarbonyl, amide group or ester group is optionally substituted, for example, by an oxo group, a halogen, an amino group, a nitrile, a nitro group, a hydroxy group, a haloalkyl group, an alkoxy group, an aryl group, a cycloalkyl group, a heterocycloalkyl group, a heteroaryl group, etc.

[0096] "Alkyl" means an optionally substituted straight-chain or optionally substituted branched-chain saturated hydrocarbon monovalent group. The alkyl 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, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl and hexyl, and longer alkyls (such as heptyl, octyl, etc.). When it appears herein, a numerical range such as "C1-C6 alkyl" means that the alkyl consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although this definition also covers the occurrence of the term "alkyl" where no numerical range is specified. In some embodiments, the alkyl is C1-C10 Alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, or C1 alkyl. Unless otherwise specifically stated in the specification, the alkyl is optionally substituted, for example, with an oxo group, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkyl is optionally substituted with an oxo group, halogen, -CN, -CF3, -OH, -OMe, -NH2, -NO2, or -C≡CH. In some embodiments, the alkyl is optionally substituted with an oxo group, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0097] "Alkylene" refers to a straight-chain or branched-chain divalent hydrocarbon chain. Unless otherwise specifically stated in the specification, the alkylene can be optionally substituted, for example, with an oxo group, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkylene is optionally substituted with an oxo group, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkylene is optionally substituted with an oxo group, 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 monovalent group having one or more carbon-carbon double bonds. In some embodiments, the alkenyl has two to about ten carbon atoms, or two to about six carbon atoms. The group can be in the cis or trans configuration with respect to one or more double bonds and is understood to include both isomers. Examples include, but are not limited to, vinyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, etc. When it appears herein, a numerical range such as "C2-C6 alkenyl" means that the alkenyl can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses the occurrence of the term "alkenyl" where no numerical range is specified. In some embodiments, the alkenyl is C2-C 10Alkenyl, C2-C9 alkenyl, C2-C8 alkenyl, C2-C7 alkenyl, C2-C6 alkenyl, C2-C5 alkenyl, C2-C4 alkenyl, C2-C3 alkenyl, or C2 alkenyl. Unless specifically stated otherwise in the specification, the alkenyl is optionally substituted, for example, by oxo groups, halogens, amino groups, nitriles, nitro groups, hydroxyl groups, haloalkyl groups, alkoxy groups, aryl groups, cycloalkyl groups, heterocycloalkyl groups, heteroaryl groups, etc. In some embodiments, the alkenyl is optionally substituted by oxo groups, halogens, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is optionally substituted by oxo groups, halogens, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted by halogens.

[0099] The term "alkenylene" or "alkenylene chain" refers to an optionally substituted straight-chain or branched-chain divalent hydrocarbon chain in which there is at least one carbon-carbon double bond connecting the remainder of the molecule to the 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 monovalent group having one or more carbon-carbon triple bonds. In some embodiments, the alkynyl 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, etc. When it appears herein, a numerical range such as "C2-C6 alkynyl" means that the alkynyl can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses the occurrence of the term "alkynyl" where no numerical range is specified. In some embodiments, the alkynyl is C2-C 10Alkynyl, C2-C9 alkynyl, C2-C8 alkynyl, C2-C7 alkynyl, C2-C6 alkynyl, C2-C5 alkynyl, C2-C4 alkynyl, C2-C3 alkynyl, or C2 alkynyl. Unless otherwise specifically stated in the specification, the alkynyl is optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkynyl is optionally substituted by oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted by oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted by halogen. The term "alkynylene" refers to an optionally substituted straight-chain or optionally substituted branched divalent hydrocarbon having one or more carbon-carbon triple bonds.

[0101] "Alkylamino" refers to a group of the formula -N(R a )2, where R a is alkyl as defined, or two R a together with the nitrogen atom can form a substituted or unsubstituted C2-C7 heterocycloalkyl ring. Unless otherwise specifically stated in the specification, the alkylamino can be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkylamino is optionally substituted by oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, the alkylamino is optionally substituted by oxo, halogen, -CN, -CF3, -OH or -OMe. In some embodiments, the alkylamino is optionally substituted by halogen.

[0102] "Alkoxy" is a group of the formula -OR a , where R a is alkyl as defined. Unless otherwise specifically stated in the specification, the alkoxy can be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkoxy is optionally substituted by oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted by oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted by halogen.

[0103] "Aminoalkyl" means an alkyl group substituted with one or more amines as defined above. In some embodiments, the alkyl group is substituted with one amine. In some embodiments, the alkyl group is substituted with one, two or three amines. Hydroxyalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl or aminopentyl. In some embodiments, the hydroxyalkyl is aminomethyl.

[0104] The term "aryl" means a group containing at least one aromatic ring, wherein each atom forming the ring is a carbon atom. The aryl group may be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. In some embodiments, the aryl group is phenyl. Depending on the structure, the aryl group may be a monovalent or divalent group (i.e., arylene). Unless otherwise specifically stated in the specification, the term "aryl" or the prefix "ar-" (as in "aralkyl") is meant to include an optionally substituted aryl group. In some embodiments, the aryl group contains a partially reduced cycloalkyl group as defined herein (e.g., 1,2-dihydronaphthalene). In some embodiments, the aryl group contains a fully reduced cycloalkyl group as defined herein (e.g., 1,2,3,4-tetrahydronaphthalene). When the aryl group contains a cycloalkyl group, the aryl group is bonded to the remainder of the molecule through an aromatic ring carbon atom. The aryl group may be a monocyclic or polycyclic (e.g., bicyclic, tricyclic or tetracyclic) ring system, which may include a fused ring system, a spiro ring system or a bridged ring system. Unless otherwise specifically stated in the specification, the aryl group may be optionally substituted, for example, with halogen, amino, alkylamino, aminoalkyl, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -S(O)2NH-C1-C6 alkyl, etc. In some embodiments, the aryl group 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, the aryl group is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl group is optionally substituted with halogen. In some embodiments, the aryl group 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 group in which each atom forming the ring (i.e., the backbone atoms) is a carbon atom. In some embodiments, the cycloalkyl is saturated or partially unsaturated. In some embodiments, the cycloalkyl is a spiro compound or a bridged compound. In some embodiments, the cycloalkyl is fused to an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having 3 to 10 ring atoms. Representative cycloalkyl groups include, but are not limited to, cycloalkyl groups having three to ten carbon atoms, three to eight carbon atoms, three to six carbon atoms, or three to five carbon atoms. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the monocyclic cycloalkyl group is cyclopentyl. In some embodiments, the monocyclic cycloalkyl group is cyclopentenyl or cyclohexenyl. In some embodiments, the monocyclic cycloalkyl group is cyclopentenyl. Polycyclic groups include, for example, adamantyl, 1,2-dihydronaphthyl, 1,4-dihydronaphthyl, tetrainyl, decahydronaphthyl, 3,4-dihydronaphthalen-1(2H)-one, spiro[2.2]pentyl, norbornyl, and bicyclo[1.1.1]pentyl. Unless specifically stated otherwise in the specification, the cycloalkyl may be optionally substituted. Representative cycloalkyl groups include, but are not limited to, cycloalkyl groups having three to fifteen carbon atoms (C3-C 15 cycloalkyl), cycloalkyl groups having three to ten carbon atoms (C3-C 10cycloalkyl), cycloalkyl having three to eight carbon atoms (C3-C8 cycloalkyl), cycloalkyl having three to six carbon atoms (C3-C6 cycloalkyl), cycloalkyl having three to five carbon atoms (C3-C5 cycloalkyl), or cycloalkyl having three to four carbon atoms (C3-C4 cycloalkyl). 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, decahydronaphthyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decahydronaphthalene, trans-decahydronaphthalene, 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]heptyl. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless specifically stated otherwise in the specification, the cycloalkyl is optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the cycloalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the cycloalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted by halogen.

[0106] "halo group" or "halogen" refers to bromine, chlorine, fluorine or iodine. In some embodiments, the halogen is fluorine or chlorine. In some embodiments, the halogen is fluorine.

[0107] "haloalkyl" refers to an alkyl substituted by one or more halogens as defined above. In some embodiments, the alkyl is substituted by one, two or three halogens. In some embodiments, the alkyl is substituted by one, two, three, four, five or six halogens. Haloalkyls can include, for example, iodoalkyl, bromoalkyl, chloroalkyl and fluoroalkyl. For example, "fluoroalkyl" refers to an alkyl as defined above, which is substituted by one or more fluorine groups as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl moiety of the fluoroalkyl is optionally substituted as defined above for alkyl.

[0108] "Heteroalkyl" means an alkyl group in which one or more backbone atoms of the alkyl group are selected from atoms other than carbon (such as oxygen, nitrogen (such as -NH-, -N(alkyl)-), sulfur, or combinations thereof). The heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C1-C6 heteroalkyl, wherein the heteroalkyl consists of 1 to 6 carbon atoms and one or more atoms other than carbon (such as oxygen, nitrogen (such as -NH-, -N(alkyl)-), sulfur, or combinations thereof), and wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls are, for example, -CH2-O-CH2-, -CH2-N(alkyl)-CH2-, -CH2-N(aryl)-CH2-, -OCH2CH2O-, -OCH2CH2OCH2CH2O-, or -OCH2CH2OCH2CH2OCH2CH2O-. Unless specifically stated otherwise in the specification, the heteroalkyl is optionally substituted, for example, by oxo groups, halogens, amino groups, nitriles, nitro groups, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, aryl groups, cycloalkyl groups, heterocycloalkyl groups, heteroaryl groups, etc. In some embodiments, the heteroalkyl is optionally substituted by oxo groups, halogens, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroalkyl is optionally substituted by oxo groups, halogens, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted by halogens. As used herein, "heteroalkylene" means a divalent heteroalkyl. Examples of such heteroalkylenes are, for example, -CH2-O-CH2-, -CH2-N(alkyl)-CH2-, -CH2-N(aryl)-CH2-, -OCH2CH2O-, -OCH2CH2OCH2CH2O-, or -OCH2CH2OCH2CH2OCH2CH2O-. Unless otherwise specified, the heteroalkylene may be optionally substituted.

[0109] The term "heterocycloalkyl" refers to a cycloalkyl group that contains at least one heteroatom (e.g., a heteroatom selected from nitrogen, oxygen, and sulfur). Unless specifically stated otherwise in the specification, heterocycloalkyl can be a monocyclic or bicyclic ring system, which can include a fused ring system (when fused to an aryl or heteroaryl ring, heterocycloalkyl is bonded through a non-aromatic ring atom) or a bridged ring system. The nitrogen, carbon, or sulfur atoms in the heterocyclic group can be optionally oxidized. The nitrogen atom can be optionally quaternized. Heterocycloalkyl is partially saturated or fully saturated. Examples of heterocycloalkyl include, but are not limited to, dioxolanyl, thieno[1,3]dithiolanyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithiolanyl, tetrahydropyranyl, thiomorpholinyl, thioxomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl. The term heterocycloalkyl also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. Unless otherwise noted, heterocycloalkyl has 2 to 12 carbons in the ring. In some embodiments, heterocycloalkyl has 2 to 10 carbons in the ring. In some embodiments, heterocycloalkyl has 2 to 10 carbons and 1 or 2 N atoms in the ring. In some embodiments, heterocycloalkyl has 2 to 10 carbons and 3 or 4 N atoms in the ring. In some embodiments, heterocycloalkyl has 2 to 12 carbons, 0 - 2 N atoms, 0 - 2 O atoms, 0 - 2 P atoms, and 0 - 1 S atom in the ring. In some embodiments, heterocycloalkyl has 2 to 12 carbons, 1 - 3 N atoms, 0 - 1 O atom, and 0 - 1 S atom in the ring. It should be understood that when referring to the number of carbon atoms in heterocycloalkyl, the number of carbon atoms in heterocycloalkyl is different from the total number of atoms (including heteroatoms) that make up heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring). Unless specifically stated otherwise in the specification, heterocycloalkyl is optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heterocycloalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heterocycloalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heterocycloalkyl is optionally substituted by halogen.

[0110] "Heteroaryl" refers to a cyclic system group containing one or more carbon atoms and one or more ring heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl is monocyclic, bicyclic, or polycyclic. Illustrative examples of monocyclic heteroaryl include pyridyl, 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, quinazoline, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. Illustrative examples of monocyclic heteroaryl include pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Illustrative examples of bicyclic heteroaryl include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinazoline, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, the heteroaryl is pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl, or furyl. In some embodiments, the heteroaryl contains 0 - 6 N atoms in the ring. In some embodiments, the heteroaryl contains 1 - 4 N atoms in the ring. In some embodiments, the heteroaryl contains 4 - 6 N atoms in the ring. In some embodiments, the heteroaryl contains 0 - 4 N atoms, 0 - 1 O atom, 0 - 1 P atom, and 0 - 1 S atom in the ring. In some embodiments, the heteroaryl contains 1 - 4 N atoms, 0 - 1 O atom, and 0 - 1 S atom in the ring. In some embodiments, the heteroaryl is a C1 - C9 heteroaryl. In some embodiments, the monocyclic heteroaryl is a C1 - C5 heteroaryl. In some embodiments, the monocyclic heteroaryl is a 5 - or 6 - membered heteroaryl. In some embodiments, the bicyclic heteroaryl is a C6 - C9 heteroaryl. In some embodiments, the heteroaryl contains a partially reduced cycloalkyl or heterocycloalkyl as defined herein (e.g., 7,8 - dihydroquinoline). In some embodiments, the heteroaryl contains a fully reduced cycloalkyl or heterocycloalkyl as defined herein (e.g., 5,6,7,8 - tetrahydroquinoline). When the heteroaryl contains a cycloalkyl or heterocycloalkyl, the heteroaryl is bonded to the remainder of the molecule through a heteroaromatic carbon or heteroatom. The heteroaryl can be a monocyclic or polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) ring system, which can include a fused ring system, a spiro ring system, or a bridged ring system. Unless specifically stated otherwise in the specification, the heteroaryl is optionally substituted, for example, by halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc.In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the 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 particular segment or functional group of a molecule. Chemical moieties are generally recognized chemical entities that are incorporated into or appended to a molecule.

[0112] As used herein, the terms "treat", "prevent", "alleviate", and "inhibit" and words derived therefrom do not necessarily imply 100% or complete treatment, prevention, alleviation, or inhibition. Rather, there are varying degrees of treatment, prevention, alleviation, and inhibition that are considered by those of ordinary skill in the art to have potential benefit or therapeutic effect. In this regard, the disclosed methods can provide any amount and any level of treatment, prevention, alleviation, or inhibition of a disorder in a mammal. For example, the disorder (including its symptoms or conditions) can 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%. In addition, the treatment, prevention, alleviation, or inhibition provided by the methods disclosed herein can include treatment, prevention, alleviation, or inhibition of one or more conditions or symptoms of a disorder (such as cancer or an inflammatory disease). As used herein, "treatment" includes the concept of "remission", which refers to reducing the frequency of occurrence or recurrence of any symptom or other adverse effect associated with a disorder and / or related side effects or reducing the severity of said symptom or other adverse effect. The term "treatment" also encompasses the concept of "management", which refers to reducing the severity of a particular disease or disorder in a patient or delaying its recurrence, such as prolonging the remission period of a patient already suffering from the disease.

[0113] In certain embodiments, the terms "prevent" or "preventing" in relation to a disease or disorder can refer to a compound that, in a statistical sample, reduces the incidence of a disorder or condition in a treated sample relative to an untreated control sample, or delays the onset of one or more symptoms of a disorder or condition or reduces the severity of one or more symptoms of a disorder or condition relative to an untreated control sample.

[0114] As used herein, the term "therapeutically effective amount" refers to an amount that is effective at the dosage and for the duration required to achieve the desired therapeutic result. The therapeutically effective amount of a composition can vary depending on factors such as the condition of the individual, age, sex, and weight, as well as the ability of the protein to elicit the desired response in the individual. A therapeutically effective amount can also be an amount that exceeds any toxic or harmful effects of the composition and has a beneficial effect on treatment.

[0115] The term "optional" or "optionally" means that the subsequent described event or circumstance may or may not occur, and the description includes the case where the event or circumstance occurs and the case where the event or circumstance does not occur. For example, "optionally substituted alkyl" means "alkyl" as defined above or "substituted alkyl". In addition, an optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F) or substituted at any level between fully substituted and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.).

[0116] As used herein, the term "substituent" means a positional variable on an atom of a core molecule that is substituted at a specified atomic position, replacing one or more hydrogens on the specified atom, provided that the normal valence of the specified atom is not exceeded and the substitution results in a stable compound. Such combinations are permissible only when the combination of substituents and / or variables results in a stable compound. One of ordinary skill in the art will note that any carbon and heteroatom having an unsatisfied valence as described or shown herein is assumed to have a sufficient number of hydrogen atoms to satisfy the valence as described or shown. In some cases, one or more substituents having a double bond (e.g., "oxo group" or "=O") as an attachment point may be described, shown or listed herein within the substituents, where the structure may only show a single bond as the attachment point to the core structure. One of ordinary skill in the art will understand that although only a single bond is shown, the double bond is still intended for those substituents.

[0117] The terms "optionally substituted" or "substituted" mean that the reference group is optionally substituted by one or more additional groups individually and independently selected from the group consisting of D, halogen, -CN, -NH2, -NH(alkyl), -N(alkyl), -OH, oxo, -C02H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl), -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl), alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone, and aryl sulfone. In some other embodiments, the optional substituents are independently selected from D, halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, oxo, -CO2H, -CO2(C1-C4 alkyl), -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C4 alkyl), -S(=O)2N(C1-C4 alkyl)2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, -SC1-C4 alkyl, -S(=O)C1-C4 alkyl and -S(=O)2C1-C4 alkyl. In some embodiments, the 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, the substituted groups are substituted by one or two of the aforementioned groups. In some embodiments, the optional substituents on aliphatic carbon atoms (acyclic or cyclic) include oxo (=O). When indicating the number of substituents, the term "one or more" means substitution from one substituent to the highest possible number, i.e., substitution of one hydrogen up to substitution of all hydrogens.

[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 are within the scope of the present disclosure.

[0120] Unless otherwise stated, structures depicted herein are also intended to include all stereochemical forms of the structure; that is, 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 present disclosure.

[0121] As used herein, the term "peptide" refers to a compound comprising two or more amino acids. The peptides described herein may include one or more non-natural amino acids. The term "peptide" also encompasses peptidomimetics. In the present disclosure, the term "amino acid" is used in its broadest sense and encompasses not only natural amino acids but also their derivatives and artificial amino acids. For example, the term "amino acid" encompasses non-natural amino acids.

[0122] As used herein, the term "non-natural amino acid" refers to an amino acid other than the 20 canonical amino acids. The 20 canonical amino acids are 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] As used herein, the term "protein" refers to a polypeptide (i.e., a string of at least 3 amino acids linked to each other by peptide bonds). A protein may include moieties other than amino acids (e.g., it may be a glycoprotein, a proteoglycan, etc.) and / or may be otherwise processed or modified. A protein may be a complete polypeptide (with or without a signal sequence) produced by a cell and / or active in a cell. In some embodiments, the protein is or comprises a characteristic moiety, such as a polypeptide produced by a cell and / or active in a cell. A protein may include more than one polypeptide chain. For example, the polypeptide chains may be linked by one or more disulfide bonds or associated in other ways.

[0124] The term "peptidomimetic" or "mimetic" refers to a bioactive compound that mimics the biological activity of a peptide or protein but is no longer entirely a peptide in its chemical nature. For example, they may contain non-peptide bonds (i.e., bonds other than the amide bonds between amino acids). As used herein, the term peptidomimetic is used in a broader sense to include molecules that are no longer entirely peptides in nature, such as pseudopeptides, semipeptides, and peptoids. Whether completely non-peptide or partially non-peptide, the peptidomimetics described herein can provide a spatial arrangement of reactive chemical moieties that is very similar to the three-dimensional arrangement of the active groups in the subject amino acid sequence or the subject molecule on which the peptidomimetic is based. Due to this similar active site geometry, peptidomimetics can have an effect on biological systems that is similar to the biological activity of the subject entity.

[0125] In some embodiments, the peptidomimetic is substantially similar to the subject amino acid sequence or subject molecule upon which the peptidomimetic is based, both in three-dimensional shape and biological activity. Examples are described in the article “Tritiated D-ala1-PeptideT Binding”, Smith C.S. et al., Drug Development Res., 15, pp. 371-379 (1988). A second approach is to modify the cyclic structure to obtain stability, such as N-to-C chain acylimides and lactams (Ede et al. in Smith and Rivier (eds.) “Peptides: Chemistry and Biology”, Escom, Leiden (1991), pp. 268-270). Examples in this regard are provided in conformationally restricted thymopentin-like compounds, such as those disclosed in US4457489. A third approach is to replace peptide bonds in the subject entity with pseudopeptide bonds that confer proteolytic resistance.

[0126] The ranges provided herein are to be understood as shorthand for all values within the range. For example, the range 1 to 50 should be 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 intermediate fractional values between the above integers, such as 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” extending from either endpoint of the range are specifically contemplated. For example, nested sub-ranges of the exemplary range of 1 to 50 can include, in one direction, 1 to 10, 1 to 20, 1 to 30, and 1 to 40, or, in the other direction, 50 to 40, 50 to 30, 50 to 20, and 50 to 10.

[0127] As used herein, C1-C x (or C 1-x ) includes C1-C2, C1-C3 …… C1-C xBy way of example only, a group designated as "C1-C4" means that there are one to four carbon atoms in this part, that is, a group containing 1, 2, 3 or 4 carbon atoms. Thus, by way of example only, "C1-C4 alkyl" means that there are one to four carbon atoms in the alkyl group, that is, the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. In addition, by way of example, C0-C2 alkylene includes direct bond, -CH2- and -CH2CH2- linkages.

[0128] As used herein, the term "cyclized" or "cyclization" means that two amino acids that are separated from each other by at least one amino acid are directly or indirectly bound to each other in a peptide to form a cyclic structure in the molecule. In some cases, the two amino acids are bound 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 ape and monkey species; farm animals, such as cows, horses, sheep, goats, pigs; domestic animals, such as rabbits, dogs and cats; laboratory animals, which include rodents, such as rats, mice and guinea pigs, etc. 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] As used herein, the term "therapeutically effective amount" means an amount that is effective at a dose that achieves the desired therapeutic outcome. The therapeutically effective amount of a composition can vary depending on factors such as the condition of the individual (e.g., age, sex and weight), the radiopharmaceutical conjugate and the method of administration (e.g., oral or parenteral).

[0131] The percent sequence identity can be calculated using a computer program or direct sequence comparison. Preferred computer program methods for determining 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 the percent identity. Exemplary parameters for amino acid sequence comparison include the following: 1) the algorithm of Needleman and Wunsch (J. Mol. Biol., 48:443-453 (1970)); 2) the BLOSSUM62 comparison matrix of 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 is publicly available as the "GAP" program (Genetics Computer Group, Madison, Wis.). The above parameters are the default parameters for polypeptide comparison (no penalty for terminal gaps). Alternatively, the percent polypeptide sequence identity can be calculated using the following formula: percent identity = (number of identical residues) / (length of aligned amino acid residues) * 100. For this calculation, the length of alignment includes internal gaps but not terminal gaps.

[0132] It should be understood that certain features of the present disclosure that are described in the context of separate embodiments can also be provided in combination in a single embodiment. Conversely, for the sake of brevity, the various features of the present disclosure that are described in the context of a single embodiment can also be provided separately or in any suitable sub-combination. For example, the conjugates of the present disclosure can include any of the peptide ligands described herein (e.g., the peptide ligands of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), or (Ic) or Table 1), any of the metal chelators described herein (e.g., selected from Figure 4A , Figure 5A , Figure 6A , Figure 7A , Figure 4B , Figure 5B , Figure 6B , Figure 7B and Figures 8 - 22a metal chelator), optionally a linker as described herein (e.g., a linker of formula (II-1), (II-1a), (II-1b) or (II-2)), and optionally a radionuclide as described herein (e.g., the radionuclide labeled "chelator" in Table 7). As another example, a conjugate of the present disclosure may comprise any peptide ligand as 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 as described herein (e.g., the radionuclide labeled "covalent" in Table 7), and optionally a linker as described herein that links the covalent radionuclide to the peptide (e.g., a linker of formula (II-1), (II-1a), (II-1b) or (II-2) or Table 6). As a further example, a peptide of formula (I) (or any other formula such as (III-1), (III-2), (III-1-RI) and (III-2-RI)) may comprise amino acids X1 to X12 as described herein, and the present disclosure encompasses any combination of embodiments of the amino acids (even in some cases where they are described in the context of separate embodiments). II. Radiopharmaceutical Conjugates

[0133] The present disclosure provides radiopharmaceutical conjugates that have an affinity for ephrin type-A receptor 2 (EphA2) and pharmaceutical compositions comprising the conjugates. The conjugates and compositions can be used for treating cancer. The conjugates and compositions can also be used for imaging and disease diagnosis.

[0134] In one aspect, the present disclosure describes a conjugate that comprises a peptide having an affinity for ephrin type-A receptor 2 (EphA2) and a metal chelator configured to bind to a radionuclide. In some embodiments, EphA2 is human EphA2. In some embodiments, the conjugate or peptide described herein does not have an affinity for human EphA1, EphA3, EphA4, EphA5, EphA6, EphA7 or EphB4. In some embodiments, the conjugate or 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, the present disclosure describes a conjugate that comprises a cyclic peptide and a metal chelator configured to bind to a radionuclide. In some embodiments, the peptide (such as a cyclic peptide) is configured to bind to a target. The conjugate described herein may further comprise a linker that covalently attaches the peptide to the metal chelator. In some embodiments, the conjugate comprises a radionuclide that binds to the metal chelator, such as 225 Ac.

[0135] In another aspect, the present disclosure describes a conjugate comprising a peptide having an affinity for ephrin type-A receptor 2 (EphA2) and a covalently attached radionuclide. In some embodiments, EphA2 is human EphA2. In some embodiments, the conjugate or peptide described herein does not have an affinity for human EphA1, EphA3, EphA4, EphA5, EphA6, EphA7, or EphB4. In some embodiments, the conjugate or 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, the present disclosure describes a conjugate comprising a cyclic peptide and a covalently attached radionuclide. In some embodiments, the peptide (such as a cyclic peptide) is configured to bind to a target. The conjugate described herein can further comprise a linker that covalently attaches the peptide to the radionuclide. In some embodiments, the conjugate comprises a covalently attached radionuclide, such as 131 I.

[0136] In one aspect, the present disclosure describes a radiopharmaceutical conjugate comprising: (a) a peptide having an affinity for ephrin type-A receptor 2 (EphA2), wherein the peptide comprises an amino acid sequence including one or more amino acid deletions, substitutions, and / or additions of the amino acids of SEQ ID NO:1 below: 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 to 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 to a radionuclide, wherein the metal chelator is conjugated to the peptide. In some embodiments, the metal chelator is covalently linked 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 having 2 or fewer amino acid deletions from amino acid SEQ ID NO:1. In some embodiments, 1-2 amino acid deletions are selected from T at position 10 and E at position 11 of SEQ ID NO:1. In some embodiments, V at position 8 of SEQ ID NO:1 is substituted. In some embodiments, E at position 11 of SEQ ID NO:1 is substituted.

[0138] In one aspect, the present disclosure describes a radiopharmaceutical conjugate comprising: (a) a peptide that has an affinity 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 containing an aromatic ring, its N-methylated amino acid, 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 containing an aromatic ring, or its N-methylated amino acid; X7 is an amino acid containing an aromatic ring (e.g., W, F, or a variant thereof); X8 is a hydrophobic amino acid, a hydrophilic amino acid, its N-methylated amino acid, or a variant; X9 is an amino acid containing an aromatic ring (e.g., W, or a variant thereof); X10 is absent or is a hydrophilic amino acid (e.g., threonine (T), or a variant thereof); X11 is absent or is a hydrophilic amino acid; and X12 is cysteine (C), or a variant thereof; and (b) (i) a metal chelator configured to bind to 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 to a radionuclide, wherein the metal chelator is conjugated to the peptide. In some embodiments, the metal chelator is covalently linked 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 an affinity 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 containing an aromatic ring, its N-methylated amino acid, or a variant thereof; X3 is absent or 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 absent or is a hydrophobic amino acid (e.g., leucine (L)), a hydrophilic amino acid (e.g., citrulline (Cit)), or a variant thereof; X5 is absent or is a hydrophilic amino acid or a variant thereof; X6 is absent or is a hydrophilic amino acid, an amino acid containing an aromatic ring, or its N-methylated amino acid; X7 is an amino acid containing an aromatic ring (e.g., W, F, or a variant thereof); X8 is a hydrophobic amino acid, a hydrophilic amino acid, its N-methylated amino acid, or a variant; X9 is an amino acid containing an aromatic ring (e.g., W, or a variant thereof); X10 is absent or is a hydrophilic amino acid (e.g., threonine (T), or a variant thereof); X11 is absent or is a hydrophilic amino acid; and X12 is cysteine (C) or a variant thereof; and (b) (i) a metal chelator configured to bind to 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 to a radionuclide, wherein the metal chelator is conjugated to the peptide. In some embodiments, the metal chelator is covalently linked 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, the present disclosure describes a radiopharmaceutical conjugate comprising: (a) a peptide that has an affinity 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 is an amino acid; and X12 is cysteine (C) or a variant thereof; (b) (i) a metal chelator configured to bind to a radionuclide; or (ii) a covalent radionuclide; and (c) (i) a linker that links the peptide to the metal chelator; or (ii) a linker that links the peptide to the covalent radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a metal chelator configured to bind to a radionuclide and a linker that links the peptide to the metal chelator. In some embodiments, the metal chelator is covalently linked to the peptide. In some embodiments, the radiopharmaceutical conjugate comprises a covalent radionuclide and a linker that links the peptide to 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 to the metal chelator. In some embodiments, the linker covalently connects the peptide to 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 attaches to the peptide via a non-terminal amino acid residue of the peptide. In some embodiments, the linker attaches to amino acid X1. In some embodiments, the linker attaches to amino acid X2. In some embodiments, the linker attaches to amino acid X3. In some embodiments, the linker attaches to amino acid X4. In some embodiments, the linker attaches to amino acid X5. In some embodiments, the linker attaches to amino acid X6. In some embodiments, the linker attaches to amino acid X7. In some embodiments, the linker attaches to amino acid X8. In some embodiments, the linker attaches to amino acid X9. In some embodiments, the linker attaches to amino acid X10. In some embodiments, the linker attaches to amino acid X11. In some embodiments, the linker attaches to amino acid X12. In some embodiments, the linker attaches to amino acid X5, X8, or X11. In some embodiments, the linker attaches to a lysine of the peptide. In some embodiments, the linker comprises one or more amino acid residues. In some embodiments, the linker comprises lysine residues, alanine residues, or both.

[0142] In one aspect, a radiopharmaceutical conjugate is described herein that has the following structure: where represents a linker.

[0143] In one aspect, a radiopharmaceutical conjugate is described herein that has the following structure: where represents a linker that is 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 to the covalent radionuclide. In some embodiments, the linker covalently connects the peptide to 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 attaches to the peptide via a non-terminal amino acid residue of the peptide. In some embodiments, the linker attaches to amino acid X1. In some embodiments, the linker attaches to amino acid X2. In some embodiments, the linker attaches to amino acid X3. In some embodiments, the linker attaches to amino acid X4. In some embodiments, the linker attaches to amino acid X5. In some embodiments, the linker attaches to amino acid X6. In some embodiments, the linker attaches to amino acid X7. In some embodiments, the linker attaches to amino acid X8. In some embodiments, the linker attaches to amino acid X9. In some embodiments, the linker attaches to amino acid X10. In some embodiments, the linker attaches to amino acid X11. In some embodiments, the linker attaches to amino acid X12. In some embodiments, the linker attaches to amino acid X5, X8, or X11. In some embodiments, the linker attaches 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 binds directly to the peptide. In some embodiments, the covalent radionuclide binds directly to the peptide via a non-terminal amino acid residue of the peptide. In some embodiments, the covalent radionuclide binds to an aromatic amino acid in the peptide. In some embodiments, the covalent radionuclide binds to amino acid X1. In some embodiments, the covalent radionuclide binds to amino acid X2. In some embodiments, the covalent radionuclide binds to amino acid X3. In some embodiments, the covalent radionuclide binds to amino acid X4. In some embodiments, the covalent radionuclide binds to amino acid X5. In some embodiments, the covalent radionuclide binds to amino acid X6. In some embodiments, the covalent radionuclide binds to amino acid X7. In some embodiments, the covalent radionuclide binds to amino acid X8. In some embodiments, the covalent radionuclide binds to amino acid X9. In some embodiments, the covalent radionuclide binds to amino acid X10. In some embodiments, the covalent radionuclide binds to amino acid X11. In some embodiments, the covalent radionuclide binds to amino acid X12. In some embodiments, the covalent radionuclide binds to amino acid X2, X6, X7, or X9.

[0146] In one aspect, the present disclosure describes a radiopharmaceutical conjugate having the following structure: wherein represents a linker; and R* represents a radionuclide.

[0147] In one aspect, the present disclosure describes a radiopharmaceutical conjugate having the following structure: wherein represents a linker attached to the C-terminus of the peptide; and R* represents a radionuclide.

[0148] In one aspect, the present disclosure describes a radiopharmaceutical conjugate having the following structure: wherein represents a residuation agent or a non-residuation agent; the linker represents a linker; and R* represents a radionuclide.

[0149] In one aspect, the present disclosure describes a radiopharmaceutical conjugate having the following structure: wherein represents a residuation agent or a non-residuation agent; the linker represents a linker attached to the C-terminus of the peptide; and R* represents a radionuclide.

[0150] In some embodiments, described herein is a conjugate comprising: (a) a targeting moiety comprising a monocyclic peptide having an affinity for ephrin type-A receptor 2 (EphA2), and (b) (i) a metal chelator configured to bind to a radionuclide; or (ii) a covalently bound radionuclide. In some embodiments, described herein is a conjugate comprising: (a) a monocyclic peptide configured to bind to EphA2 and (b) (i) a metal chelator configured to bind to a radionuclide; or (ii) a covalently bound radionuclide. In some embodiments, described herein is a conjugate comprising: (a) a targeting moiety comprising a monocyclic peptide; and (b) (i) a metal chelator configured to bind to a radionuclide; or (ii) a covalently bound radionuclide. In some embodiments, the monocyclic peptide is cyclized via a non-disulfide bond. In some embodiments, the monocyclic peptide does not contain 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. The conjugates described herein may further comprise a linker that covalently attaches the peptide ring to the metal chelator or the covalently bound radionuclide. In some embodiments, the conjugate comprises a radionuclide bound to the metal chelator, such as 225 Ac. In some embodiments, the conjugate comprises a covalently bound radionuclide, such as 18 F, 74 As, 76 Br, 123 I, 124 I, 125 I, 131 I and 211 At. In some embodiments, the covalently bound radionuclide is attached to the peptide or linker via a residuation agent or a non-residuation agent.

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

[0152] In some embodiments, the conjugates described herein are in salt form. In some embodiments, the conjugates described herein are in free base form.

[0153] In one aspect, the present disclosure describes a conjugate comprising (a) a peptide that has an affinity for ephrin type-A receptor 2 (EphA2), wherein the peptide competes with a peptide having an amino acid sequence with one or several amino acid deletions, substitutions, and / or additions among the amino acids of SEQ ID NO:1 below for binding to human EphA2: 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 to a radionuclide; or (ii) a covalently bound radionuclide. In one aspect, the present disclosure describes a conjugate comprising (a) a peptide that has an affinity for ephrin type-A receptor 2 (EphA2), wherein the peptide competes with a peptide having a structure of formula (I) as described herein (e.g., formula (I-1), (I-2), (I-3), or (I-4)) for binding to human EphA2; or a pharmaceutically acceptable salt thereof; and (b) (i) a metal chelator configured to bind to a radionuclide; or (ii) a covalently bound radionuclide. In some embodiments, the peptide competes with human EphA2 for binding at one or more amino acid residues selected from the group consisting of Asp53, Met55, Asn57, Met59, Met66, Thr101, Arg103, Phe156, Glu157, Arg159, Val161, Val189, and Ala190. In some embodiments, the peptide competes with human EphA2 for binding at one or more amino acid residues selected from Asp53, Phe156, and Glu157. In some embodiments, the peptide competes with human EphA2 for binding 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 directly or indirectly through a linker. In some embodiments, the metal chelator is conjugated to the peptide covalently or non-covalently. In some embodiments, the radionuclide is covalently bound to the peptide directly or indirectly through a linker.

[0155] The conjugate described herein may have a suitable plasma half-life (T 1 / 2)。In some embodiments, the plasma half-life of the 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°C. In some embodiments, the plasma half-life of the conjugate is at least 280 minutes, as determined in vitro in human plasma at 37°C. In some embodiments, the plasma half-life of the conjugate is at least 250 minutes, as determined in vitro in human plasma at 37°C. In some embodiments, the plasma half-life of the 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°C. 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 humans. In some embodiments, the plasma half-life is at least 280 minutes, as determined in vivo in humans. In some embodiments, the plasma half-life is at least 250 minutes, as determined in vivo in humans. In some embodiments, the plasma half-life of the conjugate is at most 30 days, 14 days, 7 days, 2 days, 1 day, or 500 minutes, as determined in vivo in humans. In some embodiments, the plasma half-life of the 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 mouse plasma at 37°C. In some embodiments, the plasma half-life of the conjugate is at least 280 minutes, as determined in vitro in mouse plasma at 37°C. In some embodiments, the plasma half-life of the conjugate is at least 250 minutes, as determined in vitro in mouse plasma at 37°C. In some embodiments, the plasma half-life of the 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°C. 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 mice. In some embodiments, the plasma half-life is at least 280 minutes, as determined in vivo in mice. In some embodiments, the plasma half-life is at least 250 minutes, as determined in vivo in mice. In some embodiments, the plasma half-life of the conjugate is at most 30 days, 14 days, 7 days, 2 days, 1 day, or 500 minutes, as determined in vivo in mice. The plasma half-life can be determined by any suitable method known in the art (e.g., the method described in Example C1). In some embodiments, the plasma half-life (T 1 / 2) is at least 250 minutes, as determined in vitro in human plasma at 37°C. In some embodiments, the plasma half-life is determined by testing the remaining percentage of the compound after incubation in plasma.

[0156] The conjugates described herein can have an uptake ratio between tumor and intestine. In some embodiments, the uptake ratio between the uptake of a radiopharmaceutical conjugate by a tumor and the uptake of the radiopharmaceutical conjugate by the kidney of a subject is determined. In some embodiments, the subject is a human. In some embodiments, the subject is a mammal. In some embodiments, the subject is a rat or a mouse (such as in a xenograft model). In some embodiments, in a human prostate xenograft mouse model, the uptake ratio (i.e., tumor uptake / kidney uptake) between the tumor uptake and the kidney uptake of a 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 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, the uptake ratio between the tumor uptake and the kidney uptake of a radiopharmaceutical conjugate is at least 1.2. In some embodiments, the uptake ratio between the tumor uptake and the kidney uptake of a radiopharmaceutical conjugate is at least 1.5. In some embodiments, the tumor uptake of a radiopharmaceutical conjugate is at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% higher than the kidney uptake of the radiopharmaceutical conjugate in the same subject compared to the kidney uptake of the radiopharmaceutical conjugate described herein.

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

[0158] In some embodiments, the conjugates described herein are designed to have a defined elimination profile. The elimination profile can be designed by modulating the sequence and length of the peptide, the properties of the linker, the type of radionuclide, etc. In some embodiments, the elimination half-life of the conjugate is from about 30 minutes to 120 hours. In some embodiments, the elimination half-life of the conjugate is from about 1 to 120 hours. In some embodiments, the elimination half-life of the conjugate is 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 elimination half-life of the conjugate is at most 120 hours, 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 elimination half-life of the conjugate is from about 2 to 24 hours. In some embodiments, the elimination half-life of the conjugate is from about 3 to 9 hours. In some embodiments, the elimination half-life of the conjugate is from about 2 to 12 hours. In some embodiments, the elimination half-life of the conjugate is from about 2 to 8 hours. In some embodiments, the elimination half-life of the conjugate is from about 2 to 5 hours. In some embodiments, the elimination half-life of the conjugate is from 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] The conjugates described herein can have an elimination half-life in the tumor and non-tumor tissues of a subject. The elimination half-life in the tumor can be the same as or different from (longer or shorter than) the elimination half-life in the non-tumor tissue. In some embodiments, the elimination half-life of the conjugate in the tumor is from about 3 hours to 14 days, from about 2 to 10 days, from about 7 to 10 days, or from about 4 to 7 days. In some embodiments, the elimination half-life of the conjugate in the tumor is greater than 14 days. In some embodiments, the elimination half-life of the conjugate in the non-tumor tissue is from about 1 hour to 14 days, from about 12 hours to 2 days, from about 1 day to 3 days, from about 2 to 10 days, from about 7 to 10 days, or from about 4 to 7 days. In some embodiments, the elimination half-life of the conjugate in the tumor of a subject is at least 1.1, 1.2, 1.3, 1.4, 1.5, 2.0, 2.5, 3.0, 4.0, or 5.0 times the elimination half-life of the conjugate in the non-tumor tissue.

[0160] As used herein, "elimination half-life" can refer to the time taken from the maximum concentration after administration to the 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 the biological half-life, which is the half-life of a cold drug in a living system. In some embodiments, the elimination half-life is measured as the 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 modulated by reversible binding between the conjugate and plasma proteins such as albumin. A suitable affinity between the conjugate and the plasma protein can utilize the plasma protein as a reservoir for the conjugate, thereby attaching and preserving the conjugate at a high concentration and releasing the conjugate at a lower concentration, thus improving the elimination profile. In some embodiments, the dissociation constant (Kd) between the conjugate and human serum albumin is at most 500 μM, as determined at room temperature under human serum conditions. 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, the conjugates of the present disclosure are selected from Table 2A-Lu, 2A-Lu177, 2A-Ac255, 2B, 2BLu, 2B-Lu177, 2B-Ac255, and 2C. In some embodiments, the conjugates of the present disclosure are selected from Table 2A-Ac255 and 2B-Ac255. In some embodiments, the conjugates of the present disclosure comprise the peptide of Table 1, a chelator selected from Figure 4- Figure 22 and the radionuclide labeled "chelator" in Table 7. In some embodiments, the conjugates of the present disclosure comprise Figures 1 - 3 the conjugate of. In some embodiments, the conjugates of the present disclosure comprise the peptide of Table 1 and the radionuclide labeled "covalent" in Table 7. In some embodiments, the conjugates of the present disclosure comprise the peptide of Table 1, a linker, and the radionuclide labeled "covalent" in Table 7. In some embodiments, the conjugates of the present disclosure comprise Figures 27 - 29 the conjugate of. EphA2

[0163] EPH receptor A2 (Ephrin type-A receptor 2) is a protein encoded by the EPHA2 gene in humans. EphA2 may be upregulated in a variety of cancers and is typically associated with disease progression, metastasis, and poor prognosis, such as in solid tumors such as breast cancer, lung cancer, gastric cancer, pancreatic cancer, prostate cancer, liver cancer, and glioblastoma.

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

[0165] In addition to other pattern formation functions, various Ephs and ephrins have been shown to play a role in blood vessel development. Knockout of EphB4 and ephrin-B2 can lead to the failure of capillary beds to remodel into blood vessels and embryonic lethality. Persistent expression of some Eph receptors and ephrins has also been observed in newly formed adult microvessels (Brantley-Sieders et al. (2004) Curr Pharm Des 10, 3431-42). The deregulated re-emergence of some ephrins and their receptors in adults can contribute to tumor invasion, metastasis, and neovascularization. In addition, some Eph family members may be overexpressed on tumor cells from a variety of human tumors (Booth et al. (2002) Nat Med 8, 1360-1).

[0166] Human EphA2 can have the sequence according to the following Seq ID NO: 276 (isoform 1, P29317-1): MELQAARACFALLWGCALAAAAAAQGKEVVLLDFAAAGGELGWLTHPYGKGWDLMQNIMNDMPIYMYSVCNVMSGDQDNWLRTNWVYRGEAERIFIELKFTVRDCNSFPGGASSCKETFNLYYAESDLDYGTNFQKRLFTKIDTIAPDEITVSSDFEARHVKLNVEERSVGPLTRKGFYLAFQDIGACVALLSVRVYYKKCPELLQGLAHFPETIAGSDAPSLATVAGTCVDHAVVPPGGEEPRMHCAVDGEWLVPIGQCLCQAGYEKVEDACQACSPGFFKFEASESPCLECPEHTLPSPEGATSCECEEGFFRAPQDPASMPCTRPPSAPHYLTAVGMGAKVELRWTPPQDSGGREDIVYSVTCEQCWPESGECGPCEASVRYSEPPHGLTRTSVTVSDLEPHMNYTFTVEARNGVSGLVTSRSFRTASVSINQTEPPKVRLEGRSTTSLSVSWSIPPPQQSRVWKYEVTYRKKGDSNSYNVRRTEGFSVTLDDLAPDTTYLVQVQALTQEGQGAGSKVHEFQTLSPEGSGNLAVIGGVAVGVVLLLVLAGVGFFIHRRRKNQRARQSPEDVYFSKSEQLKPLKTYVDPHTYEDPNQAVLKFTTEIHPSCVTRQKVIGAGEFGEVYKGMLKTSSGKKEVPVAIKTLKAGYTEKQRVDFLGEAGIMGQFSHHNIIRLEGVISKYKPMMIITEYMENGALDKFLREKDGEFSVLQLVGMLRGIAAGMKYLANMNYVHRDLAARNILVNSNLVCKVSDFGLSRVLEDDPEATYTTSGGKIPIRWTAPEAISYRKFTSASDVWSFGIVMWEVMTYGERPYWELSNHEVMKAINDGFRLPTPMDCPSAIYQLMMQCWQQERARRPKFADIVSILDKLIRAPDSLKTLADFDPRVSIRLPSTSGSEGVPFRTVSEWLESIKMQQYTEHFMAAGYTAIEKVVQMTNDDIKRIGVRLPGHQKRIAYSLLGLKDQVNTVGIPI(SEQ ID NO:276).

[0167] Human EphA2 may have the sequence according to SEQ ID NO: 277 below (isoform 2, P29317-2): MELQAARACFALLWGCALAAAAAAQGKEVVLLDFAAAGGELGWLTHPYGKGWDLMQNIMNDMPIYMYSVCNVMSGDQDNWLRTNWVYRGEAERIFIELKFTVRDCNSFPGGASSCKETFNLYYAESDLDYGTNFQKRLFTKIDTIAPDEITVSSDFEARHVKLNVEERSVGPLTRKGFYLAFQDIGACVALLSVRVYYKKCPELLQGLAHFPETIAGSDAPSLATVAGTCVDHAVVPPGGEEPRMHCAVDGEWLVPIGQCLCQAGYEKVEDACQACSPGFFKFEASESPCLECPEHTLPSPEGATSCECEEGFFRAPQDPASMPCTRPPSAPHYLTAVGMGAKVELRWTPPQDSGGREDIVYSVTCEQCWPESGECGPCEASVRYSEPPHGLTRTSVTVSDLEPHMNYTFTVEARNGVSGLVTSRSFRTASVSINQTEPPKVRLEGRSTTSLSVSWSIPPPQQSRVWKYEVTYRKKVTPRGAGLALAGPTAGDRLVT (SEQ ID NO: 277).

[0168] As used herein, the expression "having an affinity for EphA2" or "binding to EphA2" means having the activity of binding to EphA2. The binding site of the peptides of the present disclosure on EphA2 is not limited, and the peptides may bind to any position on the EphA2 protein. The binding to EphA2 can be measured by any method for measuring the binding between known molecules. By way of non-limiting example, this can be determined by competitive binding assays (such as surface plasmon resonance (SPR) assays, scattering assays, and / or radioimmunoassay (RIA), enzyme immunoassay (EIA), and sandwich and competitive assays) and in any known suitable manner (including different variants of the given examples known in the art).

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

[0170] As used herein, the term "EphA2" refers to any form of EphA2 and variants thereof that retain at least a portion of the activity of EphA2. EphA2 includes all native sequences of EphA2 in mammals (e.g., human, dog, cat, horse, and cow) unless specifically described otherwise as human EphA2 (hEphA2). An example of EphA2 is hEphA2 (Gene ID: 1969), which is human EphA2 and is a protein having the amino acid sequence (SEQ ID NO: 276, isoform 1, P29317-1). peptide ligand

[0171] In one aspect, the conjugates described herein comprise a peptide (e.g., a binding peptide) that has an affinity for ephrin type-A receptor 2 (EphA2). The EphA2 can be mammalian EphA2. The EphA2 can be human EphA2. The EphA2 can be wild-type or mutant 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 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 5 to 14 amino acid residues. In some embodiments, the peptide comprises 7 to 12 amino acid residues. In some embodiments, the peptide comprises 8 to 12 amino acid residues. In some embodiments, the peptide comprises 8 to 10 amino acid residues. In some embodiments, the peptide comprises 7 to 13 amino acid residues. In some embodiments, the peptide comprises 12 to 15 amino acid residues. In some embodiments, the peptide comprises 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. The peptides described herein can be binding peptides that bind 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 peptides of the technology of the present invention are isolated peptides. In some embodiments, the peptides of the technology of the present invention are purified peptides.

[0172] In one aspect, described herein is a peptide (e.g., a cyclic peptide) that has an affinity for ephrin type-A receptor 2 (EphA2), wherein the peptide comprises an amino acid sequence that includes one or more (e.g., 1 - 6) amino acid deletions, substitutions, and / or additions of the amino acids of SEQ ID NO:1 below: 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 having a total of at most 6 deletions, substitutions, and / or additions of one or several amino acids among the amino acids of SEQ ID NO:1. In some embodiments, the peptide comprises an amino acid sequence having a total of at most 5 deletions, substitutions, and / or additions of one or several amino acids among the amino acids of SEQ ID NO:1. In some embodiments, the peptide comprises an amino acid sequence having a total of at most 4 deletions, substitutions, and / or additions of one or several amino acids among the amino acids of SEQ ID NO:1. In some embodiments, the peptide comprises an amino acid sequence having a total of at most 3 deletions, substitutions, and / or additions of one or several amino acids among the amino acids of SEQ ID NO:1. In some embodiments, the peptide comprises an amino acid sequence having a total of at most 2 deletions, substitutions, and / or additions of one or several amino acids among the amino acids of SEQ ID NO:1. In some embodiments, the peptide comprises an amino acid sequence having a total of at most 1 deletion, substitution, and / or addition of one or several amino acids among the amino acids of SEQ ID NO:1. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. The deletion, addition, or substitution positions may be at the termini or in the middle of the peptide. In some embodiments, 1-5 amino acids selected from N at position 3, L at position 4, MeF at position 6, T at position 10, and E at position 11 of SEQ ID NO:1 are deleted, optionally without additional additions and / or substitutions. 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 MeF at position 2, MeF at position 6, V at position 8, and E at position 11 are substituted. In some embodiments, the peptide comprises an amino acid sequence having 2 or fewer amino acid deletions from SEQ ID NO:1, optionally without additional additions and / or substitutions. In some embodiments, 1-2 amino acids selected from T at position 10 and E at position 11 of SEQ ID NO:1 are deleted, optionally without additional additions and / or substitutions. In some embodiments, V at position 8 is substituted. In some embodiments, E at position 11 is substituted.

[0175] For the purposes of this disclosure, a "substitution" event of an amino acid or amino acid sequence should not be considered two separate events of a deletion plus an addition. Thus, for the avoidance of doubt, for example, a sequence change of "at most two deletions, substitutions, and / or additions" includes one deletion and one substitution, one deletion and one addition (at different positions), one substitution and one addition, only one deletion, only one substitution, only one addition, two deletions, two substitutions, two additions, etc. The deletion, addition, or substitution positions 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 in which 1-5 amino acids selected from the 3rd N, 4th L, 5th Hgl, 6th MeF, 10th T, and 11th E of SEQ ID NO:1 are deleted in the peptide. In some embodiments, the peptide comprises an amino acid sequence in which 1, 2, 3, 4, or 5 amino acids selected from the 3rd N, 4th L, 5th Hgl, 6th MeF, 10th T, and 11th E of SEQ ID NO:1 are deleted in the peptide. In some embodiments, the 3rd N is deleted. In some embodiments, the 4th L is deleted. In some embodiments, the 5th Hgl is deleted. In some embodiments, the 6th MeF is deleted. In some embodiments, the 11th E is deleted. In some embodiments, the peptide comprises an amino acid sequence in which 1-5 amino acids selected from the amino acids at positions 3, 4, 5, 6, 10, and 11 of SEQ ID NO:1 are deleted in the peptide. In some embodiments, the peptide comprises an amino acid sequence in which 1, 2, 3, 4, or 5 amino acids selected from the amino acids at positions 3, 4, 5, 6, 10, and 11 of SEQ ID NO:1 are deleted in the peptide. In some embodiments, the 3rd amino acid is deleted. In some embodiments, the 4th amino acid is deleted. In some embodiments, the 5th amino acid is deleted. In some embodiments, the 6th amino acid is deleted. In some embodiments, the 10th amino acid is deleted. In some embodiments, the 11th amino acid is deleted. In certain embodiments, the peptide has a deletion of 1-5 amino acids of SEQ ID NO:1 and no additional residues are added. In certain embodiments, the peptide has a deletion of 1-5 amino acids of SEQ ID NO:1 and no additional residues are substituted. In certain embodiments, the peptide has a deletion of 1-5 amino acids of SEQ ID NO:1 and no additional residues are added or substituted. In certain embodiments, the peptide has a deletion of 1-5 amino acid residues of SEQ ID NO:1 and no residues are added. In certain embodiments, the peptide has a deletion of 1-5 amino acid residues of SEQ ID NO:1 and no residues are substituted. In certain embodiments, the peptide has a deletion of 1-5 amino acid residues of SEQ ID NO:1 and no residues are added and substituted.

[0177] In one aspect, described herein is a peptide that has an affinity 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 containing an aromatic ring, its N-methylated amino acid or its variant; X3 is a hydrophilic amino acid (e.g., N, Q, Cit, K or its variant), glycine (G), alanine (A) or its variant (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 its variant; X5 is a hydrophilic amino acid or its variant; X6 is a hydrophilic amino acid, an amino acid containing an aromatic ring, or its N-methylated amino acid; X7 is an amino acid containing an aromatic ring (e.g., W, F or its variant); X8 is a hydrophobic amino acid, a hydrophilic amino acid, its N-methylated amino acid or variant; X9 is an amino acid containing an aromatic ring (e.g., W or its variant); X10 is absent or is a hydrophilic amino acid (e.g., threonine (T) or its variant); X11 is absent or is a hydrophilic amino acid; and X12 is cysteine (C) or its variant.

[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 an affinity 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 its variant, wherein the unsubstituted benzene ring of F is replaced by (i) a benzene ring substituted with 1 or 2 substituents each independently selected from: -OH, -CN, amino, halogen, -C 1-3 haloalkyl and -C 1-3 alkyl (e.g., -CH3), or (ii) a 6-membered heteroaryl ring optionally substituted with 1 or 2 substituents each independently selected from: -OH, -CN, amino, halogen, -C 1-3 haloalkyl and -C 1-3 alkyl, wherein F or a 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 straight-chain, branched-chain 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 having a functional side chain (e.g., not glycine)); X6 is its N-methylated amino acid; X7 is W, Y or a variant thereof (e.g., an amino acid having a 6-membered aryl or heteroaryl, or a 9- or 10-membered bicyclic aryl or heteroaryl connected to the α-carbon through carbon (e.g., methylene)), wherein the 6-, 9- and 10-membered heteroaryls have 1-3 heteroatoms (e.g., N), and wherein the 6-, 9- and 10-membered aryl or heteroaryl is optionally substituted (e.g., optionally substituted with 1-4 substituents independently selected from the following: -OH, -CN, amino, halogen, -C 1-3 haloalkyl and -C 1-3 alkyl); X8 is an amino acid having -H on the α-amino (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 is a polar amino acid (e.g., T or a variant thereof); X11 is absent or is an amino acid (e.g., a hydrophilic amino acid; Dab, Dap, R, E or a variant thereof; or an amino acid having 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, wherein the unsubstituted benzene ring of F is replaced with a benzene ring substituted with 1 or 2 substituents independently selected from the following: -OH, -CN and -C 1-3 alkyl (e.g., -CH3). In some embodiments, X2 is F or a variant thereof, wherein the unsubstituted benzene ring of F is replaced with a 6-membered heteroaryl ring optionally substituted with 1 or 2 substituents independently selected from the following: -OH, -CN, amino, halogen, -C 1-3 haloalkyl and -C 1-3Alkyl. In some embodiments, F or its variant 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 W, Y or a variant thereof (e.g., an amino acid having a 6-membered aryl or heteroaryl or a 9- or 10-membered bicyclic aryl or heteroaryl connected to the α-carbon through carbon (e.g., methylene), wherein the 6-, 9- and 10-membered heteroaryls have 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: -CH3, -ethyl, -Cl and -F).

[0182] In one aspect, described herein is a peptide that has an affinity 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 containing an aromatic ring or a substituted form thereof, an N-methylated amino acid or a substituted form thereof; substituted form; X3 is absent, or is N or a substituted form thereof; X4 is absent, or is any hydrophobic amino acid or a substituted form thereof; X5 is absent, or is a hydrophilic amino acid or a substituted form thereof, or an amino acid having a functional side chain (e.g., Dab, Dap, K); ; X6 is absent, or is a hydrophilic amino acid or an amino acid having an aromatic ring, an N-methylated amino acid or a substituted form thereof; substituted form; X7 is W or a substituted form thereof; X8 is V, a hydrophilic amino acid or a substituted form thereof, an N-methylated amino acid or an amino acid having a functional side chain; ; X9 is W or a substituted form thereof; X10 is absent, or is T or a substituted form thereof; X11 is absent, or is any hydrophilic amino acid, or an amino acid having a functional side chain; and X12 is C or a substituted form 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., a D-amino acid); X2 is an amino acid containing an aromatic ring or a variant thereof, or an N-methylated amino acid thereof; X3 is absent, or is N or a variant thereof; X4 is absent, or is any hydrophobic amino acid or a variant thereof; X5 is absent, or is a hydrophilic amino acid or a variant thereof, or an amino acid having a functional side chain (e.g., Dab, Dap, K); X6 is absent, or is a hydrophilic amino acid or an amino acid having an aromatic ring, or an N-methylated amino acid thereof; methylated amino acid; X7 is W or a variant thereof; X8 is V, a hydrophilic amino acid or a variant thereof, an N-methylated amino acid or an amino acid having a functional side chain; chain; X9 is W or a variant thereof; X10 is absent, or is T or a variant thereof; X11 is absent, or is any hydrophilic amino acid, or an amino acid having a functional side chain; and X12 is C or a variant thereof.

[0184] In some embodiments of the peptide of formula (I) or a pharmaceutically acceptable salt thereof, wherein X1 is any amino acid; X2 is an amino acid containing an aromatic ring or an N-methylated amino acid thereof; X3 is absent, or is 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, or is a hydrophobic amino acid or a hydrophilic amino acid (e.g., Cit or a variant thereof); X5 is absent, or is a hydrophilic amino acid, or an amino acid having a functional side chain; X6 is absent, or is a hydrophilic amino acid, or an amino acid having an aromatic ring, or an N-methylated amino acid thereof; X7 is an amino acid containing 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 having a functional side chain; X9 is an amino acid containing an aromatic ring (e.g., W or a variant thereof); X10 is absent or is a polar amino acid (e.g., T or a variant thereof); X11 is absent, or is 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 the peptide of formula (I) or a pharmaceutically acceptable salt thereof, wherein X1 is an amino acid (e.g., a D-amino acid); X2 is an amino acid containing an aromatic ring or an N-methylated amino acid thereof; X3 is absent, or is 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, or is a hydrophilic amino acid, an amino acid containing an aromatic ring (e.g., W) or an N-methylated amino acid thereof; X7 is an amino acid containing 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 containing an aromatic ring (e.g., W or a variant thereof); X10 is absent, or is a hydrophilic amino acid (e.g., T or a variant thereof); X11 is absent, or is a hydrophilic amino acid; and X12 is C or a variant thereof.

[0186] In some embodiments of the peptide of formula (I) or a pharmaceutically acceptable salt thereof, wherein X1 is an amino acid (e.g., a D-amino acid); X2 is F or a variant thereof, Y or a variant thereof, or W or a variant thereof, or an N-methylated amino acid thereof; X3 is absent, or is N, Q, Cit or a variant thereof, G, Aib, Hgn, K or a variant thereof, Ala or da; X4 is absent, or is G substituted with a straight-chain or branched C 1-5 alkyl, A substituted with a C 3-7 cycloalkyl, or Cit or a variant thereof; X5 is absent, or is 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 containing: -NH2, -C(O)OH, -NHC(NH)NH2, -NHC(O)NH2, -C(O)NH2 or -NHC(O)CH3; X6 is absent, or is a hydrophilic amino acid, F or a variant thereof, Y or a variant thereof, W or a variant thereof, or an 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 by one or two straight-chain or branched-chain C 1-5 alkyl, A substituted by C 3-7 cycloalkyl, or a hydrophilic amino acid, wherein the hydrophilic amino acid comprises an L-amino acid containing the following: -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, or is Q, Hgn, S or a variant thereof, T or a variant thereof (e.g., optionally T substituted by straight-chain or branched-chain C 1-5 alkyl), K or a variant thereof, Cit or a variant thereof, or an L-amino acid substituted by the following: -NHC(NH)NH2, -NHC(O)NH2, -C(O)NH2 or -NHC(O)CH3; X11 is absent, or is 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, a cyclic peptide is described herein, the cyclic peptide having an affinity 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 is an amino acid; and X12 is cysteine (C) or a variant thereof.

[0188] In some embodiments of the 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, Q-glucosamine, 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 the 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 the 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 an N-methylated amino acid thereof; X3 is absent or is 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 or is 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, Q-glucosamine, hCit, Aib, norleucine or norvaline; X9 is W1Me, W1Me7Cl, W1Me7N, F23dMe, W1Et, W7Me, W, F or 7-azatrp; X10 is absent or is T, Q, S, Hgn, α-methylserine, hSer, hThr, N, OrnAc, LysAc, Cit or hCit; X11 is absent or is 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 the 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 containing an aromatic ring or a variant thereof, or an N-methylated amino acid thereof; X3 is absent or 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 absent or is a hydrophilic amino acid or an amino acid having an aromatic ring, or an N-methylated amino acid thereof; X7 is W or a variant thereof; X8 is V, a hydrophilic amino acid or a variant thereof, or an N-methylated amino acid; X9 is W or a variant thereof; X10 is absent or is T or a variant thereof; X11 is absent or is any hydrophilic amino acid; and X12 is C or a variant thereof.

[0193] In one aspect, there is described herein a radiopharmaceutical conjugate comprising: (a) a cyclic peptide having an affinity for ephrin type-A receptor 2 (EphA2), wherein the peptide has the 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 the structure, wherein ring A2 is phenyl or a 6-membered heteroaryl (e.g., heteroaryl having 1 or 2 Ns); R X2 are each independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, SF5, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally and independently substituted by one or more R XA substituents; kx2 is 0, 1, 2 or 3; mx2 is 0, 1, 2, 3 or 4; R NX2 is H, C1-C6 alkyl or C1-C6 haloalkyl; *X1 indicates the attachment point to X1; and, *X3 indicates the attachment point to X3; X3 has the structure of, where kx3 is 0, 1, 2, or 3; R NX3 is H, a C1-C6 alkyl, or a C1-C6 haloalkyl; R X3 is H, a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 hydroxyalkyl, a C1-C6 aminoalkyl, or a C1-C6 heteroalkyl; *X2 indicates the attachment point to X2; and, *X4 indicates the attachment point to X4; X4 is a hydrophobic amino acid (e.g., an amino acid having 4 or more carbon atoms in a side chain containing a straight-chain, branched-chain, or cyclic carbon chain), and wherein X4 is optionally N-methylated by C 1-3 alkyl; X5 is a hydrophilic L-amino acid, such as an amino acid having the structure of, where: R NX5 is H, -CN, a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 hydroxyalkyl, a C1-C6 aminoalkyl, or a C1-C6 heteroalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, or heteroalkyl is optionally and independently substituted by one or more R XA substituents; R X5 is -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, SF5, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=NR b )NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR bS(=O)2R a 、 -C(=O)R a 、 -C(=O)OR b 、 -C(=O)NR c R d 、 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; wherein said alkyl, haloalkyl, hydroxyalkyl, aminoalkyl or heteroalkyl is optionally and independently substituted by one or more R XA substituted; provided that R NX5 and R X5 in at least one contains a moiety selected from the following: -OH, -NH2 and -NH- (e.g., -NH-C(=NH)-NH2, -CO-NH2, -NH2, -COOH, -C(OH)-C 0-6 alkyl, -NH-CO-C 1-6 alkyl); *X4 indicates the attachment point to X4; and, *X6 indicates the attachment point to X6; X6 is (e.g., N, F), wherein R NX6 is H, C1-C6 alkyl or C1-C6 haloalkyl; R X6 is -CN, -NO2, -OH, -OR a 、 -OC(=O)R a 、 -OC(=O)OR b 、 -OC(=O)NR c R d 、 -SH, SF5, -SR a 、 -S(=O)R a 、 -S(=O)2R a 、 -S(=O)2NR c R d 、 -NR c R d 、 -NR b C(=O)NR c R d 、 -NR b C(=NR b )NR c R d 、 -NR b C(=O)R a 、 -NR b C(=O)OR b 、 -NR b S(=O)2Ra 、 -C(=O)R a 、 -C(=O)OR b 、 -C(=O)NR c R d 、 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally and independently substituted by one or more R XA substituted; *X5 indicates the attachment point to X5; and, *X7 indicates the attachment point to X7; X7 has the structure of, wherein R NX7 is H, C1-C6 alkyl or C1-C6 haloalkyl; Ring A7 is aryl or heteroaryl; R X7 each independently is halogen, -CN, -NO2, -OH, -OR a 、 -OC(=O)R a 、 -OC(=O)OR b 、 -OC(=O)NR c R d 、 -SH, SF5, -SR a 、 -S(=O)R a 、 -S(=O)2R a 、 -S(=O)2-halogen, -S(=O)2NR c R d 、 -NR c R d 、 -N R b C(=O)NR c R d 、 -NR b C(=O)R a 、 -NR b C(=O)OR b 、 -NR b S(=O)2R a 、 -C(=O)R a 、 -C(=O)OR b 、 -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein said alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally and independently substituted by one or more R XA substituted; kx7 is 0, 1, 2 or 3; mx7 is 0, 1, 2, 3, 4 or 5; *X6 indicates the attachment point to X6; and, *X8 indicates the attachment point to X8; X8 is an L-amino acid having -H on the α-amino group; X9 has the structure of, wherein R NX9 is H, C1-C6 alkyl or C1-C6 haloalkyl; ring A9 is aryl or heteroaryl; R X9 are each independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, SF5, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally and independently substituted with one or more R XA substituents; kx9 is 0, 1, 2 or 3; mx9 is 0, 1, 2, 3, 4 or 5; *X8 indicates the attachment point to X8; and, *XC indicates the attachment point to (i) X10 or (i) when X10 and X11 are absent, the attachment point to X12; X10 is absent or is an L-amino acid; X11 is absent or is 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 R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl) or C1-C6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R; Each R b is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl) or C1-C6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R; Each R c and R dindependently is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl) or C1-C6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R; or R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; and each R and R XA independently is halogen, -CN, -OH, -OC1-C6 alkyl, SF5, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2-halogen, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NR b C(=NR b )NR c R d 、-NHC(=O)OC1-C6 alkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; (b)(i) a metal chelator configured to bind to a radionuclide; or (ii) a covalent radionuclide; and (c)(i) optionally, a linker that links a peptide to a metal chelator; or (ii) optionally, a linker that links a peptide to a covalent radionuclide.

[0194] In some embodiments, X3 has the structure of, wherein the definitions of the groups are provided herein. In some embodiments, A2 is phenyl. In some embodiments, A2 is a 6-membered heteroaryl. In some embodiments, R X2 each independently is halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -SH, -S(=O)2NR c R d , -NRc R d 、 -NR b C(=O)R a 、 -C(=O)R a 、 -C(=O)OR b 、 -C(=O)NR c R d 、 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl or heteroalkyl is optionally and independently substituted by one or more R XA . 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, R NX2 is H. In some embodiments, R NX2 is methyl.

[0195] In some embodiments, X3 has the structure of , where the definitions of 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, R NX3 is H. In some embodiments, R NX3 is methyl. In some embodiments, R X3 is H. In some embodiments, R X3 is C1-C6 alkyl. In some embodiments, R X3 is C1-C3 alkyl.

[0196] In some embodiments, X5 has the structure of , where the definitions of the groups are provided herein. In some embodiments, R NX5 is H. In some embodiments, R NX5 is methyl. In some embodiments, R X5 is -CN, -NO2, -OH, -OR a , -OC(=O)R a , -SH, -NR c R d , --NR b C(=O)R a , -C(=O)R a , -C(=O)ORb 、 -C(=O)NR c R d 、 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl or heteroalkyl is optionally and independently substituted by one or more R XA . In some embodiments, at least one of R NX5 and R X5 contains a moiety selected from the following: -NH-C(=NH)-NH2, -CO-NH2, -NH2, -COOH, -C(OH)-C 0-6 alkyl, -NH-CO-C 1-6 alkyl. In some embodiments, at least one of R NX5 and R X5 contains a moiety selected from -CO-NH2.

[0197] In some embodiments, X6 has the structure of , wherein the definitions of the groups are provided herein. In some embodiments, R NX6 is H. In some embodiments, R NX6 is methyl. In some embodiments, R X6 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl or heteroalkyl is optionally and independently substituted by one or more R XA . In some embodiments, R X6 is C1-C6 alkyl, which is optionally substituted.

[0198] In some embodiments, X7 has the structure of , wherein the definitions of 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 a bicyclic heteroaryl, which is optionally substituted. In some embodiments, the 6-, 9- or 10-membered heteroaryl has a heteroatom selected from N, O and S. In some embodiments, ring A7 is an optionally substituted 5-6, 6-6 or 6-5 fused heteroaryl. In some embodiments, ring A7 is an optionally substituted 5-6 or 6-5 fused heteroaryl. In some embodiments, R NX7 is H. In some embodiments, each R X7 is independently halogen, -CN, -NO2, -OH, -OR a , amino, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments, RX7 Each independently is halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-SH, -NR c R d 、--NR b C(=O)R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d 、C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl or heteroalkyl is optionally and independently substituted by one or more R XA Substituted. In some embodiments, each R X7 is 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 the structure of, where the definitions of the groups are provided herein. In some embodiments, X9 is where each R X9 is independently selected from -OH, CN, NH2, C1-C3 alkyl, -Cl, -F, -Br, -CONH2 and -SO2F.

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

[0202] In some embodiments, each R X9 is independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -SH,, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b , -NR a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl. In some embodiments, each R X9 is independently halogen, -CN, -NO2, -OH, -OR a , amino, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments, R NX9 is H. In some embodiments, R NX9 is 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's.

[0205] In some embodiments, R X5 is C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, -C0-6 Alkylene-NH-C(=NH)-NH2, -C 0-6 Alkylene-CO-NH2, -C 0-6 Alkylene-COOH or -NH-CO-C 1-6 Alkyl.

[0206] In some embodiments of formulae (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 canonical amino acid. In some embodiments, X1 is a non-natural amino acid. In some embodiments, X1 is an 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, a metal chelator or linker is attached to X1. In some embodiments of formulae (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., 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 contains a chloroacetyl group. In some embodiments, X1 contains a bromoacetyl group. In some embodiments, in the cyclic peptide, the chloroacetyl group or bromoacetyl group has 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 a non-natural 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 containing an aryl group. In some embodiments, X2 is an amino acid containing an optionally substituted phenyl group. In some embodiments, X2 is an amino acid containing an optionally substituted naphthyl group. In some embodiments, X2 is an amino acid containing a heteroaryl group. In some embodiments, X2 is an amino acid containing an optionally substituted monocyclic heteroaryl group. In some embodiments, X2 is an amino acid containing an optionally substituted bicyclic heteroaryl group. In some embodiments, the aryl or heteroaryl group is optionally substituted with 1, 2 or 3 substituents independently selected from: -CH3, -ethyl, -Cl and -F. In some embodiments, the aryl or heteroaryl group is optionally substituted with 1, 2 or 3 substituents independently selected from: -OH, oxo group, halogen, CN, amino, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkyl. In some embodiments, X2 is F or a variant thereof, wherein the unsubstituted benzene ring of F is replaced with: (i) a benzene ring substituted with 1 or 2 substituents each independently selected from: -OH, -CN, -C 1-3 alkyl, or (ii) a 6-membered heteroaryl ring optionally substituted with 1 or 2 substituents each independently selected from: -OH, -CN, -C 1-3An alkyl group, wherein F or its variant 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 group. In some embodiments, X2 is histidine (H). In some embodiments, X2 is phenylalanine, tryptophan, tyrosine or their variants. In some embodiments, X2 is phenylalanine or its variant. In some embodiments, X2 is tryptophan or its variant. In some embodiments, X2 is W1Me. In some embodiments, X2 is tyrosine or its variant. In some embodiments, X2 is absent. In some embodiments, a metal chelator or linker is attached to X2. In some embodiments of formula (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 containing an aromatic ring or its N-methylated amino acid. In some embodiments, X2 is an N-methylated amino acid. In some embodiments, X2 is an amino acid containing an aromatic ring. In some embodiments, X2 is an N-methylated amino acid containing an aromatic ring. In some embodiments, X2 is F or its variant, Y or its variant, or W or its variant, or their N-methylated amino acids. In some embodiments, X2 is F or its variant. In some embodiments, X2 is N-methyl F or its variant. In some embodiments, X2 is Y or its variant. In some embodiments, X2 is N-methyl Y or its variant. In some embodiments, X2 is W or its variant. In some embodiments, X2 is N-methyl W or its variant. 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 a non-natural amino acid. In some embodiments, X3 is an N-alkylated amino acid. In some embodiments, X3 is asparagine (N). In some embodiments, X3 is a substituted form 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 variants thereof), glycine (G), alanine (A), or variants 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 containing an -OH, -NH2, -C(O)OH, -NHC(=NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3 group. In some embodiments, X3 has a 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 containing a charged side chain (e.g., K or variants thereof), an amino acid containing a polar uncharged side chain (e.g., Q, Cit, N, or variants thereof), or G, A, or variants thereof. In some embodiments, X3 is an amino acid containing a charged side chain. In some embodiments, X3 is an amino acid containing a polar uncharged side chain. In some embodiments, X3 has a zwitterionic (e.g., KCOpipza a) side chain. In some embodiments, X3 is zwitterionic. In some embodiments, X3 contains an -OH, -COOH, -NH-, or NH2 moiety. In some embodiments, X3 contains an -OH, -C(O)OH, -NHC(=NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3.In some embodiments, X3 comprises the following side chains: C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, -C. 0-6 alkylene-NH-C(=NH)-NH2, -C 0-6 alkylene-CO-NH2, -C 0-6 alkylene-COOH or -NH-CO-C 1-6 alkyl. In some embodiments, X3 is absent or is 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, the variant including D-amino acids (such as da) and variants such as Q-glucosamine. In some embodiments, X3 is absent or is 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 or is 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 substituted form thereof. 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, a metal chelator or linker is attached to X3. In some embodiments, a 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 a non-natural amino acid. In some embodiments, X4 is a canonical amino acid. In some embodiments, X4 is leucine. In some embodiments, X4 contains 4 or more carbon atoms in a side chain comprising a straight-chain, branched-chain, or cyclic carbon chain. In some embodiments, X4 contains 4 or more consecutive carbon atoms in the side chain. In some embodiments, X4 contains an ethylene, propylene, or butylene group in the 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), and substituted forms 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 containing a hydrophobic side chain (e.g., L), an amino acid containing a polar uncharged side chain (e.g., Cit or a variant thereof). In some embodiments, X4 is an amino acid containing a hydrophobic side chain. In some embodiments, X4 is an amino acid containing 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 or is a hydrophobic amino acid or a hydrophilic amino acid (e.g., Cit or a variant thereof). In some embodiments, X4 is absent or is G substituted with a straight-chain or branched-chain C 1-5 alkyl group, A substituted with a C 3-7 cycloalkyl group, or Cit or a variant thereof. In some embodiments, X4 is absent or is 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 substituted with a straight-chain or branched-chain C 1-5Alkyl-substituted G. In some embodiments, X4 is G substituted with: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, or isopentyl. In some embodiments, X4 is C 3-7 Cycloalkyl-substituted A. 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, a metal chelator or linker is attached to X4. In some embodiments, X1 binds directly to X4. In some embodiments of formula (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 containing: -OH, -NH2, -C(O)OH, -NHC(=NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3 groups. In some embodiments, X4 has a 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 contains an -OH, -COOH, -NH-, or NH2 moiety. In some embodiments, X4 contains -OH, -C(O)OH, -NHC(=NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3. In some embodiments, X4 contains the following side chains: C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, -C 0-6 alkylene-NH-C(=NH)-NH2, -C 0-6Alkylene-CO-NH2, -C 0-6 Alkylene-COOH or -NH-CO-C 1-6 Alkyl. 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 consecutive carbon atoms in a straight or branched chain. In some embodiments, X4 comprises at least 5 consecutive carbon atoms in a straight or branched chain. 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 a non-natural 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 uncharged. In some embodiments, X5 is a canonical amino acid. In some embodiments, X5 is an 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, where the variants include D-amino acids (such as da) and variants such as Q-glucosamine. In some embodiments, X5 is Hgn, N, Q-glucosamine, 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 Q-glucosamine. 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 containing a charged side chain (e.g., E, Hgl, D, or a variant thereof) or an amino acid containing a polar uncharged side chain (e.g., Q, Cit, Hgn, N, or a variant thereof). In some embodiments, X5 is an amino acid containing a charged side chain. In some embodiments, X5 is an amino acid containing 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 or is a hydrophilic amino acid or a variant thereof.In some embodiments, X5 is absent, or is 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 containing: -NH2, -C(O)OH, -NHC(NH)NH2, -NHC(O)NH2, -C(O)NH2 or -NHC(O)CH3. In some embodiments, X5 is absent, or is 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 containing: -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 containing: -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, a metal chelator or linker is attached to X5. In some embodiments, a covalently bound radionuclide or linker is attached to X5. In some embodiments, X1 binds directly to X5.

[0211] In some embodiments of formulae (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 a non-natural amino acid. In some embodiments, X6 is a hydrophilic amino acid or an amino acid having an aromatic ring, or an N-methylated amino acid thereof or a substituted form thereof. In some embodiments, X6 is an amino acid having an aromatic ring or a substituted form thereof. In some embodiments, X6 is an amino acid containing an aryl group. In some embodiments, X6 is an amino acid containing an optionally substituted phenyl group. In some embodiments, X6 is an amino acid containing an optionally substituted naphthyl group. In some embodiments, X6 is an amino acid containing a heteroaryl group. In some embodiments, X6 is an amino acid containing an optionally substituted monocyclic heteroaryl group. In some embodiments, X6 is an amino acid containing an optionally substituted bicyclic heteroaryl group. In some embodiments, the aryl or heteroaryl group is optionally substituted with 1, 2 or 3 substituents independently selected from: -CH3, -ethyl, -Cl and -F. In some embodiments, the aryl or heteroaryl group is optionally substituted with 1, 2 or 3 substituents independently selected from: -OH, oxo group, halogen, CN, amino, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkyl. In some embodiments, X6 is an N-methylated amino acid. In some embodiments, X6 is a hydrophilic amino acid or a substituted form thereof. In some embodiments, X6 is an amino acid having an aromatic ring or a substituted form thereof. In some embodiments, X6 is an N-methylated amino acid or a substituted form 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 Q-glucosamine. In some embodiments, X6 is MeF4C. In some embodiments, X6 is absent. In some embodiments of formulae (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 containing a charged side chain (e.g., E, Hgl, D or a variant thereof) or an amino acid containing a polar uncharged side chain (e.g., Q, Cit, Hgn, N or a variant). In some embodiments, X6 is an amino acid containing a charged side chain. In some embodiments, X6 is an amino acid containing a polar uncharged side chain.In some embodiments of formulae (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 or is a hydrophilic amino acid, an amino acid containing an aromatic ring or an N-methylated amino acid thereof. In some embodiments of formulae (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 containing: a -OH, -NH2, -C(O)OH, -NHC(=NH)NH2, -NHC(O)NH2, -C(O)NH2 or -NHC(O)CH3 group. In some embodiments, X6 has a 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 contains a -OH, -COOH, -NH- or NH2 moiety. In some embodiments, X6 contains -OH, -C(O)OH, -NHC(=NH)NH2, -NHC(O)NH2, -C(O)NH2 or -NHC(O)CH3. In some embodiments, X6 contains the following side chains: C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, -C. 0-6 alkylene-NH-C(=NH)-NH2, -C 0-6 alkylene-CO-NH2, -C 0-6 alkylene-COOH or -NH-CO-C 1-6Alkyl. In some embodiments, X6 is absent, or is a hydrophilic amino acid, F or a variant thereof, Y or a variant thereof, W or a variant thereof, or an N-methylated amino acid thereof, where the hydrophilic amino acid comprises a substituent selected from: -C(O)OH, -C(O)NH2, and -NHC(O)CH3. In some embodiments, X6 is absent, or is 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 an 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 an N-methylated amino acid thereof. 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 heteroaryl group. In some embodiments, X6 is F or a variant thereof, or an 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 an 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, a metal chelator or linker is attached to X6. In some embodiments, a covalently bound radionuclide or linker is attached to X6. In some embodiments, X1 binds directly 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 a non-natural amino acid. In some embodiments, X7 is an 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 an aromatic ring or a substituted form thereof. In some embodiments, X7 is an amino acid containing an aryl group. In some embodiments, X7 is an amino acid containing an optionally substituted phenyl group. In some embodiments, X7 is an amino acid containing an optionally substituted naphthyl group. In some embodiments, X7 is an amino acid containing a heteroaryl group. In some embodiments, X7 is an amino acid containing an optionally substituted monocyclic heteroaryl group. In some embodiments, X7 is an amino acid containing an optionally substituted bicyclic heteroaryl group. In some embodiments, the aryl or heteroaryl group is optionally substituted with 1, 2, or 3 substituents independently selected from: -CH3, -ethyl, -Cl, and -F. In some embodiments, the aryl or heteroaryl group is optionally substituted with 1, 2, or 3 substituents independently selected from: -OH, oxo, halogen, CN, amino, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl. In some embodiments, X7 is W, Y, or a variant thereof (such as an amino acid having a 6-membered aryl or heteroaryl or a 9- or 10-membered bicyclic aryl or heteroaryl linked to the α-carbon through carbon (e.g., methylene), wherein the 6-, 9-, and 10-membered heteroaryls have one heteroatom (e.g., N), and wherein the 6-, 9-, and 10-membered aryl or heteroaryl groups are optionally substituted with 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 containing an aromatic ring. In some embodiments, X7 is an amino acid containing 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, a metal chelator or linker is attached to X7. In some embodiments, a covalently bound radionuclide or linker is attached to X7. In some embodiments, X1 binds directly to X7.

[0213] In some embodiments of formulae (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 canonical amino acid. In some embodiments, X8 is a non-natural amino acid. In some embodiments, X8 is V, a hydrophilic amino acid, an N-methylated amino acid or a substituted form 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 an N-methylated amino acid or a substituted form thereof. In some embodiments, X8 is an N-alkylated amino acid or a substituted form 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 Q-glucosamine. In some embodiments, X8 is Cit. In some embodiments, X8 is hCit. In some embodiments, X8 is absent. In some embodiments of formulae (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-chain or branched C 1-5 alkyl, G substituted with C 3-7Cycloalkyl-substituted A, or hydrophilic amino acids, wherein the hydrophilic amino acids comprise L-amino acids containing the following: -NH2, one or more -OH, -C(O)OH, -NHC(NH)NH2, -NHC(O)NH2, -C(O)NH2, -NHC(O)CH3; or the hydrophilic amino acids comprise zwitterions. In some embodiments, X8 is V, A, E, N, K, Q glucosamine, KCOpipzaa, Q, Hse, N, Cit, Hcit, Kac, DapAc, OrnAc, T, alT, Aib, Alb or 3Py6NH2. In some embodiments, X8 is A, E, N, K, Q glucosamine, KCOpipzaa, Q, Hse, N, Cit, Hcit, Kac, DapAc, OrnAc, T, alT, Aib, Alb or 3Py6NH2. In some embodiments, X8 is KCOpip zaa, N, Cit, Q glucosamine, 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, Q glucosamine, Cit, Hcit, K or 3Py6NH2. In certain embodiments, X8 is KCOpipzaa, Q glucosamine, Cit, Hcit, K or 3Py6NH2. In some embodiments, X8 is V, KCOpipzaa, Cit, Q glucosamine, hCit, Aib, Alb, norleucine or norvaline. In some embodiments, X8 is KCOpipzaa, Cit, Q glucosamine, hCit, Aib, Alb, norleucine or norvaline. In some embodiments, X8 is KCOpipzaa, N, Cit, hCit, KAc, DapAc, OrnAc, A, T, alT, Aib, Alb, Q glucosamine, Hgl, Q, E, Hgn or K. In some embodiments, X8 is a hydrophobic amino acid. In some embodiments, X8 is C 1-5 alkyl-substituted G. In some embodiments, X8 is G substituted with one or more substituents selected from the following: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and isopentyl. In some embodiments, X8 is C 3-7A substituted with cycloalkyl. 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 zwitterions. 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 Q-glucosamine. In some embodiments, a metal chelator or linker is attached to X8. In some embodiments, a covalently bound radionuclide or linker is attached to X8. In some embodiments, X1 binds directly 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 a non-natural amino acid. In some embodiments, X9 is an 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 is an amino acid having an aromatic ring or a substituted form 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 containing an aromatic ring. In some embodiments, X9 is an amino acid containing an aryl group. In some embodiments, X9 is an amino acid containing an optionally substituted phenyl group. In some embodiments, X9 is an amino acid containing an optionally substituted naphthyl group. In some embodiments, X9 is an amino acid containing a heteroaryl group. In some embodiments, X9 is an amino acid containing an optionally substituted monocyclic heteroaryl group. In some embodiments, X9 is an amino acid containing an optionally substituted bicyclic heteroaryl group. In some embodiments, the aryl or heteroaryl group is optionally substituted with 1, 2 or 3 substituents independently selected from: -CH3, -ethyl, -Cl and -F. In some embodiments, the aryl or heteroaryl group is optionally substituted with 1, 2 or 3 substituents independently selected from: -OH, oxo group, halogen, CN, amino, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkyl. In some embodiments, X9 is W, Y or a variant thereof (such as an amino acid having a 6-membered aryl or heteroaryl or a 9- or 10-membered bicyclic aryl or heteroaryl connected to the α-carbon through carbon (such as methylene), wherein the 6-, 9- and 10-membered heteroaryls have one heteroatom (such as N), and wherein the 6-, 9- and 10-membered aryl or heteroaryl groups are optionally substituted with 1 or 2 substituents independently selected from: -CH3, -ethyl, -Cl and -F). In some embodiments, X9 is an amino acid containing an aromatic ring (such as 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, a metal chelator or linker is attached to X9. In some embodiments, a 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 or is T or a variant thereof. In some embodiments, X10 is a canonical amino acid. In some embodiments, X10 is a non-natural 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 is a polar amino acid (e.g., T or a variant thereof). In some embodiments, X10 is absent or is Q, Hgn, S or a variant thereof, T, or optionally a straight or branched C 1-5An alkyl-substituted variant thereof, 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 or is T, Q, S, Hgn, α-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, α-methylserine, or hSer. In some embodiments, X10 is S. In some embodiments, X10 is α-methylserine. In some embodiments, X10 is hSer. In some embodiments, X10 is T or optionally substituted with a straight-chain or branched C 1-5 An alkyl-substituted variant thereof. 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, a metal chelator or linker is attached to X10. In some embodiments, a covalently bound radionuclide or linker is attached to X10. In some embodiments, X1 binds directly 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, or is a hydrophilic amino acid or a substituted form thereof. In some embodiments, X11 is serine, threonine, tyrosine, asparagine, glutamine or a substituted form thereof. In some embodiments, X11 is a canonical amino acid. In some embodiments, X11 is a non-natural amino acid. In some embodiments, X11 is Hgn. In some embodiments, X11 is K. In some embodiments, X11 is glutamic acid. 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, or is 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 containing a charged side chain (e.g., E, Hgl, D, R, hArg, K or a variant thereof) or an amino acid containing a polar uncharged side chain (e.g., Q, Cit, Hgn, N or a variant thereof). In some embodiments, X11 is an amino acid containing a charged side chain. In some embodiments, X11 is an amino acid containing a polar uncharged side chain. In some embodiments, X11 is an amino acid containing one of the following: -OH, -NH2, -C(O)OH, -NHC(=NH)NH2, -NHC(O)NH2, -C(O)NH2 or -NHC(O)CH3 groups. In some embodiments, X11 has a 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 contains an -OH, -COOH, -NH- or NH2 moiety.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 the following side chains: C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, -C. 0-6 alkylene-NH-C(=NH)-NH2, -C 0-6 alkylene-CO-NH2, -C 0-6 alkylene-COOH or -NH-CO-C 1-6Alkyl. In some embodiments, X11 is absent or is 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 or is E, Hgn, R, hArg, Cit, hCit, Hgl, Orn, D, N, Q, DapAc, OrnAc, DabAc or norCit. In some embodiments, X11 is absent or is arginine (R), asparagine (N), aspartic acid (D), glutamine (Q), lysine (K) or a non-natural hydrophilic amino acid. In some embodiments, X11 is absent or is 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, the variant including D-amino acids (such as da) and variants such as Q-glucosamine. 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, the variant including D-amino acids (such as da) and variants such as Q-glucosamine. 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, a metal chelator or linker is attached to X11. In some embodiments, a covalently bound radionuclide or linker is attached to X11. In some embodiments, X1 binds directly to X11.

[0217] In some embodiments of formulae (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 a non-natural amino acid. In some embodiments, X12 is cysteine. In some embodiments, X12 is a substituted form 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, a metal chelator or linker is attached to X12. In some embodiments of formulae (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, a metal chelator or linker is attached to X12. In some embodiments, a covalently bound radionuclide or linker is attached to X12. In some embodiments, X1 binds directly to X12.

[0218] In some embodiments, the peptide of formula (I) has the structure of formula (I-1), or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from NH2 and OH; R 2 is selected from H or C 1-3 alkyl; R3 Selected from H or C 1-3 alkyl; The attachment point to the metal chelator or linker is not shown, and X1-X11 are described in formula (I).

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

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

[0221] In some embodiments, the peptide of formula (I-1) has the 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), R 1 is OH. In some embodiments of formula (I-1), (I-2), (I-3) or (I-4), R 1 is NH2. In some embodiments of formula (I-1), (I-2), (I-3) or (I-4), R 1 is attached to a linker or metal chelator. In some embodiments, the linker or metal chelator is attached to the peptide through the group R 1

[0223] In some embodiments of formula (I-1), (I-2), (I-3) or (I-4), R 2 is H. In some embodiments of formula (I-1), (I-2), (I-3) or (I-4), R 2 is C 1-3 alkyl. In some embodiments of formula (I-1), (I-2), (I-3) or (I-4), R 2 is methyl.

[0224] In some embodiments of formula (I-1), (I-2), (I-3) or (I-4), R 3 is H. In some embodiments of formula (I-1), (I-2), (I-3) or (I-4), R 3 is C 1-3 alkyl. In some embodiments of formula (I-1), (I-2), (I-3) or (I-4), R 3 is methyl. ​

[0225] In some embodiments, the peptide of formula (I) has the structure of formula (I-5), or a pharmaceutically acceptable salt thereof, wherein X1-X12 are as defined above, and Lcyc is a ring-closing group covalently linking X1 and X12.

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

[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 containing 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 acid or a variant thereof; X5 is a hydrophilic amino acid or a variant thereof; X6 is a hydrophilic amino acid or an amino acid having an aromatic ring, or an N-methylated amino acid thereof; X7 is W or a variant thereof; X8 is V or a 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 a 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 an N-methylated amino acid (such as leucine, Cbg or Chg); X5 is Hgn, asparagine (N), 2,4-diaminobutyric acid (Dab), Q-glucosamine, KCOpipzaa, Hgl, Nmm, Ndm or lysine (K); X6 is asparagine (N) or N-methylated glutamate (E), N-methylated asparagine, N-methylated phenylalanine (F) or a substituted form thereof (such as Q-glucosamine, MeE, MeN, Me3Py, MeF, MeF4C or N); X7 is W1Me, W1Me7Cl or W1Me7N; X8 is KCOpipzaa, V, Q-glucosamine, 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, glutamate (E), lysine (K); and X12 is cysteine.

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

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

[0232] In some embodiments, the peptide described herein 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., D-amino acid); X2 is an amino acid containing 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 group or a variant thereof, X5 is a hydrophilic amino acid or a variant thereof; X6 is a hydrophilic amino acid, or an amino acid having an 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, the peptides described herein have 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., a D-amino acid); X2 is an amino acid containing an aromatic ring or a variant thereof, or an 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, the peptides described herein have 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., a D-amino acid); X2 is an amino acid containing an aromatic ring or a variant thereof, or an 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 peptides of formula (I), (Ia), (Ib), and / or (Ic) are monocyclic. In some embodiments, the amino acid in X1 is linked to cysteine or a substituted form of cysteine.

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

[0237] In some embodiments, the peptides of the present disclosure have good contact with Asp53 and / or Glu157 of human EphA2 according to SEQ ID NO: 276. In some embodiments, the peptides of the present disclosure interact with Asp53 and / or Glu157 of human EphA2 according to SEQ ID NO: 276. In some embodiments, the peptides of the present disclosure interact with Asp53 and / or Glu157 of 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 π-π stacking interactions. In some embodiments, the peptides of the present disclosure interact 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, the peptides of the present disclosure bind to Asp53 and Glu157 of human EphA2. In some embodiments, the amino acid residue X5 of formula (I) interacts with Glu157 of human EphA2. In some embodiments, the amino acid residue X6 of formula (I) interacts with Arg159 of human EphA2. In some embodiments, the amino acid residue X7 of formula (I) interacts with one or more of Phe156, Thr101, Asn57, Val161, Met59, Ala190, and Met66 of human EphA2. In some embodiments, the amino acid residue X9 of formula (I) interacts with one or more of Phe156, Arg103, and Val189. In some embodiments, the amino acid residue X11 of formula (I) interacts with Asp53 of human EphA2. In some embodiments, the amino acid residue X7 of formula (I) forms a π-π stacking interaction with Phe156 of human EphA2. In some embodiments, the amino acid residue X9 of formula (I) forms a π-π stacking interaction with Phe156 of human EphA2. In some embodiments, the amino acid residue X2 of formula (I) interacts with the backbone carbonyl of C70 of the human EphA2 protein via intermolecular aromatic H-bond interactions.

[0238] In some embodiments, when the peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, the amino acid residue X2 of formula (I) is located less than from C70 of human EphA2. In some embodiments, X2 is located less than from C70. In some embodiments, X2 is located less than from C70. In some embodiments, X2 is located less than position

[0239] In some embodiments, when the peptide of formula (I) or a conjugate comprising said peptide binds to human EphA2, amino acid residue X7 of formula (I) is less than from Phe156 of human EphA2. In some embodiments, X7 is less than from Phe156. In some embodiments, X7 is less than from Phe156.

[0240] In some embodiments, when the peptide of formula (I) or a conjugate comprising said peptide binds to human EphA2, amino acid residue X7 of formula (I) is less than from Thr101 of human EphA2. In some embodiments, X7 is less than from Thr101. In some embodiments, X7 is less than from Thr101. In some embodiments, X7 is less than from Thr101. In some embodiments, X7 is less than from Thr101.

[0241] In some embodiments, when the peptide of formula (I) or a conjugate comprising said peptide binds to human EphA2, amino acid residue X7 of formula (I) is less than from Asn57 of human EphA2. In some embodiments, X7 is less than from Asn57. In some embodiments, X7 is less than from Asn57. In some embodiments, X7 is less than from Asn57. In some embodiments, X7 is less than from Asn57.

[0242] In some embodiments, when the peptide of formula (I) or a conjugate comprising said peptide binds to human EphA2, amino acid residue X7 of formula (I) is less than from Val161 of human EphA2. In some embodiments, X7 is less than from Val161. In some embodiments, X7 is less than from Val161. In some embodiments, X7 is less than from Val161. In some embodiments, X7 is less than from Val161.

[0243] In some embodiments, when the peptide of formula (I) or a conjugate comprising said peptide binds to human EphA2, amino acid residue X7 of formula (I) is less than from Met59 of human EphA2. In some embodiments, X7 is less than from Met59. In some embodiments, X7 is less than from Met59. In some embodiments, X7 is less than from Met59. In some embodiments, X7 is less than from Met59.

[0244] In some embodiments, when the peptide of formula (I) or a conjugate comprising said peptide binds to human EphA2, amino acid residue X7 of formula (I) is less than from Ala190 of human EphA2. In some embodiments, X7 is less than from Ala190. In some embodiments, X7 is less than from Ala190. In some embodiments, X7 is less than from Ala190. In some embodiments, X7 is less than from Ala190.

[0245] In some embodiments, when the peptide of formula (I) or a conjugate comprising said peptide binds to human EphA2, amino acid residue X7 of formula (I) is less than from Met66 of human EphA2. In some embodiments, X7 is less than from Met66. In some embodiments, X7 is less than from Met66. In some embodiments, X7 is less than from Met66. In some embodiments, X7 is less than from Met66.

[0246] In some embodiments, when the peptide of formula (I) or a conjugate comprising said peptide binds to human EphA2, amino acid residue X9 of formula (I) is less than from Phe156 of human EphA2. In some embodiments, X9 is less than from Phe156. In some embodiments, X9 is less than from Phe156.

[0247] In some embodiments, when the peptide of formula (I) or a conjugate comprising said peptide binds to human EphA2, the amino acid residue X9 of formula (I) is located less than from Asn3 of human EphA2. In some embodiments, X9 is located less than from Asn3. In some embodiments, X9 is located less than from Asn3. In some embodiments, X9 is located less than from Asn3.

[0248] In some embodiments, when the peptide of formula (I) or a conjugate comprising said peptide binds to human EphA2, the amino acid residue X9 of formula (I) is located less than from Arg103 of human EphA2. In some embodiments, X9 is located less than from Arg103. In some embodiments, X9 is located less than from Arg103. In some embodiments, X9 is located less than from Arg103.

[0249] In some embodiments, when the peptide of formula (I) or a conjugate comprising said peptide binds to human EphA2, the amino acid residue X9 of formula (I) is located less than from Val189 of human EphA2. In some embodiments, X9 is located less than from Val189. In some embodiments, X9 is located less than from Val189. In some embodiments, X9 is located less than from Val189.

[0250] In some embodiments, when the peptide of formula (I) or a conjugate comprising said peptide binds to human EphA2, the amino acid residue X8 of formula (I) is located less than from Phe156 of human EphA2. In some embodiments, X8 is located less than from Phe156. In some embodiments, X8 is located less than from Phe156.

[0251] In some embodiments, when the peptide of formula (I) or a conjugate comprising said peptide binds to human EphA2, the amino acid residue X2 of formula (I) is located less than from C70 of human EphA2. In some embodiments, X2 is located less than from C70. In some embodiments, X2 is located less than from C70. In some embodiments, X2 is located less than at

[0252] In some embodiments, when the peptide of formula (I) or a conjugate comprising said peptide binds to human EphA2, amino acid residue X7 of formula (I) is less than at from Phe156 of human EphA2. In some embodiments, X7 is less than at from Phe156. In some embodiments, X7 is less than at from Phe156.

[0253] In some embodiments, when the peptide of formula (I) or a conjugate comprising said peptide binds to human EphA2, amino acid residue X9 of formula (I) is less than at from Thr101 of human EphA2. In some embodiments, X9 is less than at from Thr101. In some embodiments, X9 is less than at from Thr101. In some embodiments, X9 is less than at from Thr101. In some embodiments, X9 is less than at from Thr101.

[0254] In some embodiments, when the peptide of formula (I) or a conjugate comprising said peptide binds to human EphA2, amino acid residue X8 of formula (I) is less than at from Asn57 of human EphA2. In some embodiments, X8 is less than at from Asn57. In some embodiments, X8 is less than at from Asn57. In some embodiments, X8 is less than at from Asn57. In some embodiments, X8 is less than at from Asn57.

[0255] In some embodiments, when the peptide of formula (I) or a conjugate comprising said peptide binds to human EphA2, amino acid residue X7 of formula (I) is less than at from Val161 of human EphA2. In some embodiments, X7 is less than at from Val161. In some embodiments, X7 is less than at from Val161. In some embodiments, X7 is less than at from Val161. In some embodiments, X7 is less than at from Val161.

[0256] In some embodiments, when the peptide of formula (I) or a conjugate comprising said peptide binds to human EphA2, amino acid residue X7 of formula (I) is located less than from Met59 of human EphA2. In some embodiments, X7 is located less than from Met59. In some embodiments, X7 is located less than from Met59. In some embodiments, X7 is located less than from Met59. In some embodiments, X7 is located less than from Met59.

[0257] In some embodiments, when the peptide of formula (I) or a conjugate comprising said peptide binds to human EphA2, amino acid residue X7 of formula (I) is located less than from Ala190 of human EphA2. In some embodiments, X7 is located less than from Ala190. In some embodiments, X7 is located less than from Ala190. In some embodiments, X7 is located less than from Ala190. In some embodiments, X7 is located less than from Ala190.

[0258] In some embodiments, when the peptide of formula (I) or a conjugate comprising said peptide binds to human EphA2, amino acid residue X7 of formula (I) is located less than from Met66 of human EphA2. In some embodiments, X7 is located less than from Met66. In some embodiments, X7 is located less than from Met66. In some embodiments, X7 is located less than from Met66. In some embodiments, X7 is located less than from Met66.

[0259] In some embodiments, when the peptide of formula (I) or a conjugate comprising said peptide binds to human EphA2, amino acid residue X2 of formula (I) is located less than from Arg103 of human EphA2. In some embodiments, X2 is located less than from Arg103. In some embodiments, X2 is located less than from Arg103. In some embodiments, X2 is located less than from Arg103.

[0260] In some embodiments, when the peptide of formula (I) or a conjugate comprising said peptide binds to human EphA2, amino acid residue X9 of formula (I) is located less than from Val189 of human EphA2. In some embodiments, X9 is located less than from Val189. In some embodiments, X9 is located less than from Val189. In some embodiments, X9 is located less than from Val189.

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

[0262] In some embodiments, a conjugate comprising a cyclic peptide of formula (I) has the structure of formula (III-2), wherein X1-X12 are as defined above, and Lcyc is a ring-closing group that covalently links X1 and X12; and - linker - represents a linker.

[0263] In some embodiments, the conjugate of the present disclosure has the structure of formula (III-1-RI), wherein X1-X12 are as defined above; - linker - represents a linker; and R* represents a covalently bound radionuclide.

[0264] In some embodiments, a conjugate comprising a cyclic peptide of formula (I) has the structure of formula (III-2-RI), wherein X1-X12 are as defined above, and Lcyc is a ring-closing group that covalently links X1 and X12; - linker - represents a linker; and R* represents a covalently bound radionuclide.

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

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

[0267] In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NO: 1-122, 159-163, and 165-171, and the peptide has a cyclic structure having a cysteine residue or a variant thereof at the 12th residue (X12). In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NO: 1-122, 159-163, and 165-171, and the peptide has a cyclic structure having a cysteine residue or a variant thereof at the 12th residue (X12), and wherein the chloroacetylated amino acid and the cysteine residue or a variant thereof at the 12th residue form a covalent bond. In some embodiments, the chloroacetyl group can be replaced by 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 with a cysteine residue or a variant thereof at the 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 with a cysteine residue or a variant thereof at the 10th residue (X10), and wherein the chloroacetylated amino acid and the cysteine residue or its variant at the 10th residue form a covalent bond. In some embodiments, the chloroacetyl group can be replaced by 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 with a cysteine residue or a variant thereof at the 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 the 8th residue (X8), and wherein the chloroacetylated amino acid and the cysteine residue or its variant at the 8th residue form a covalent bond. In some embodiments, the chloroacetyl group can be replaced by 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 with a cysteine residue or a variant thereof at the 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 the 7th residue (X7), and wherein the chloroacetylated amino acid and the cysteine residue or its variant at the 7th residue form a covalent bond. In some embodiments, the chloroacetyl group can be replaced by a bromoacetyl group.

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

[0272] In some embodiments, the peptide or a pharmaceutically acceptable salt thereof has a cyclic structure, the cyclic structure having a chloroacetylated amino acid and a cysteine or substituted cysteine residue in X1, and wherein the chloroacetylated amino acid in X1 binds to the cysteine or substituted cysteine. In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NO: 1-171. In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NO: 1-171 and the peptide has a cyclic structure. In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NO: 1-171 and the peptide has a cyclic structure having a chloroacetylated amino acid and a cysteine or substituted cysteine residue at the C-terminus, and wherein the chloroacetylated amino acid binds to the cysteine or substituted cysteine at the C-terminus. In some embodiments, the peptide has a cyclic structure having a chloroacetylated amino acid bound to (i) a cysteine or substituted cysteine residue at the 12th residue, and wherein the chloroacetylated amino acid binds to the cysteine or substituted cysteine at the 12th residue; or (ii) a cysteine or substituted cysteine residue at the 10th residue, and wherein the chloroacetylated amino acid binds to the cysteine or substituted cysteine at the 10th residue. In some embodiments, the chloroacetyl group can be replaced by a bromoacetyl group.

[0273] For example, the cyclic peptide of formula (I) can have the structure as shown below For example, the cyclic peptide of formula (I) can have the structure as shown below

[0274] In some embodiments, the conjugate comprising the cyclic peptide of formula (I) has the following structure:

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

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

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

[0278] In some embodiments, the peptide or a salt thereof comprises an amino acid sequence that is at least 95% identical to a sequence selected from the following SEQ ID NOs: (1) X1-X12 of SEQ ID NO: 1-122, 159-163, and 165-171; (2) X1-X10 of SEQ ID NO: 123-149 and 164; (3) X1-X8 of SEQ ID NO: 150-157; and (4) X1-X7 of SEQ ID No: 158. In some embodiments, the peptide or a salt thereof comprises an amino acid sequence that is at least 90% identical to a sequence selected from the following SEQ ID NOs: (1) X1-X12 of SEQ ID NO: 1-122, 159-163, and 165-171; (2) X1-X10 of SEQ ID NO: 123-149 and 164; (3) X1-X8 of SEQ ID NO: 150-157; and (4) X1-X7 of SEQ ID No: 158. In some embodiments, the peptide or a salt thereof comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, or 98% identical to a sequence selected from the following SEQ ID NOs: (1) X1-X12 of SEQ ID NO: 1-122, 159-163, and 165-171; (2) X1-X10 of SEQ ID NO: 123-149 and 164; (3) X1-X8 of SEQ ID NO: 150-157; and (4) X1-X7 of SEQ ID No: 158. In some embodiments, the peptide or a salt thereof consists of an amino acid sequence selected from the following SEQ ID NOs: (1) X1-X12 of SEQ ID NO: 1-122, 159-163, and 165-171; (2) X1-X10 of SEQ ID NO: 123-149 and 164; (3) X1-X8 of SEQ ID NO: 150-157; and (4) X1-X7 of SEQ ID No: 158. In some embodiments, the peptide or a salt thereof comprises an amino acid sequence having at most 1, 2, 3, 4, or 5 different amino acid residues compared to a sequence selected from the following SEQ ID NOs: (1) X1-X12 of SEQ ID NO: 1-122, 159-163, and 165-171; (2) X1-X10 of SEQ ID NO: 123-149 and 164; (3) X1-X8 of SEQ ID NO: 150-157; and (4) X1-X7 of SEQ ID No: 158.In some embodiments, the peptide or a salt thereof comprises an amino acid sequence having at most 1, 2, 3, 4, or 5 additions, deletions, and / or substitutions (including conservative substitutions) compared to a sequence selected from the following 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 a salt thereof comprises an amino acid sequence having at most 1 addition, deletion, or substitution (including conservative substitution) compared to a sequence selected from the following 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, the radiopharmaceutical conjugate described herein comprises a peptide of SEQ ID No: 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 present disclosure have a -C(=O)-halogen group attached to the N-terminus. In some embodiments, the radiopharmaceutical conjugates of the present disclosure have a -C(=O)-CH2-halogen group attached to the N-terminus. In some embodiments, the radiopharmaceutical conjugates of the present disclosure have a -C(=O)-halogen group attached at residue position 1 (e.g., X1). In some embodiments, the radiopharmaceutical conjugates of the present disclosure have a -C(=O)-CH2-halogen group attached at residue position 1 (e.g., X1). In some embodiments, the radiopharmaceutical conjugates of the present disclosure have a -C(=O)-Cl group attached to the N-terminus. In some embodiments, the radiopharmaceutical conjugates of the present disclosure have a -C(=O)-CH2-Cl group attached to the N-terminus. In some embodiments, the radiopharmaceutical conjugates of the present disclosure have a -C(=O)-Cl group attached at residue position 1 (e.g., X1). In some embodiments, the radiopharmaceutical conjugates of the present disclosure have a -C(=O)-CH2-Cl group attached at residue position 1 (e.g., X1). In some embodiments, the radiopharmaceutical conjugates of the present disclosure have a -C(=O)-Br group attached at residue position 1 (e.g., X1). In some embodiments, the radiopharmaceutical conjugates of the present disclosure have a -C(=O)-CH2-Br group attached at residue position 1 (e.g., X1). In some embodiments, the peptide in the radiopharmaceutical conjugates of the present disclosure is monocyclic.

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

[0282] 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)-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)-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).

[0283] In some embodiments, the conjugates described herein are selected from the conjugates described in Table 2A-Lu, Table 2A-Lu177, or Table 2A-Ac255. In some embodiments, the conjugates described herein are selected from the conjugates described in Table 2B, Table 2B-Lu, Table 2B-Lu177, or Table 2B-Ac255. In some embodiments, the conjugates described herein are selected from the 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 at position 1 and cysteine (e.g., at position 10 or 12) is covalently bound by a different group. For example, the amino acid residue at position 1 may comprise a group selected from maleimide, halide, disulfide, electron-deficient alkyne, thioester, and alkene, which forms a covalent bond with cysteine.

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

[0286] In one aspect, described herein is a peptide that has an affinity for ephrin type-A receptor 2 (EphA2), wherein the peptide competes with a peptide having an amino acid sequence with one or several amino acid deletions, substitutions, and / or additions of the amino acids of SEQ ID NO:1 herein for binding to human EphA2: 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 an affinity for ephrin type-A receptor 2 (EphA2), wherein the peptide competes with a peptide having a structure of formula (I) (e.g., formula (I-1) and formula (I-2)) as described herein for binding to human EphA2; or a pharmaceutically acceptable salt thereof.

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

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

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

[0291] The lowercase letter d means D-amino acid. For example, dF means d-phenylalanine;

[0292] Me means methyl. For example, MeG represents N-methyl-glycine;

[0293] Ala or A means alanine;

[0294] Arg or R means arginine;

[0295] Asn or N means asparagine;

[0296] Asp or D means aspartic acid;

[0297] Cys or C means cysteine;

[0298] Gln or Q means glutamine;

[0299] Gly or G means glycine;

[0300] His or H means histidine;

[0301] Ile or I means isoleucine;

[0302] Leu or L means leucine;

[0303] Lys or K means lysine;

[0304] Met or M means methionine;

[0305] Phe or F means phenylalanine;

[0306] Pro or P means proline;

[0307] Ser or S means serine;

[0308] Thr or T means threonine;

[0309] Trp or W means tryptophan;

[0310] Tyr or Y means tyrosine;

[0311] Val or V means valine;

[0312] Ahp means 2-aminoheptanoic acid;

[0313] Nal1 means 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-chlorotryptophan;

[0320] Har refers to homoarginine (i.e., hArg). Table 2B-Lu. Exemplary conjugates (10-mer peptides) of the present disclosure containing chelated Lu Table 2B-Lu177. Exemplary conjugates (10-mer peptides) of the present disclosure containing chelated lutetium-177 Table 2B - Ac225. Exemplary conjugates of the present disclosure containing chelated actinium - 225 (10 - mer peptide) Table 3. Structures of exemplary unnatural amino acids that can be incorporated into the peptides described herein

[0323] The structures and names of exemplary unnatural amino acids of the present disclosure are further provided below: Alb(S) - 2 - amino - 3 - ureidopropionic acid (CAS No. 1483 - 07 - 4) da or Da (2R) - 2 - aminopropionic acid; dkCOpipzaa (2R) - 2 - amino - 6 - {[4 - (carboxymethyl)piperazine - 1 - carbonyl]amino}hexanoic acid Dahp (2R) - 2 - aminoheptanoic acid df3CON (2R) - 2 - amino - 3 - (3 - aminocarbonylphenyl)propionic acid (CAS No. 1217637 - 40 - 5) MeF (2S) - 2 - (methylamino) - 3 - phenylpropionic acid; Me3Py (2S) - 2 - (methylamino) - 3 - (pyridin - 3 - yl)propionic acid (CAS No. 1979173 - 93 - 7) Nal1 1 - naphthylalanine; 4Py (2S) - 2 - amino - 3 - (pyridin - 4 - yl)propionic acid (CAS No. 169555 - 95 - 7) MeHph (2S) - 2 - (methylamino) - 4 - phenylbutyric acid (CAS No. 1065076 - 30 - 3); W7N(2S)-2-Amino-3-{1H-pyrrolo[2,3-b]pyridin-3-yl}propanoic acid (CAS No. 737007-45-3) QPh(2S)-2-Amino-4-(phenylcarbamoyl)butanoic acid (CAS No. 198134-12-2); MeF3CN(2S)-3-(3-Cyanophenyl)-2-(methylamino)propanoic acid (CAS No. 2642331-80-2) MeF3H(2S)-3-(3-Hydroxyphenyl)-2-(methylamino)propanoic acid alT(2S,3S)-2-Amino-3-hydroxybutanoic acid; W1Me(2S)-2-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)-2-Amino-2-cyclohexylacetic acid (CAS No. 161321-36-4) Cba(2S)-2-Amino-3-cyclobutylpropanoic acid (CAS No. 478183-62-9) KCOpipzaa(2S)-2-Amino-6-{[4-(carboxymethyl)piperazine-1-carbonyl]amino}hexanoic acid Hgn(2S)-2-Amino-5-carbamoylvaleric acid (CAS No. 1263046-43-0) Nmm(2S)-2-Amino-3-(methylcarbamoyl)propanoic acid (CAS No. 149204-93-3) Ndm(2S)-2-Amino-3-(dimethylcarbamoyl)propanoic acid (CAS No. 138585-02-1) Hcit or hCit(2S)-2-Amino-6-(carbamoylamino)hexanoic acid (CAS No. 201485-17-8) Q Glucosamine (2S)-2-amino-4-{[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]carbamoyl}butyric acid mBph 3-phenylphenylalanine; MeE (2S)-2-(methylamino)pentanedioic acid; MeN (2S)-3-carbamoyl-2-(methylamino)propanoic acid; MeF4C (2S)-3-(4-chlorophenyl)-2-(methylamino)propanoic acid (CAS No. 1217779-77-5); Hph (2S)-2-amino-4-phenylbutyric acid; W1Me7N (2S)-2-amino-3-{1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl}propanoic acid (CAS No. 1813528-10-7) W1Me7Cl (2S)-2-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-guanidinohexanoic 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-Aminoadipic acid.

[0324] In some embodiments, the peptides described herein have a binding affinity for 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) assays. In some embodiments, the peptides described herein have a binding affinity for human EphA2 of at most 100 nM, as determined by Kd in surface plasmon resonance (SPR) assays. In some embodiments, the peptides described herein have a binding affinity for human EphA2 of at most 1 nM, as determined by Kd in surface plasmon resonance (SPR) assays. In some embodiments, the peptides described herein have a binding affinity for human EphA2 of at most 2 nM, as determined by Kd in surface plasmon resonance (SPR) assays. In some embodiments, the peptides described herein have a binding affinity for human EphA2 of at most 5 nM, as determined by Kd in surface plasmon resonance (SPR) assays. In some embodiments, the peptides described herein have a binding affinity for human EphA2 of at most 10 nM, as determined by Kd in surface plasmon resonance (SPR) assays.

[0325] In some embodiments, the conjugates described herein have a binding affinity for human EphA2 of at most 1, 5, 10, 50, 100, 200, 500, 1000, 5000, or 10,000 nM, as determined by Kd in a surface plasmon resonance (SPR) assay. In some embodiments, the conjugates described herein have a binding affinity for human EphA2 of at most 100 nM, as determined by Kd in a surface plasmon resonance (SPR) assay. In some embodiments, the conjugates described herein have a binding affinity for human EphA2 of at most 1 nM, as determined by Kd in a surface plasmon resonance (SPR) assay. In some embodiments, the conjugates described herein have a binding affinity for human EphA2 of at most 2 nM, as determined by Kd in a surface plasmon resonance (SPR) assay. In some embodiments, the conjugates described herein have a binding affinity for human EphA2 of at most 5 nM, as determined by Kd in a surface plasmon resonance (SPR) assay. In some embodiments, the conjugates described herein have a binding affinity for human EphA2 of at most 10 nM, as determined by Kd in a surface plasmon resonance (SPR) assay. 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 a surface plasmon resonance (SPR) assay. In some implementations, the Kd of the peptide or radiopharmaceutical conjugate of the present disclosure is 100 nM or 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 peptide can vary. In some embodiments, the molecular weight of the peptide is from about 0.1 to about 25 kDa. In some embodiments, the molecular weight of the peptide is from about 0.2 to about 20 kDa, from about 0.5 to about 15 kDa, from about 0.75 to about 10 kDa, from about 0.5 to about 10 kDa, from about 0.5 to about 5 kDa, from about 0.5 to about 2.5 kDa, from about 0.5 to about 2 kDa, from about 0.5 to about 1.5 kDa, from about 0.5 to about 1 kDa, from about 1 to about 10 kDa, from about 1 to about 5 kDa, from about 1 to about 2.5 kDa, from about 1 to about 2 kDa, from about 1 to about 1.5 kDa, from about 1 to about 1.25 kDa, or from about 0.5 to about 1.25 kDa. In some embodiments, the molecular weight of the peptide is from about 0.5 to 5 kDa. In some embodiments, the molecular weight of the peptide is from about 0.5 to 2 kDa. In some embodiments, the molecular weight of the peptide is from about 0.75 to 1.75 kDa. In some embodiments, the molecular weight of the peptide is from about 1 to 1.5 kDa. In some embodiments, the peptide is monocyclic.

[0327] The peptides described herein can be cyclized (i.e., macrocyclized). Cyclization can be achieved less desirably via a single disulfide bond or more desirably via a peptide bond, alkyl bond, alkenyl bond, ester bond, thioester bond, ether bond, thioether bond, phosphoether 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, etc. (but not limited thereto). In some embodiments, the peptide is a cyclic peptide, and the cyclic peptide is cyclized via a peptide bond, alkyl bond, alkenyl bond, ester bond, thioester bond, ether bond, thioether bond, phosphoether 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 via a thioether bond. In some embodiments, the cyclic peptide is cyclized via an oxime cyclization reaction. Cyclization of the peptide sometimes stabilizes the peptide structure, thereby enhancing the affinity for the target. Cyclization can occur between the N-terminus and the C-terminus, or it can occur between a terminal amino acid and a non-terminal amino acid. In some embodiments, cyclization occurs between two non-terminal amino acids. In some embodiments, the peptide is cyclized via an oxime cyclization. In some embodiments, the peptide is cyclized between a cysteine and a haloacyl group. In some embodiments, the peptide contains a haloacetyl group (e.g., chloroacetyl or bromoacetyl) at the N-terminus. In some embodiments, the peptide contains a haloacetyl group (e.g., chloroacetyl or bromoacetyl) at the C-terminus. In some embodiments, the peptide contains Cys at the C-terminus. In some embodiments, the peptide contains Cys at the N-terminus. In some embodiments, cyclization occurs via a thioether bond between Cys and a haloacetyl group. In some embodiments, cyclization occurs between the N-terminus and the C-terminus of the peptide.

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

[0329] In some embodiments, for example, chloroacetylated amino acids can be used as the amino acid (I-A). Examples of 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-diaminopropionic 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-tryptophan, and their corresponding D-amino acid derivatives (e.g., 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, mercaptopronvaline, mercaptopronleucine, 2-amino-7-mercaptoheptanoic acid, 2-amino-8-mercaptooctanoic acid, and amino acids obtained by protecting the SH groups of these amino acids and then removing the protecting groups, and their corresponding D-amino acid derivatives.

[0331] The cyclization method can be carried out, for example, according to the methods described in the following: 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, amino acids (II - A) selected from the following can be used: propargylglycine, homopropargylglycine, 2 - amino - 6 - heptynoic acid, 2 - amino - 7 - octynoic acid, and 2 - amino - 8 - nonynoic acid. In addition, 4 - pentynoyl - acylated amino acids or 5 - hexynoyl - acylated amino acids can also be used. Examples of 4 - pentynoyl - acylated 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 - pentynoyl - amido)benzoyl - L - phenylalanine, N - 3-(4 - pentynoyl - amido)benzoyl - L - tyrosine, N - 3-(4 - pentynoyl - amido)benzoyl - L - tryptophan, β - N-(4 - pentenoyl)-L - diaminopropionic acid, γ - N-(4 - pentenoyl)-L - diaminobutyric acid, σ - N-(4 - pentenoyl)-L - ornithine, and ε - N-(4 - pentenoyl)-L - lysine, and their corresponding D - amino acid derivatives.

[0333] In some embodiments, for example, amino acids (II - B) selected from the following can be used: azidolalanine, 2 - amino - 4 - azidobutyric acid, azidonorvaline, azidonorleucine, 2 - amino - 7 - azidoheptanoic acid, and 2 - amino - 8 - azidooctanoic acid. In addition, azido - acylated amino acids or 3 - azidopentanoyl - acylated amino acids can also be used. Examples of azido - acylated amino acids include N - azidoacetyl - L - alanine, N - azidoacetyl - L - phenylalanine, N - azidoacetyl - L - tyrosine, N - azidoacetyl - L - tryptophan, N - 3-(4 - pentynoyl - amido)benzoyl - L - phenylalanine, N - 3-(4 - pentynoyl - amido)benzoyl - L - tyrosine, N - 3-(4 - pentynoyl - amido)benzoyl - L - tryptophan, β - N - azidoacetyl - L - diaminopropionic acid, γ - N - azidoacetyl - L - diaminobutyric acid, α - N - azidoacetyl - L - ornithine, and ε - N - azidoacetyl - L - lysine, and their corresponding D - amino acid derivatives.

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

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

[0336] Examples of the amino acid (III - B) include, but are not limited to, 5 - hydroxytryptophan (WoH). The cyclization method can be carried out, for example, according to the methods described in Yamagishi, Y. et al., ChemBioChem 10, 1469 - 1472 (2009) or WO 2008 / 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, mercaptopropionylglycine, mercaptopropionylleucine, 2 - amino - 7 - mercaptoheptanoic acid, and 2 - amino - 8 - mercaptooctanoic acid, amino acids obtained by protecting the SH groups of these amino acids and then removing the protecting groups, and their corresponding D - amino acid derivatives. The cyclization method can be carried out, for example, according to the methods described in WO 2012 / 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 - tryptophan.

[0340] Examples of the amino acid (V - B) include, but are not limited to, cysteine, homocysteine, mercaptopropionylglycine, mercaptopropionylleucine, 2 - amino - 7 - mercaptoheptanoic acid, and 2 - amino - 8 - mercaptooctanoic acid, and amino acids obtained by protecting the SH groups of these amino acids and then removing the protecting groups, and their corresponding D - amino acid derivatives.

[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 involves forming a thioether bond using an amino acid containing a thioalkyl group (e.g., cysteine, homocysteine, mercaptopropionylglycine, mercaptopropionylleucine, 2 - amino - 7 - mercaptoheptanoic acid, and 2 - amino - 8 - mercaptooctanoic acid).

[0342] The peptides described herein may 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 containing additional amine groups. Positively charged amino acids may comprise a heteroaryl substitution having one or more ring nitrogen atoms, such as pyridine, imidazole, pyrazole, or triazole. Negatively charged amino acids include, for example, amino acids containing additional carboxylic acid groups (such as glutamic acid, etc.).

[0343] In some embodiments, the cyclic peptides of formula (I), formula (I-1), formula (I-2), formula (Ia), formula (Ib), or formula (Ic) have a net charge of from -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, the cyclic peptides of formula (I), formula (I-1), formula (I-2), formula (Ia), formula (Ib), or formula (Ic) have a net charge of at most -4. In some embodiments, the cyclic peptide has a net charge of -4. In some embodiments, the cyclic peptides of formula (I), formula (I-1), formula (I-2), formula (Ia), formula (Ib), or formula (Ic) have 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 summing the charges of each of the X1 to X12 amino acids (or each amino acid in the peptide). For example, aspartic acid (D) and glutamic acid (E) each have a charge of -1, lysine (K), arginine (R), and histidine (H) each have a charge of +1, and the remaining canonical amino acids each have a charge of 0.

[0344] In some embodiments, the cyclic peptide of formula (I) has a net charge of from -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 summing the charges of each amino acid of the cyclic peptide.

[0345] In some embodiments, the cyclic peptides described herein (e.g., cyclic peptides of formula (I), formula (I-1), formula (I-2), formula (Ia), formula (Ib), or formula (Ic)) are configured to bind to EphA2 with a defined affinity, such as measured as the percentage of plasma protein albumin binding (PPB). The binding % can be determined by the 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., about 10% to about 95% PPB). 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, the conjugates described herein (e.g., conjugates comprising a cyclic peptide of Formula (I), Formula (I-1), Formula (I-2), Formula (Ia), Formula (Ib), or Formula (Ic)) are configured to bind to plasma proteins with a defined affinity, such as measured as the percentage of plasma protein albumin binding (PPB). 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., about 10% to about 95% PPB). 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, the cyclic peptides of Formula (I), Formula (I-1), Formula (I-2), Formula (Ia), Formula (Ib), or Formula (Ic) do not contain any S-S bonds.

[0348] In some embodiments, the peptides of the present disclosure can be cyclized by forming the groups shown in Table 4B. Table 4B. Ring-Closing Groups (m and n are independently integers from 0 or 1 to 6). <![CDATA[-C(=O)-CH2-]]> <![CDATA[-C(=O)-CH2-S-]]> <![CDATA[-C(=O)-CH2-S-CH2-]]> <![CDATA[-C(=O)-CH2-S-CH2-CH2-]]> <![CDATA[-(CH2) m -NH-CO-(CH2) n -]]> <![CDATA[-(CH2) m -CO-NH-(CH2)n-]]> <![CDATA[-(CH2) m -S-(CH2) n -]]> <![CDATA[-(CH2) m -CH=CH-(CH2) n -]]> <![CDATA[-(CH2) m -NH-(CH2) n -]]> <![CDATA[-(CH2) m -S-CH2-benzene-CH2-S-(CH2) n -]]> <![CDATA[-(CH2) m -triazole-(CH2) n -]]> <![CDATA[-(CH2) m -succinimidyl-S-(CH2) n -]]> <![CDATA[-C(=O)-CH2-NH-CH2- <!-- 112 -->]]> <![CDATA[-C(=O)-CH2-O-CH2-]]> <![CDATA[-C(=O)-CH2-CH2-S-]]> <![CDATA[-(CH2) m -S-S-(CH2) n -]]> <![CDATA[-(CH2) m -C(=O)-NH-(CH2) n -]]> <![CDATA[-(CH2) m -CH2-CH2-(CH2) n -]]>

[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, the peptides 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 of the peptides of Table 1 can further comprise amino acid residues at the N- and / or C-terminus of the peptide that are 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 that connects the peptide to the covalent radionuclide. In some embodiments, the conjugate further comprises a covalent radionuclide, such as 18 F, 74 As, 76 Br, 123 I, 124 I, 125 I, 131 I or 211 At.

[0352] The peptides described herein can be peptidomimetics. For example, the peptide can contain non-peptide bonds and it can contain one or more non-natural amino acids. Unless otherwise indicated, each amino acid in the peptides described herein (other than the natural amino acid glycine) can independently be in its D or L form. The present disclosure encompasses both D and L forms.

[0353] In the present disclosure, the term amino acid includes derivatives of amino acids. Derivatives include, for example, amino acids obtained by modifying natural amino acids that make up proteins produced by biological substances encoded by the cellular DNA. Examples of such non-natural amino acids include hydroxyproline and hydroxylysine (which are amino acids with a hydroxy group introduced therein) and diaminopropionic acid (which is an amino acid with an amino group introduced therein).

[0354] The peptides described herein can contain N-substituted amino acids. 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 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 N-aryl, such as N-phenyl or N-biphenyl. In some embodiments, the N-substitution is N-heteroaryl, such as N-pyridyl. In some embodiments, the N-substituted amino acid is located 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, the peptides described herein contain one or more amino acids from Tables 5A to 5F. Table 5A. Exemplary amino acids at the N-terminus or C-terminus N - chloroacetyl - L - alanine acetyl - L - alanine N - chloroacetyl - L - phenylalanine acetyl - L - phenylalanine N - chloroacetyl - L - phenylalanine acetyl - L - tyrosine N - chloroacetyl - L - tyrosine acetyl - L - tryptophan N - chloroacetyl - L - tryptophan acetyl - D - alanine N - chloroacetyl - D - alanine acetyl - D - phenylalanine N - chloroacetyl - D - phenylalanine acetyl - D - tyrosine N - chloroacetyl - D - tyrosine acetyl - D - tryptophan N - chloroacetyl - D - tryptophan N - (3 - chloromethylbenzoyl) - L - tyrosine N - (3 - chloromethylbenzoyl) - L - tryptophan Table 5B. Exemplary amino acids for cross-linking peptides Nγ - (2 - chloroacetyl) - α,γ - diaminobutyric acid Nγ - (2 - chloroacetyl) - α,γ - diaminopropionic acid Table 5C. D-amino acids D - serine D - phenylalanine D - tyrosine D - tryptophan Table 5D. Exemplary N-alkyl amino acids N - alkyl - glycine N - alkyl - alanine N - alkyl - phenylalanine N - alkyl - tyrosine N - alkyl - serine N - alkyl - histidine N - alkyl - tryptophan

[0356] Exemplary alkyls in Table 5D include methyl, ethyl, and propyl. Table 5E. Exemplary peptidomimetic units N - ethyl - glycine N - n - propyl - glycine N - n - butyl - glycine N - n - pentyl - glycine N - n - hexyl - glycine N - n - heptyl - glycine N - n - octyl - glycine N - iso - pentyl - glycine N - (2 - phenylethyl) - glycine N - (3 - phenylpropyl) - glycine N - [2 - (p - hydroxyphenyl)ethyl] - glycine Table 5F. Exemplary non-natural amino acids p - biphenylalanine p - trifluoromethylphenylalanine p - azidophenylalanine p - biotinyl - aminophenylalanine e - N - biotinyl - lysine e - N - acetyl - lysine L - citrulline L - 5 - hydroxytryptophan L - 1,2,3,4 - tetrahydroisoquinoline - 3 - carboxylic acid aminoisobutyric acid N - methyl - aminoisobutyric acid N - methyl - phenylglycine

[0357] The amino acids used in the disclosed peptides can be replaced by similar amino acids. In some embodiments, an amino acid can be replaced by another amino acid having similar hydrophobicity. In some embodiments, an amino acid can be replaced by another amino acid having similar hydrophilicity. In some embodiments, an amino acid can be replaced by another amino acid having similar size. In some embodiments, an amino acid can be replaced by another amino acid having similar charge. In some embodiments, an amino acid can be replaced by another amino acid having similar functional groups. In some embodiments, an amino acid can be replaced by another amino acid having the same functional groups.

[0358] In some embodiments, the amino acids described herein can be replaced by their variants. Examples of amino acid substitutions or variants include derivatives having an amine group, an amide group, an ester group, or a carboxyl group as their C-terminus and / or N-terminus. Further examples of amino acid / peptide variants include those obtained by modification (such as phosphorylation, alkylation (e.g., methylation), acetylation, adenylation, ADP-ribosylation, or glycosylation), and fusion proteins obtained by fusion with another peptide or protein. These variants can be prepared by those skilled in the art in known ways or methods based thereon. Amino acid variants further encompass amino acids having the same functional groups but different side-chain lengths (e.g., LysAc compared to OrnAc and cysteine compared to homocysteine). Amino acid variants further encompass amino acids having different aromatic moieties compared to canonical amino acids (e.g., indole in tryptophan compared to 7-azaindole in 7-azatrp; phenyl in phenylalanine compared to pyridine in 4Py). Amino acid variants further encompass amino acids having optional substituents, i.e., optionally substituted amino acids. In some embodiments, the optionally substituted amino acid is optionally substituted with one or more substituents independently selected from the following: halogen, hydroxy, cyano, amino, amide, nitro, ureido, C1-C6 alkyl, C1-C6 alkoxy, C6-C 10Aryl, C3-C6 cycloalkyl, 6-10 membered heteroalkyl, and 6-10 membered heteroaryl. In some embodiments, the optionally substituted amino acid is optionally substituted with one or more substituents independently selected from the following: 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, heteroalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone, and aryl sulfone. In some embodiments, the substituents can include any of the substituents described herein, such as: halogen, hydroxy, oxo(=O), thio(=S), cyano(-CN), nitro(-NO2), imino(=N-H), oxime(=N-OH), hydrazino(=N-NH2), SF 5 , -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -O-R c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t ORa (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, and heterocycle, any of which may optionally be substituted with: alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo group (=O), thioxo group (=S), cyano group (-CN), nitro group (-NO2), imino group (=N-H), oxime group (=N-OH), hydrazino group (=N-NH2), -R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2、-R b -O-R c -C(O)N(R a )2、-R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (where t is 1 or 2)、-R b -S(O) t R a (where t is 1 or 2)、-R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2); where each R a is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, and heterocycle, where each R aOptionally, when the valence allows, it can be substituted by the following: alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo group (=O), thio group (=S), cyano group (-CN), nitro group (-NO2), imino group (=N-H), oxime group (=N-OH), hydrazine (=N-NH2), -R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2、-R b -O-R c -C(O)N(R a )2、-R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2(where t is 1 or 2); and where each R b is independently selected from a direct bond or a straight-chain or branched alkylene, alkenylene or alkynylene chain, and each R c is a straight-chain or branched alkylene, alkenylene or alkynylene chain.

[0359] In some embodiments, variants of the amino acid are 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-C3 alkyl), -N(C1-C3 alkyl)2, oxo group, -OH, -CO2H, -CO2-C1-C3 alkyl, -C(=O)NH2, -C(=O)NH(C1-C3 alkyl), -C(=O)N(C1-C3 alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C3 alkyl), -S(=O)2N(C1-C3 alkyl)2, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C6-C 10 aryl, C3-C6 cycloalkyl, 6-10 membered heteroalkyl, and 6-10 membered heteroaryl.

[0360] In some embodiments, variants are 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-C3 alkyl), -N(C1-C3 alkyl)2, oxo group, -OH, -CO2H, -CO2-C1-C3 alkyl, -C(=O)NH2, -C(=O)NH(C1-C3 alkyl), -C(=O)N(C1-C3 alkyl)2, and C1-C6 alkyl. In some embodiments, variants are 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-C3 alkyl), -N(C1-C3 alkyl)2, and C1-C6 alkyl. In some embodiments, variants are selected from amino acids having one or two substituents based on the amino acid, and wherein the substituents are independently selected from C1-C6 alkyl.

[0361] In some embodiments, variants of the amino acid are selected from amino acids having 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, the hydrophilic amino acid has a charged side chain. In some embodiments, the hydrophilic amino acid has a positive charge. In some embodiments, the hydrophilic amino acid has a negative charge. In some embodiments, the hydrophilic amino acid is zwitterionic (e.g., KCOpipzaa). In some embodiments, the hydrophilic amino acid contains an -OH, COOH, -NH-, or NH2 moiety. In some embodiments, the hydrophilic amino acid contains -OH, -C(O)OH, -NHC(=NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3. In some embodiments, the hydrophilic amino acid contains the following side chains: C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, -C 0-6 alkylene-NH-C(=NH)-NH2, -C 0-6 alkylene-CO-NH2, -C 0-6 alkylene-COOH or -NH-CO-C 1-6 alkyl.

[0363] In some embodiments, the hydrophobic amino acid is uncharged. In some embodiments, the hydrophobic amino acid contains at least 2 consecutive carbon atoms. In some embodiments, the hydrophobic amino acid contains at least 3 consecutive carbon atoms in a straight or branched chain. In some embodiments, the hydrophobic amino acid contains at least 4 consecutive carbon atoms in a straight or branched chain. In some embodiments, the hydrophobic amino acid contains at least 5 consecutive carbon atoms in a straight or branched chain. In some embodiments, the hydrophobic amino acid contains an ethylene moiety in the side chain. In some embodiments, the hydrophobic amino acid contains a propylene moiety in the side chain. In some embodiments, the hydrophobic amino acid contains a butylene moiety in the side chain. In some embodiments, the hydrophobic amino acid contains a phenyl moiety. In some embodiments, the hydrophobic amino acid contains a heteroaryl moiety. In some embodiments, the hydrophobic amino acid is Trp, Tyr, Phe, or a derivative thereof.

[0364] In some embodiments, variants of an amino acid are selected from amino acids having the same functional groups as the amino acid, and wherein the variant has a different side-chain length compared to the amino acid. In some embodiments, variants of an amino acid are selected from amino acids having the same functional groups as the amino acid, and wherein the variant has a different side-chain carbon-chain length compared to the amino acid (e.g., leucine compared to (S)-2-amino-5-methylhexanoic acid, or 2-(methylamino)glutaric acid compared to 2-(methylamino)adipic acid). In some embodiments, variants of an amino acid are selected from amino acids having the same charge as the amino acid. In some embodiments, variants of an amino acid are selected from amino acids having the same polarity as 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 group can be a variant of another amino acid having a phenyl group. In some embodiments, an amino acid comprising a heteroaryl group can be a variant of another amino acid having a heteroaryl group. In some embodiments, an amino acid comprising a heteroaryl group 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, 4Py2NH 2, and Me4Py. Thus, variants of an amino acid comprising a heteroaryl ring encompass amino acids comprising different heteroaryl groups. In some embodiments, F or its variants encompass amino acids in which the benzene ring is replaced by a heteroaryl group (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, variants of an amino acid are selected from amino acids having similar polarity and / or charge to 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, Q-glucosamine).

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

[0367] In some embodiments, the variant has a molecular weight that varies by no 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 varies by no more than 14 g / mol compared to the amino acid. In some embodiments, the variant has a molecular weight that varies by no more than 50 g / mol compared to the amino acid. In some embodiments, the variant has a molecular weight that varies by no more than 28 g / mol compared to the amino acid.

[0368] Amino acid variants further encompass amino acids in which one functional group is replaced by another functional group having similar properties. For example, cysteine can be replaced by homocysteine. In some embodiments, an aryl functional group can be replaced by an aryl or heteroaryl group. In some embodiments, a heteroaryl functional group can be replaced by an aryl or heteroaryl group. In some embodiments, an amino functional group can be replaced by an NH(alkyl) group.

[0369] As used herein, the phrase "conservative amino acid substitution" refers to the substitution of amino acids that are functionally equivalent or similar. Conservative amino acid substitutions in a peptide result in a static change in the amino acid sequence of the peptide. For example, one or two or more amino acids having similar polarity function equivalently to each other and result in a static change in the amino acid sequence of the peptide. Generally, substitutions within certain groups can be considered conservative in terms of structure and function. However, as will be clear to those of ordinary skill in the art, the role played by a defined amino acid residue can be determined by its influence on the three-dimensional structure of the molecule containing the amino acid. For example, the oxidized (disulfide) form of a cysteine residue can have lower polarity compared to the reduced (thiol) form. The long aliphatic portion of the arginine side chain can constitute a structurally and functionally important feature. In addition, side chains containing aromatic rings (tryptophan, tyrosine, phenylalanine) can contribute to ion-aromatic or cation-π interactions. In such cases, even if the amino acids having these side chains are replaced by amino acids belonging to acidic or nonpolar groups, they can be conservative in terms of structure and function. Residues such as proline, glycine, cysteine (disulfide form), etc. may have a direct impact on the three-dimensional structure of the backbone and generally will not be substituted without structural distortion.

[0370] As shown below, conservative amino acid substitutions include specific substitutions based on side chain similarity (e.g., substitutions as described in Lehninger, Biochemistry, Revised Edition 2nd Edition, published in 1975, pages 73 to 75: L. Lehninger, Biochemistry, 2nd Edition, pages 73 to 75, Worth Publisher, New York (1975), which is incorporated herein by reference) and typical substitutions.

[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 can be further divided into the following groups: · Aliphatic amino acids: Amino acids having a fatty acid or hydrogen in the side chain, including, for example, Ala, Gly, Val, Ile, and Leu. · Aliphatic / branched-chain amino acids: Amino acids having a branched-chain fatty acid in the side chain, including, for example, Val, Ile, and Leu. · Aromatic amino acids: Amino acids having an aromatic ring in the side chain, including, for example, Trp, Tyr, and Phe.

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

[0374] Hydrophilic amino acids include amino acids that exhibit hydrophilicity, including, for example, 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"), lysine (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 can be further divided into the following groups: · Acidic amino acids: Amino acids whose side chains exhibit acidity, including Asp and Glu. ● Basic amino acids: Amino acids whose side chains exhibit basicity, including Lys, Arg, and His. ● 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 variants thereof (the variants including D-amino acids (such as da) and modifications such as Q-glucosamine (which has a glucosamine moiety added to the NH2 terminus of its side chain)).

[0377] In some embodiments, the peptides described herein contain amino acids that affect the backbone direction, such as Gly and Pro. In some embodiments, the peptides described herein contain sulfur-containing amino acids, such as Cys and Met. In some embodiments, the peptides described herein contain amino acids containing an aromatic ring, which may optionally be substituted. Amino acids containing an aromatic ring include, for example, F (Phe; phenylalanine), Y (Tyr; tyrosine), W (Trp; tryptophan).

[0378] In some embodiments, W or its variant 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 acid having a substituent in the benzene ring of W, etc.

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

[0380] In some embodiments, W, Y or their variants can be an amino acid of W, Y, a 6-membered aryl or heteroaryl, a 9- or 10-membered bicyclic aryl or heteroaryl connected to the α-carbon through carbon (such as methylene). In some embodiments, the 6-, 9- and 10-membered heteroaryls have 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 -methyl, -ethyl, -Cl and -F. In certain embodiments, W or Y or their variants are W1Me, W1Me7Cl, or F23dMe, Nal1, Nal2, W1Et, Nal21N, 3Bzf, 3Bzt, Nal15N, Nal14N, Nal24N, Nal28N, F23dC or W1Me7N. In some embodiments, the variant of W is W1Me. In some embodiments, the variant of W is W1Me7Cl. In some embodiments, the variant of Y is F23dMe.

[0381] Examples of amino acids include natural protein L-amino acids, unnatural amino acids, and chemically synthesized compounds having properties known in the art as characteristic of amino acids. Examples of unnatural amino acids include, but are 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 of which has a backbone structure different from that of natural amino acids; amino acids with side chain structures different from those of natural amino acids (such as norleucine and homohistidine); amino acids having an additional methylene in their side chains (such as "homo" amino acids, homophenylalanine, and homohistidine); and amino acids obtained by replacing the carboxylic acid functional amino group in their side chains with a sulfonic acid group (such as sulfopropylalanine).

[0382] In some embodiments, the amino acids described herein are N-alkylated. In some embodiments, the amino acids described herein are not N-alkylated (e.g., amino acids having -H on the α-amino). In certain embodiments, such amino acids are A, E, N, K, Q glucosamine, KCOpipzaa, Q, Hse, Cit, Hcit, KAc, DapAc, OrnAc, T, alT, Aib or 3Py6NH2, more preferably V, Q glucosamine, Cit, Hcit, K or 3Py6NH2.

[0383] The peptides described herein can include one or more unnatural amino acids. Unnatural amino acids include, but are not limited to, (1) amino acids corresponding to amino acid residues on a polypeptide that undergo modification after expression (e.g., phosphorylated tyrosine, acetylated lysine, or farnesylated cysteine), (2) amino acids that are not used for expression on ribosomes but are naturally occurring, and (3) artificial amino acids (unnatural amino acids) that are not naturally occurring. 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-propargyl tyrosine, 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 analog of a tyrosine amino acid; an unnatural analog of a glutamine amino acid; an unnatural analog of a phenylalanine amino acid; an unnatural analog of an alanine amino acid; an unnatural analog of a serine amino acid; an unnatural analog of a threonine amino acid; an alkyl, aryl, acyl, azido, cyano, halo, hydrazine, hydrazide, hydroxyl, alkenyl, alkynyl, ether, thiol, sulfonyl, seleno, ester, thioacid, borate, boronate, phosphorylated, phosphonic acid, phosphine, heterocyclic, enone, imine, aldehyde, hydroxylamine, ketone, or amino-substituted amino acid; or a combination thereof. In some embodiments, the unnatural amino acid is an amino acid with a photoactivatable crosslinker; 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; an amino acid containing biotin or a biotin analog; an amino acid containing a ketone; an amino acid containing polyethylene glycol or a polyether; a heavy atom-substituted amino acid; a chemically cleavable or photocleavable amino acid; an amino acid with an extended 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 α-hydroxy-containing acid; an amino sulfonic 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] Non-natural amino acids include, for example, N-alkyl amino acids, where the above natural amino acids are N-alkylated, such as those modified with a lower alkyl (e.g., C1 to C5, C1 to C3, and C1), where the nitrogen forming the peptide bond is branched or unbranched. Exemplary N-alkyl amino acids include, for example, N-ethyl amino acid, N-butyl amino acid, and N-methyl amino acid. Also included are amino acids in which a functional group is further added to the side chain of a natural amino acid or the functional group is replaced by another functional group (e.g., an amino acid having a substitution or addition in a portion of the side chain such as arylene, alkylene, etc.; an amino acid in which the arylene or alkyl of the side chain has an increased number of C; an amino acid having a substitution in the aromatic ring of the side chain; a heterocyclic or fused cyclic amino acid; etc.). Exemplary N-alkyl amino acids further include, for example, N-alkyl lysine and N-methyl lysine. Exemplary N-alkyl amino acids further include, for example, N-methyl lysine in which an albumin binder is incorporated.

[0385] In a non-limiting manner, non-natural amino acids include, but are not limited to, N-methyl amino acid, da, kCOpipzaa, dahp, df3CON, 4Py, W7N, QPh, alT, W1Me, Cbg, Chg, Cba, Hgl, Hgn, Nmm, Ndm, Hcit, Q-glucosamine, 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, etc. Note that D-amino acids such as da can be classified as D-amino acids, but they can also be classified according to the characteristics of their side chains, and N-methyl amino acids can be classified as N-alkyl amino acids and can also be classified according to the characteristics of their side chains.

[0386] In some embodiments, the unnatural amino acids incorporated into the peptides include one or more of the following: 1) a keto functional group (such as found in para- or meta-acetyl-phenylalanine), which can react specifically with hydrazine, hydroxylamine, 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. January 7, 2003; 100(1):56-61; Bioorg Med Chem Lett. October 15, 2006; 16(20):5356-9. Genetic introduction of a diketone-containing amino acid into proteins. Zeng ...

Claims

1. A radiopharmaceutical conjugate, the radiopharmaceutical conjugate comprising: (a) a cyclic peptide that has an affinity 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 containing an aromatic ring, its N-methylated amino acid 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 containing an aromatic ring, or its N-methylated amino acid; X7 is an amino acid containing an aromatic ring (e.g., W, F or a variant thereof); X8 is a hydrophobic amino acid, a hydrophilic amino acid, its N-methylated amino acid or a variant; X9 is an amino acid containing an aromatic ring (e.g., W or a variant thereof); X10 is absent or is a hydrophilic amino acid (e.g., threonine (T) or a variant thereof); X11 is absent or is a hydrophilic amino acid; and X12 is cysteine (C) or a variant thereof; and (b) (i) a metal chelator configured to bind to 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, the radiopharmaceutical conjugate comprising: (a) a cyclic peptide that has an affinity for ephrin type A receptor 2 (EphA2), wherein the peptide comprises an amino acid sequence including one or more (e.g., 1-6) amino acid deletions, substitutions, and / or additions of the following 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 to 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 according to claim 1 or 2, the radiopharmaceutical conjugate comprising a metal chelator configured to bind to a radionuclide, wherein the metal chelator is conjugated to the peptide.

4. The radiopharmaceutical conjugate according to claim 2, wherein 1-5 amino acids selected from N at position 3, L at position 4, MeF at position 6, T at position 10, and E at position 11 of SEQ ID NO:1 are deleted, optionally without additional addition and / or substitution.

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

6. The radiopharmaceutical conjugate according to any one of claims 2, 4, or 5, wherein one or more amino acid residues selected from MeF at position 2, MeF at position 6, V at position 8, and E at position 11 are substituted.

7. The radiopharmaceutical conjugate according to claim 1 or any one of claims 4 to 6, wherein 1 to 2 amino acids selected from T at position 10 and E at position 11 of SEQ ID NO:1 are deleted, optionally without additional addition and / or substitution.

8. The radiopharmaceutical conjugate according to claim 2 or any one of claims 4 to 6, wherein V at position 8 is substituted.

9. The radiopharmaceutical conjugate according to claim 2 or any one of claims 4 to 6, wherein E at position 11 is substituted.

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

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

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

13. The radiopharmaceutical conjugate according to claim 12, wherein the alpha-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 according to claim 12, wherein the alpha-emitting radionuclide is Ac-225.

15. The radiopharmaceutical conjugate according to claim 11, wherein the radionuclide is a beta-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 according to claim 15, wherein the beta-emitting radionuclide is Lu-177.

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

19. The radiopharmaceutical conjugate according to 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 according to claim 19, wherein the metal chelator has the following structure:

21. The radiopharmaceutical conjugate according to claim 19, wherein the metal chelator has the following structure:

22. The radiopharmaceutical conjugate according to any one of claims 1 to 21, further comprising a linker that covalently links the peptide to the metal chelator.

23. The radiopharmaceutical conjugate according to claim 22, wherein the conjugate has the following structure: wherein Denote said joint.

24. The radiopharmaceutical conjugate according to 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 according to claim 24, wherein the linker is attached to the 5th amino acid residue or X5.

26. The radiopharmaceutical conjugate according to claim 24, wherein the linker is attached to the 8th amino acid residue or X8.

27. The radiopharmaceutical conjugate according to claim 24, wherein the linker is attached to the 11th amino acid residue or X11.

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

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

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

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

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

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

34. The radiopharmaceutical conjugate according to claim 32 or 33, wherein the intermediate atoms comprise 1 to 6 nitrogens and 0 to 4 oxygens.

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

37. The radiopharmaceutical conjugate according to 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 according to any one of claims 22 to 30, wherein the linker has the structure of formula (II-1): wherein each L is independently -O-, -NR L -, -N(R L )2-, -OP(=O)(OR L )O-, -S-, -S(=O)-, -S(=O)2-, =CH-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR L -, -NR L C(=O)-, -OC(=O)NR L -, -NR L C(=O)O-, -NR L C(=O)NR L -, -NR L C(=S)NR L -, -CR L =N-, -N=CR L , -NR L S(=O)2-, -S(=O)2NR L -, -C(=O)NR L S(=O)2-, -S(=O)2NR L C(=O)-, substituted or unsubstituted C3-C 15 cycloalkyl, substituted or unsubstituted C1-C 12 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C 30 alkylene, substituted or unsubstituted C2-C 30 alkenylene, substituted or unsubstituted C2-C 30 alkynylene, substituted or unsubstituted C1-C 30 heteroalkylene, -(C1-C 30 alkylene)-O-, -O-(C1-C 30 alkylene)-, -(C1-C 30 alkylene)-NR L -, -NR L -(C1-C 30 alkylene)-, -(C1-C 30 alkylene)-N(R L )2- or -N(R L )2-(C1-C 30 alkylene)-; and Each R L is independently hydrogen, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C1-C4 heteroalkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C5 alkynyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted C2-C7 heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group; and n is from 1 to 20.

39. The radiopharmaceutical conjugate according to claim 38, wherein the linker comprises the structure of formula (II-1a), wherein L 1 and L 3 each independently is -O-, -NR L -, -N(R L )2-, -OP(=O)(OR L )O-, -S-, -S(=O)-, -S(=O)2-, -CH=CH-, =CH-, -C≡C-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR L -, -NR L C(=O)-, -OC(=O)NR L -, -NR L C(=O)O-, -NR L C(=O)NR L -, -NR L S(=O)2-, -S(=O)2NR L -, -C(=O)NR L S(=O)2- or -S(=O)2NR L C(=O)-; and L 2 is absent, or is a substituted or unsubstituted C1-C 30 alkylene, or a substituted or unsubstituted C1-C 30 heteroalkylene.

40. The radiopharmaceutical conjugate according to claim 39, wherein L 1 is -NH-.

41. The radiopharmaceutical conjugate according to claim 39 or 40, wherein L 2 is a substituted or unsubstituted C1-C 30 alkylene, or a substituted or unsubstituted C1-C 30 heteroalkylene.

42. The radiopharmaceutical conjugate according to claim 39 or 40, wherein L 2 is a substituted or unsubstituted C1-C 18 alkylene, or a substituted or unsubstituted C1-C 18 heteroalkylene.

43. The radiopharmaceutical conjugate according to any one of claims 39 to 42, wherein L 2 is optionally substituted with one or more substituents selected from the following: -OH, -SH, oxo group, amino group, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, -C(=O)OR L , -OC(=O)R L , -OC(=O)OR L , -C(=O)N(R L )2, -NR L C(=O)R L , -OC(=O)N(R L )2 and -NR L C(=O)OR L ; and the C1-C6 alkyl is further optionally substituted with one or more substituents selected from the following: -OH, -SH, oxo group, amino group, C6-C 10 aryl, 6- to 10-membered heteroaryl, -C(=O)OR L , -OC(=O)R L , -OC(=O)OR L , -C(=O)N(R L )2, -NR L C(=O)R L , -OC(=O)N(R L )2 and -NR L C(=O)OR L .

44. The radiopharmaceutical conjugate according to any one of claims 39 to 43, wherein L 3 is -NH-.

45. The radiopharmaceutical conjugate according to claim 39, wherein the linker has the following structure:

46. The radiopharmaceutical conjugate according to claim 39, wherein the linker has the following structure:

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

49. The radiopharmaceutical conjugate according to claim 48, wherein the peptide consists of an amino acid sequence selected from SEQ ID NO: 1-122, 159-163, and 165-171, and the peptide has a cyclic structure having a cysteine residue or a variant thereof at the 12th residue, and wherein the amino acid X1 and the cysteine residue or a variant thereof at the 12th residue are covalently linked (e.g., by reacting the chloroacetyl group in the amino acid of X1 with the cysteine residue or a variant thereof).

50. The radiopharmaceutical conjugate according to claim 48, wherein the peptide consists of an amino acid sequence selected from SEQ ID NO: 123 - 149 and 164, and the peptide has a cyclic structure having a cysteine residue or a variant thereof at the 10th residue, and wherein the amino acid X1 and the cysteine residue or its variant at the 10th residue are covalently linked.

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

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

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

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

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

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

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

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

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

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

61. The radiopharmaceutical conjugate according to claim 59, wherein X11 is arginine (R), asparagine (N), aspartic acid (D), glutamine (Q), lysine (K) or a non - natural hydrophilic amino acid.

62. The radiopharmaceutical conjugate according to any one of claims 1 to 61, wherein the peptide has the 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, wherein the unsubstituted benzene ring of F is replaced by the following (i) A benzene ring substituted by 1 or 2 substituents each independently selected from -OH, -CN and -C 1-3 alkyl, or (ii) A 6-membered heteroaryl ring optionally substituted with 1 or 2 substituents each independently selected from -OH, -CN, and -C 1-3 alkyl, wherein the F or its variant 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 containing a straight-chain, branched-chain 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 having a functional side chain); X6 is its N-methylated amino acid; X7 is W, Y or a variant thereof (e.g., an amino acid having a 6-membered aryl or heteroaryl or a 9- or 10-membered bicyclic aryl or heteroaryl connected to the α-carbon through a carbon (e.g., methylene), wherein the 6-, 9- and 10-membered heteroaryls have 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 the following: -CH3, -ethyl, -Cl and -F); X8 is an amino acid having -H on the α-amino; X9 is W or Y or a variant thereof (e.g., W or a variant thereof); X10 is absent or is a polar amino acid (e.g., T or a variant thereof); X11 is absent or is an amino acid (e.g., a hydrophilic amino acid; Dab, Dap, R, E or a variant thereof; or an amino acid having a functional side chain); and X12 is C or a variant thereof.

63. The radiopharmaceutical conjugate according to claim 62, wherein X8 is KCOpipzaa, N, Cit, Q-glucosamine, hCit, K, KAc, Aib, Alb, DapAc, OrnAc, A, T, alT, norleucine, norvaline, Hgl, E, Hgn, Q, I or L.

64. The radiopharmaceutical conjugate according to claim 62 or 63, wherein X11 is absent or is arginine (R), asparagine (N), aspartic acid (D), glutamine (Q), lysine (K) or a non-natural hydrophilic amino acid.

65. The radiopharmaceutical conjugate according to any one of claims 1 to 61, wherein the peptide has the 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., a D-amino acid); X2 is an amino acid containing an aromatic ring, its N-methylated amino acid 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 containing an aromatic ring (e.g., W or F or a variant thereof), or an N-methylated amino acid thereof; X7 is an amino acid containing 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 containing an aromatic ring (e.g., W, F or a variant thereof); and X12 is C or a variant thereof.

66. The radiopharmaceutical conjugate according to 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., a D-amino acid); X2 is an amino acid containing 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 containing an aromatic ring (e.g., W or F or a variant thereof), or an N-methylated amino acid thereof; X7 is an amino acid containing 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 containing 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 according to claim 66, wherein X8 is KCOpipzaa, N, Cit, Q-glucosamine, hCit, K, KAc, Aib, Alb, DapAc, OrnAc, A, T, alT, norleucine, norvaline, Hgl, E, Hgn, Q, I or L.

68. The radiopharmaceutical conjugate according to claim 66 or 67, wherein X11 is arginine (R), asparagine (N), aspartic acid (D), glutamine (Q), lysine (K) or a non-natural hydrophilic amino acid.

69. The radiopharmaceutical conjugate according to any one of claims 1 to 61, wherein X1 is an amino acid (e.g., a 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 a linear or branched C 1-5 alkyl group, G substituted with a C 3-7 cycloalkyl group, or A substituted with a C 3-7 cycloalkyl group); X5 is a hydrophilic L-amino acid, wherein the L-amino acid contains 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, their N-methylated amino acids or variants 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 by one or two linear or branched C 1-5 alkyl groups, G substituted by C 3-7 cycloalkyl groups, A substituted by C 3-7 cycloalkyl groups or a hydrophilic L-amino acid, where the hydrophilic L-amino acid contains -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 contains zwitterions; X9 is F, W or a variant thereof; X10 is absent, or is Q, S, K, Cit, N, T or a variant thereof (e.g., Q, S, K, Cit, N or T optionally substituted with a straight-chain or branched C 1-5 alkyl), or an L-amino acid containing -NHC(NH)NH2, -NHC(O)NH2, -C(O)NH2 or -NHC(O)CH3; X11 is absent, or is E, Q, R, Cit, K, D or N or a variant thereof; and X12 is C or a variant thereof.

70. The radiopharmaceutical conjugate according to claim 69, wherein X8 is KCOpipzaa, N, Cit, Q-glucosamine, hCit, K, KAc, Aib, Alb, DapAc, OrnAc, A, T, alT, norleucine, norvaline, Hgl, E, Hgn, Q, I or L.

71. The radiopharmaceutical conjugate according to claim 69 or 70, wherein X11 is absent, or is arginine (R), asparagine (N), aspartic acid (D), glutamine (Q), lysine (K) or a non-natural hydrophilic amino acid.

72. The radiopharmaceutical conjugate according to any one of claims 1 or 10 to 71, wherein the variant of the 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-C3 alkyl), -N(C1-C3 alkyl)2, oxo group, -OH, -CO2H, -CO2-C1-C3 alkyl, -C(=O)NH2, -C(=O)NH(C1-C3 alkyl), -C(=O)N(C1-C3 alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C3 alkyl), -S(=O)2N(C1-C3 alkyl)2, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C6-C 10 aryl, C3-C6 cycloalkyl, 6-10 membered heteroalkyl and 6-10 membered heteroaryl.

73. The radiopharmaceutical conjugate according to 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-C3 alkyl), -N(C1-C3 alkyl)2, oxo group, -OH, -CO2H, -CO2-C1-C3 alkyl, -C(=O)NH2, -C(=O)NH(C1-C3 alkyl), -C(=O)N(C1-C3 alkyl)2 and C1-C6 alkyl.

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

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

76. The radiopharmaceutical conjugate according to any one of claims 1 or 10 to 75, wherein the variant has a molecular weight that varies by no more than 14, 28, 30, 45 or 60 g / mol compared to the amino acid.

77. The radiopharmaceutical conjugate according to 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, or is 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, or is 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, Q-glucosamine, 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, or is T, Q, S, Hgn, α-methylserine, hSer, hThr, N, OrnAc, LysAc, Cit or hCit; X11 is absent, or is 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 according to claim 77, wherein X8 is KCOpipzaa, N, Cit, Q-glucosamine, hCit, K, KAc, Aib, Alb, DapAc, OrnAc, A, T, alT, norleucine, norvaline, Hgl, E, Hgn, Q, I or L.

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

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

81. The radiopharmaceutical conjugate according to 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, Q-glucosamine, Hgl, Q, E, Hgn or K; and X9 is W1Me, Nal1, W1Et, Nal21N, 3Bzf, 3Bzt, Nal18N, F23dMe or F23dC.

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

83. A radiopharmaceutical conjugate comprising: (a) a cyclic peptide having an affinity 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 is an amino acid; and X12 is cysteine (C) or a variant thereof; (b) a metal chelator configured to bind to a radionuclide; and (c) optionally, a linker that links the peptide to the metal chelator.

84. The radiopharmaceutical conjugate according to claim 83, wherein X8 is KCOpipzaa, N, Cit, Q-glucosamine, hCit, K, KAc, Aib, Alb, DapAc, OrnAc, A, T, alT, norleucine, norvaline, Hgl, E, Hgn, Q, I or L.

85. The radiopharmaceutical conjugate according to claim 83 or 84, wherein X11 is absent or is arginine (R), asparagine (N), aspartic acid (D), glutamine (Q), lysine (K) or a non-natural hydrophilic amino acid.

86. A radiopharmaceutical conjugate comprising: (a) a cyclic peptide having an affinity for ephrin type-A receptor 2 (EphA2), wherein the peptide has the 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 the structure, where Ring A2 is phenyl or a 6-membered heteroaryl (e.g., heteroaryl having 1 or 2 Ns); R X2 each independently is halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d 、-SH、SF5、-SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d 、C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally and independently substituted by one or more R XA substituted; kx2 is 0, 1, 2 or 3; mx2 is 0, 1, 2, 3 or 4; R NX2 is H, a C1-C6 alkyl or a C1-C6 haloalkyl; *X1 indicates the attachment point to X1; and, *X3 indicates the attachment point to X3; X3 has the structure of, where kx3 is 0, 1, 2 or 3; R NX3 is H, a C1-C6 alkyl or a C1-C6 haloalkyl; R X3 is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; *X2 indicates the attachment point to X2; and, *X4 indicates the attachment point to X4; X4 is a hydrophobic amino acid (e.g., an amino acid having 4 or more carbon atoms in a side chain containing a straight-chain, branched-chain, or cyclic carbon chain), and wherein X4 is optionally C 1-3 alkyl N-methylation; X5 is a hydrophilic L-amino acid, such as an amino acid having a structure of, wherein: R NX5 is H, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; wherein said alkyl, haloalkyl, hydroxyalkyl, aminoalkyl or heteroalkyl is optionally and independently substituted by one or more R XA substituents; R X5 is -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, SF5, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=NR b )NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; wherein said alkyl, haloalkyl, hydroxyalkyl, aminoalkyl or heteroalkyl is optionally and independently substituted by one or more R XA substituted; The condition is R NX5 and R X5 at least one of which contains a moiety selected from the following: -OH, -NH2, and -NH- (e.g., -NH-C(=NH)-NH2, -CO-NH2, -NH2, -COOH, -C(OH)-C 0-6 alkyl, -NH-CO-C 1-6 alkyl); *X4 indicates the attachment point to X4; and, *X6 indicates the attachment point to X6; X6 is (for example, N, F), where R NX6 is H, a C1-C6 alkyl or a C1-C6 haloalkyl; R X6 is -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, SF5, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b , -NR c R d , -NR b , -NR b C(=NR c )NR d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally and independently substituted by one or more R XA substituted; *X5 indicates the attachment point to X5; and, *X7 indicates the attachment point to X7; X7 has structure, where R NX7 is H, a C1-C6 alkyl or a C1-C6 haloalkyl; Ring A7 is aryl or heteroaryl; R X7 Each independently is halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, SF5, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2-halogen, -S(=O)2NR c R d , -NR c R d , -NR b , -NR c R d , -NR b , -NR a , -NR b , -NR b , -NR b , -NR a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally and independently substituted by one or more R XA substituted; kx7 is 0, 1, 2, or 3; mx7 is 0, 1, 2, 3, 4, or 5; *X6 indicates the attachment point to X6; and, *X8 indicates the attachment point to X8; X8 is an L - amino acid containing - H on the α - amino group; X9 has structure, where R NX9 is H, a C1-C6 alkyl group or a C1-C6 haloalkyl group; Ring A9 is aryl or heteroaryl; R X9 each independently is halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d 、-SH、SF5、-SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d 、C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally and independently substituted by one or more R XA substituted; kx9 is 0, 1, 2, or 3; mx9 is 0, 1, 2, 3, 4, or 5; *X8 indicates the attachment point to X8; and, *XC indicates the attachment point to (i) X10 or (i) when X10 and X11 are absent, the attachment point to X12; X10 is absent or is an L - amino acid; X11 is absent or is 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 R a independently is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl) or C1-C6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R; Each R b independently is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl) or C1-C6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more Rs; Each R c and R d independently is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl) or C1-C6 alkyl(heteroaryl); where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more Rs; or R c and R d together with the atom(s) to which they are attached form a heterocycloalkyl optionally substituted with one or more R; and Each R and R XA independently is halogen, -CN, -OH, -OC1-C6 alkyl, SF5, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2-halogen, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NR b C(=NR b )NR c R d , -NHC(=O)OC1-C6 alkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; (b) a metal chelator configured to bind to a radionuclide; and (c) optionally, a linker that links the peptide to the metal chelator.

87. The radiopharmaceutical conjugate according to 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 a heteroatom selected from N, O, and S.

88. The radiopharmaceutical conjugate according to claim 86 or 87, wherein R NX7 is H.

89. The radiopharmaceutical conjugate according to any one of claims 86 to 88, wherein each R X7 is independently selected from -CH3, -ethyl, -Cl and -F, and mx7 is 0, 1 or 2.

90. The radiopharmaceutical conjugate according to 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 according to claim 90, wherein X7 is W1Me, F23dMe, or W1Me7Cl.

92. The radiopharmaceutical conjugate according to any one of claims 86 to 91, wherein X9 is Each R X9 is independently selected from -OH, CN, NH2, C1-C3 alkyl, -Cl, -F, -Br, -CONH2, and -SO2F.

93. The radiopharmaceutical conjugate according to any one of claims 86 to 92, wherein is 94. The radiopharmaceutical conjugate according to any one of claims 86 to 93, wherein R X9 is independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -SH, a , -SR a , -S(=O)R a , -S(=O)2R c R d , -NR c R d , -NR b C(=O)R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl.

95. The radiopharmaceutical conjugate according to 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 according to claim 95, wherein X9 is W1Me or F23dMe.

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

98. A radiopharmaceutical conjugate according to any one of claims 86 to 97, wherein R X5 is C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, -C 0-6 alkylene-NH-C(=NH)-NH2, -C 0-6 alkylene-CO-NH2, -C 0-6 alkylene-COOH or -NH-CO-C 1-6 alkyl.

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

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

102. The radiopharmaceutical conjugate according to claim 81 or 99, wherein X7 is W1Me; X8 is KCOpipzaa, N, Cit, hCit, KAc, DapAc, OrnAc, A, T, alT, Aib, Alb, Q-glucosamine, Hgl, Q, E, Hgn or K; and X9 is W1Me.

103. The radiopharmaceutical conjugate according to 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 an amino acid having an aromatic ring; X7 is W or a variant thereof; X8 is V or a 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 according to claim 103, wherein X8 is KCOpipzaa, N, Cit, Q-glucosamine, hCit, K, KAc, Aib, Alb, DapAc, OrnAc, A, T, alT, norleucine, norvaline, Hgl, E, Hgn, Q, I or L.

105. The radiopharmaceutical conjugate according to claim 103 or 104, wherein X11 is arginine (R), asparagine (N), aspartic acid (D), glutamine (Q), lysine (K) or a non-natural hydrophilic amino acid.

106. The radiopharmaceutical conjugate according to 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 group or a variant thereof, X5 is a hydrophilic amino acid or a variant thereof; X6 is a hydrophilic amino acid or an amino acid having an 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 according to any one of claims 1 to 106, wherein the peptide has a monocyclic structure.

108. The radiopharmaceutical conjugate according to claim 107, wherein the amino acid X1 is bound to the cysteine or a variant thereof.

109. The radiopharmaceutical conjugate according to claim 107, wherein the peptide has the structure of formula (I-1), wherein R 1 Selected from NH2 and OH; R 2 selected from H or C 1-3 alkyl; R 3 Selected from H or C 1-3 alkyl; wherein X1 to X11 have the definitions as described in formula (I), and wherein the attachment points to the radionuclide or the linker are not shown.

110. The radiopharmaceutical conjugate according to claim 109 or a pharmaceutically acceptable salt thereof, wherein the peptide of formula (I-1) has the structure of formula (I-2), 111. The radiopharmaceutical conjugate according to any one of claims 22 to 110, wherein the conjugate has the structure of formula (III-1) wherein X1 to X11 have the definitions as described in formula (I), and wherein -linker- represents the linker that connects the peptide to the metal chelator.

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

113. The radiopharmaceutical conjugate according to any one of claims 1 to 112, wherein the peptide or a salt thereof comprises an amino acid sequence that is at least 90% identical to a sequence selected from SEQ ID NO: 1-171.

114. The radiopharmaceutical conjugate according to any one of claims 1 to 112, wherein the peptide or a salt thereof consists of an amino acid sequence selected from SEQ ID NO: 1-171.

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

282.

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

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

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

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

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

121. The radiopharmaceutical conjugate according to any one of claims 1 to 120, wherein in a human prostate xenograft mouse model, the uptake ratio between tumor uptake and renal uptake of 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.

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

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

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

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

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

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

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

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

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

277.

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

132. A radiopharmaceutical conjugate comprising: (a) a peptide that has an affinity for ephrin type-A receptor 2 (EphA2), wherein the peptide competes with a peptide having an amino acid sequence with one or several amino acid deletions, substitutions and / or additions in the amino acids of SEQ ID NO: 1 for binding to human EphA2: 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 to a radionuclide, wherein the metal chelator is conjugated to the peptide.

133. The radiopharmaceutical conjugate according to claim 2 or 132, wherein the V at position 8 is substituted.

134. The radiopharmaceutical conjugate according to any one of claims 2, 132 or 133, wherein the E at the 11th position is substituted.

135. A radiopharmaceutical conjugate, the radiopharmaceutical conjugate comprising: (a) a peptide that has an affinity for ephrin type-A receptor 2 (EphA2), wherein the peptide competes with a peptide having a structure of formula (I) for binding to human EphA2; 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 containing an aromatic ring, its N-methylated amino acid 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 containing an aromatic ring, or its N-methylated amino acid; X7 is an amino acid containing an aromatic ring (e.g., W, F or a variant thereof); X8 is a hydrophobic amino acid, a hydrophilic amino acid, its N-methylated amino acid or a variant; X9 is an amino acid containing an aromatic ring (e.g., W or a variant thereof); X10 is absent or is a hydrophilic amino acid (e.g., threonine (T) or a variant thereof); X11 is absent or is a hydrophilic amino acid; and X12 is cysteine (C) or a variant thereof; and (b) a metal chelator configured to bind to a radionuclide, wherein the metal chelator is conjugated to the peptide.

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

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

138. The radiopharmaceutical conjugate according to any one of claims 1 or 135 - 137, wherein X11 is absent or is arginine (R), asparagine (N), aspartic acid (D), glutamine (Q), lysine (K), or a non - natural hydrophilic amino acid.

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

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

277.

142. A radiopharmaceutical conjugate, wherein the conjugate is a salt of the conjugate according to any one of the foregoing claims.

143. A pharmaceutical composition, the pharmaceutical composition comprising a radiopharmaceutical conjugate according to 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 according to any one of claims 1 to 142.

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

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

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

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

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

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

151. The method according to claim 148, wherein the cancer is triple-negative breast cancer.

152. The method according to claim 148 or 149, wherein the method comprises administering (i) a first radiopharmaceutical conjugate comprising a radionuclide formulated for companion diagnostics (such as PET imaging) and (ii) a second radiopharmaceutical conjugate comprising a radionuclide selected from an α or β particle emitter, wherein the first conjugate and the second conjugate have the same structure, differing only in the radionuclide.

153. The method according to 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 a disease or disorder characterized by EphA2 overexpression or reduced expression, wherein the kit comprises a radiopharmaceutical conjugate according to any one of claims 1 to 142 or a pharmaceutical composition according to claim 143.

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