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

Abstract

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

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 411,307, filed September 29, 2022, and U.S. Provisional Patent Application No. 63 / 411,380, filed September 29, 2022, each of which is incorporated by reference herein in its entirety.

[0002] joint research agreement The subject matter disclosed herein was developed, and the claimed invention made, by or on behalf of one or more parties to a Joint Research Agreement (JRA) within the meaning of 35 U.S.C. §100(h) and 37 C.F.R. §1.9(e), 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, CA, USA). The claimed invention was made as a result of activities conducted within the scope of said Joint Research Agreement.

[0003] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in XML format, which is incorporated herein by reference in its entirety. Created on September 28, 2023, said XML copy is named 59541-729_601_SL.xml and is 2,096,382 bytes in size. [Background technology]

[0004] In the United States, cancer is the leading cause of death among people under 65 years of age, accounting for approximately 21% of all deaths in 2018. Traditional radiation therapy, such as external beam radiation therapy, has been used for decades as the standard treatment for diagnosed cancer patients. While some patients respond to external beam radiation therapy, many others do not. Furthermore, metastatic and circulating tumor cells can spread and persist in the bloodstream or body fluids after standard treatment, resulting in resistance to therapy. The presence of cancer cells in various parts of the body reduces the therapeutic effectiveness of traditional radiation therapy. Therefore, strategies for targeted radiation therapy are under development, and there remains a need for targeted radiation therapy with desirable affinity, stability, and exertion profiles. Summary of the Invention

[0005] In one aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: (a) A cyclic peptide having avidity for ephrin type-A receptor 2 (EphA2), comprising the formula (I): X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) [In the formula, X1 is an amino acid; X2 is an aromatic ring-containing amino acid, an N-methylated amino acid thereof, or a variant thereof; X3 is a hydrophilic amino acid (e.g., N, Q, Cit, K or a variant thereof), glycine (G), alanine (A) or a variant thereof (e.g., da, 2-aminoisobutyric acid (Aib)); X4 is a hydrophobic amino acid (e.g., leucine (L)), a hydrophilic amino acid (e.g., citrulline (Cit)), or a variant thereof; X5 is a hydrophilic amino acid or variant thereof; X6 is a hydrophilic amino acid, an amino acid containing an aromatic ring, 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, an N-methylated amino acid, or a variant thereof; X9 is an amino acid containing an aromatic ring (e.g., W or a variant thereof); X10 is absent or a hydrophilic amino acid (e.g., threonine (T) or a variant thereof); X11 is absent or a hydrophilic amino acid; X12 is cysteine ​​(C) or a variant thereof. or a pharmaceutically acceptable salt thereof; and (b) (i) a metal chelator configured to bind a radionuclide, the metal chelator being conjugated to the peptide; or (ii) a covalent radionuclide (or a radionuclide covalently attached to a cyclic peptide). In some embodiments, the radiopharmaceutical conjugate comprises a metal chelator configured to bind to a radionuclide, the metal chelator 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 a 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 provides a method for manufacturing a semiconductor device comprising: (a) a cyclic peptide having avidity for ephrin type-A receptor 2 (EphA2), the peptide being represented by SEQ ID NO: 1: an amino acid sequence containing one or more (e.g., 1 to 6) amino acid deletions, substitutions, and / or additions in the amino acid sequence of da-MeF-NL-Hgl-MeF-W1Me-V-W1Me-TEC (SEQ ID NO: 1); a cyclic peptide consisting of 10 or 12 amino acid residues, or a pharmaceutically acceptable salt thereof; and (b) (i) a metal chelator configured to bind a radionuclide, the metal chelator conjugated to the peptide, or (ii) a covalently bound radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a metal chelator configured to bind to a radionuclide, the metal chelator 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 a peptide.

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

[0008] In some embodiments, the metal chelator is 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- In some embodiments, the metal chelator comprises NODA, NH-MPAA-NODA, PCTA, p-NH-Bn-PCTA, p-SCN-Bn-PCTA, p-SCN-Bn-HEHA, H-MACROPA-NCS, H-MACROPA, H-MACROPA-NH, H-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. [ka] It has the following structure.

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

[0010] In some embodiments, the radiopharmaceutical conjugate comprises: [ka] (In the formula, [ka] represents the linker) It has the following structure.

[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 attached to an amino acid that comprises an aromatic ring. 18 F, 74 As, 76 Br, 123 I, 124 I, 125 I, 131 I, or 211At. In some embodiments, the radionuclide is 18 F, 125 I, 131 I, or 211 At. In some embodiments, the radionuclide is bound to X1, X2 or MeF, X6 or MeF, X7 or W1Me, or X9 or W1Me. In some embodiments, the radionuclide is bound to a tyrosine residue. In some embodiments, the radiopharmaceutical conjugate comprises a linker connecting the peptide to the radionuclide. In some embodiments, the linker connects the peptide to the radionuclide by a covalent bond.

[0013] In some embodiments, the radiopharmaceutical conjugate comprises: [ka] (In the formula, [ka] represents a linker; R * represents a 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 residualizing agent. In some embodiments, the residualizing agent is [ka] In some embodiments, [ka] teeth, [ka] (In the formula, k1 and k2 each independently represent 0 or an integer selected from 1 to 10; R * is a radionuclide) The compound has a structure selected from:

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

[0015] In some embodiments, the radiopharmaceutical conjugate comprises a metal chelator configured to bind to a radionuclide, the metal chelator 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 a 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 a metal chelator configured to bind to a radionuclide, the metal chelator conjugated to the peptide. In some embodiments, the radiopharmaceutical conjugate comprises a ... X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) [In the formula, X1 is an amino acid; X2 is F or an unsubstituted phenyl ring of F, (i) -OH, -CN, and -C 1~3 a phenyl ring substituted by one or two substituents each independently selected from alkyl, or (ii) -OH, -CN, and -C 1~3 and variants thereof, where the heteroaryl ring is replaced by a 6-membered heteroaryl ring optionally substituted with 1 or 2 substituents each independently selected from alkyl; wherein F or a variant thereof may be 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 four or more carbon atoms in its side chain, including a linear, branched, or cyclic carbon chain), and X4 may be 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 the 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 linked to the alpha carbon via a carbon (e.g., a methylene group), where the 6-, 9-, and 10-membered heteroaryl has one heteroatom (e.g., N), and the 6-, 9-, and 10-membered aryl or heteroaryl may optionally be substituted with one or two substituents independently selected from -CH3, -ethyl, -Cl, and -F); X8 is an amino acid having -H on the alpha amino group; X9 is W or Y or a variant thereof (e.g., W or a variant thereof); X10 is absent or a polar amino acid (e.g., T or a variant thereof); X11 is absent or an amino acid (e.g., a hydrophilic amino acid; Dab, Dap, R, E or a variant thereof; or an amino acid having a functional side chain); X12 is C or a variant thereof] or a pharmaceutically acceptable salt thereof.

[0016] In some embodiments, the radiopharmaceutical conjugate has Formula (Ia): X1-X2-X3-X4-X5-X6-X7-X8-X9-X12 Formula (Ia) [In the formula, X1 is an amino acid (e.g., a D-amino acid); X2 is an aromatic ring-containing amino acid, 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); X12 is C or a variant thereof] or a pharmaceutically acceptable salt thereof.

[0017] In some embodiments, the radiopharmaceutical conjugate has Formula (I): X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) [In the formula, X1 is an amino acid (e.g., a D-amino acid); X2 is an aromatic ring-containing amino acid, 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; X12 is C or a variant thereof] or a pharmaceutically acceptable salt thereof.

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

[0019] In one aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: (a) A cyclic peptide having avidity for ephrin type-A receptor 2 (EphA2), comprising the formula (I): X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) [In the formula, X1, X2, X3, X4, X5, X6, and X8 are each independently an amino acid; X7 is W1Me or a variant thereof; X9 is W1Me or a variant thereof; X10 and X11 are each independently absent or an amino acid; X12 is cysteine ​​(C) or a variant thereof. or a pharmaceutically acceptable salt thereof; (b) (i) a metal chelator configured to bind a radionuclide; or (ii) a covalently bound radionuclide (or a radionuclide covalently bound to a cyclic peptide); and (c) (i) optionally, a linker connecting the peptide to a metal chelator; or (ii) optionally, a linker connecting the peptide to a covalently bound radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a metal chelator configured to bind to a radionuclide and optionally a linker connecting the peptide to the metal chelator. In some embodiments, the radiopharmaceutical conjugate comprises a covalently bound radionuclide and optionally a linker connecting the peptide to the covalently bound radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a radionuclide covalently bound to a peptide. In some embodiments, the radiopharmaceutical conjugate comprises a linker connecting the peptide to the covalently bound radionuclide.

[0020] In one aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: (a) A cyclic peptide having avidity for ephrin type-A receptor 2 (EphA2), comprising the formula (I): X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) [In the formula, X1 is any D- or L-amino acid; X2 is [ka] (In the formula, Ring A2 is phenyl or a 6-membered heteroaryl (e.g., heteroaryl with 1 or 2 N); 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 , -NRb 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 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally independently selected from one or more R XA may be substituted with; 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 point of attachment to X1; * X3 indicates the point of attachment to X3) having the structure X3 is [ka] (In the formula, 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 point of attachment to X2; * X4 indicates the point of attachment to X4) having the structure X4 is a hydrophobic amino acid (e.g., an amino acid having four or more carbon atoms in its side chain, including a straight, branched, or cyclic carbon chain), and X4 is C 1~3 may be N-alkylated with an alkyl group; The X5 is [ka] (In the formula, R NX5 is H, —CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; where alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, or heteroalkyl is selected from the group consisting of one or more R XA may optionally be independently substituted with; R X5 -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 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, or heteroalkyl is selected from the group consisting of one or more R XA may be optionally and independently substituted with However, R NX5 and R X5 at least one of which is a moiety selected from -OH, -NH, and -NH- (e.g., -NH-C(=NH)-NH, -CO-NH, -NH, -COOH, -C(OH)-C 0~6 Alkyl, -NH-CO-C 1~6 alkyl); * X4 indicates the point of attachment to X4; * X6 indicates the point of attachment to X6) is a hydrophilic L-amino acid, such as an amino acid having the structure: The X6 is [ka] (e.g., N, F) (In the formula, R NX6 is H, C1-C6 alkyl, or C1-C6 haloalkyl; R X6 -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 )NRc 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 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is selected from the group consisting of one or more R XA may optionally be independently substituted with; * X5 indicates the point of attachment to X5; * X7 indicates the point of attachment to X7) and; The X7 is [ka] (In the formula, 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 Rd , -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 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is selected from the group consisting of one or more R XA may optionally be independently substituted with; kx7 is 0, 1, 2, or 3; mx7 is 0, 1, 2, 3, 4 or 5; * X6 indicates the point of attachment to X6; * X8 indicates the point of attachment to X8) having the structure X8 is an L-amino acid with an -H on the alpha amino group; X9 is [ka] (In the formula, 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)NRc 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 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally independently selected from one or more R XA may be substituted with; kx9 is 0, 1, 2, or 3; mx9 is 0, 1, 2, 3, 4, or 5; * X8 indicates the point of attachment to X8; * XC indicates the point of attachment to (i) X10 or (i) X12 if X10 and X11 are absent. having the structure X10 is absent or an L-amino acid; X11 is absent or is an L-amino acid, with the proviso that if X10 is absent then X11 is also absent; X12 is an L-amino acid with a reactive thiol group, such as Cys and Cys variants; R a are each 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 optionally and independently substituted with one or more R; R b are each 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 optionally and independently substituted with one or more R; R c and R d are each 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 optionally and independently substituted with one or more R; or Rc and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; R and R XA are each independently 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. a peptide having an amino acid sequence of (b) (i) a metal chelator configured to bind a radionuclide; or (ii) a covalently bound radionuclide; and (c) (i) optionally, a linker connecting the peptide to a metal chelator; or (ii) optionally, a linker connecting the peptide to a covalently bound radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a metal chelator configured to bind to a radionuclide and optionally a linker connecting the peptide to the metal chelator. In some embodiments, the radiopharmaceutical conjugate comprises a covalently bound radionuclide and optionally a linker connecting the peptide to the covalently bound radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a radionuclide covalently bound to a peptide. In some embodiments, the radiopharmaceutical conjugate comprises a linker connecting the peptide to the covalently bound radionuclide.

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

[0022] In some embodiments, the radiopharmaceutical conjugate has Formula (I): X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) [In the formula, X1 is any amino acid; X2 is an amino acid or variant thereof having an aromatic ring; X3 is N; X4 is a hydrophobic amino acid or variant thereof; X5 is a hydrophilic amino acid or 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 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 (e.g., C) or a pharmaceutically acceptable salt thereof.

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

[0024] In some embodiments, the peptide has the structure of formula (I-1): [ka] [In the formula, R 1 is selected from the group consisting of NH2 and OH; R 2 is H or C 1~3 selected from the group consisting of alkyl; R 3 is H or C 1~3 selected from the group consisting of alkyl; X1-X11 have the definitions set forth in formula (I), and the point of attachment to the radionuclide or linker is not indicated. It has the following structure.

[0025] In some embodiments, the peptide of formula (I-1) has formula (I-2): [ka] It has the following structure.

[0026] In some embodiments, the conjugate has formula (III-1): [ka] [In the formula, X1 to X11 have the definitions described in formula (I), -Linker- represents a linker connecting the peptide and the metal chelator. It has the following structure.

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

[0028] In some embodiments, the conjugate has formula (III-2): [ka] [In the formula, Lcyc is a ring-closing group covalently connecting X1 to X12; -linker- represents a linker connecting the peptide and the metal chelator; X1 to X12 have the definitions described in formula (I). It has the following structure.

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

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

[0031] In some embodiments, the radiopharmaceutical conjugate comprises a peptide that interacts with human EphA2 at one or more amino acid residues selected from Asp53, Met55, Asn57, Met59, Met66, Thr101, Arg103, Phe156, Glu157, Arg159, Val161, Val189, and Ala190. In some embodiments, the peptide interacts with human EphA2 at Asp53 and Glu157. In some embodiments, the peptide is of formula (I), wherein, when the peptide binds to human EphA2, amino acid residue X7 is located less than 10 Å from Phe156 of human EphA2. In some embodiments, the peptide is of formula (I), wherein, when the peptide binds to human EphA2, amino acid residue X9 is located less than 10 Å from Phe156 of human EphA2. In some embodiments, the peptide is of formula (I), and when the peptide binds to human EphA2, amino acid residue X8 is located less than 10 Å from Phe156 of 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 described in Table 1, 2A, 2B, 2B-Lu, 2B-Lu-177, 2B-Ac-225, or 2C.

[0033] In one aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: (a) a peptide having avidity for ephrin type-A receptor 2 (EphA2), the peptide being represented by SEQ ID NO: 1: A peptide that competes for binding to human EphA2 with a peptide having an amino acid sequence containing one or more amino acid deletions, substitutions, and / or additions in the amino acid sequence of da-MeF-NL-Hgl-MeF-W1Me-V-W1Me-TEC (SEQ ID NO: 1), or a pharmaceutically acceptable salt thereof; and (b) (i) a metal chelator configured to bind a radionuclide, the metal chelator conjugated to the peptide, or (ii) a covalently bound radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a metal chelator configured to bind to a radionuclide, the metal chelator 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 a peptide.

[0034] In one aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: (a) A peptide having avidity for ephrin type-A receptor 2 (EphA2), the peptide having formula (I): X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) [In the formula, X1 is an amino acid; X2 is an aromatic ring-containing amino acid, an N-methylated amino acid thereof, or a variant thereof; X3 is a hydrophilic amino acid (e.g., N, Q, Cit, K or a variant thereof), glycine (G), alanine (A) or a variant thereof (e.g., da, 2-aminoisobutyric acid (Aib)); X4 is a hydrophobic amino acid (e.g., leucine (L)), a hydrophilic amino acid (e.g., citrulline (Cit)), or a variant thereof; X5 is a hydrophilic amino acid or variant thereof; X6 is a hydrophilic amino acid, an amino acid containing an aromatic ring, 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, an N-methylated amino acid, or a variant thereof; X9 is an amino acid containing an aromatic ring (e.g., W or a variant thereof); X10 is absent or a hydrophilic amino acid (e.g., threonine (T) or a variant thereof); X11 is absent or a hydrophilic amino acid; X12 is cysteine ​​(C) or a variant thereof. or a pharmaceutically acceptable salt thereof; and (b) (i) a metal chelator configured to bind a radionuclide, the metal chelator conjugated to the peptide, or (ii) a covalently bound radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a metal chelator configured to bind to a radionuclide, the metal chelator 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 a peptide.

[0035] In one aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: (a) A cyclic peptide having avidity for ephrin type-A receptor 2 (EphA2), comprising the formula (I): X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) [In the formula, X1, X2, X3, X4, X5, X6, and X8 are each independently an amino acid; X7 is W1Me or a variant thereof; X9 is W1Me or a variant thereof; X10 and X11 are each independently absent or an amino acid; X12 is cysteine ​​(C) or a variant thereof. or a pharmaceutically acceptable salt thereof; (b) (i) a metal chelator configured to bind a radionuclide; or (ii) a covalently bound radionuclide; and (c) (i) a linker connecting the peptide to a metal chelator; or (ii) a linker connecting the peptide to a covalently bound 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 connecting the peptide to the metal chelator. In some embodiments, the radiopharmaceutical conjugate comprises a covalently bound radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a linker connecting the peptide to the covalently bound radionuclide.

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

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

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

[0040] In one aspect, the present disclosure relates to a method of treating cancer in a subject in need thereof, comprising administering to the subject a radiopharmaceutical conjugate described herein, or a pharmaceutical composition thereof. In some embodiments, the cancer is selected from glioblastoma, prostate cancer, lung cancer, breast cancer, gastric cancer, ovarian cancer, bladder cancer, colon cancer, esophageal cancer, multiple myeloma, and fibrosarcoma. In some embodiments, the cancer is non-small cell lung 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 configured for companion diagnostics (such as PET imaging) and (ii) a second radiopharmaceutical conjugate comprising a radionuclide selected from alpha or beta particle emitters, wherein the first and second conjugates 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 In some embodiments, the radionuclide of the second conjugate is selected from: 131 I and 211 At is selected.

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

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

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

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

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

[0046] Incorporation by Reference All publications, patents, and patent applications mentioned herein are hereby incorporated by reference for the specific purposes identified herein.

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

[0048] [Figure 1-1]Figure 1 illustrates the structure of an exemplary conjugate of the present disclosure, comprising a peptide, a linker, and a metal chelator. Figure 1 discloses SEQ ID NOs: 296, 433, 424, 434, 435, 436, and 437, respectively, in order of appearance. [Figure 1-2] Figure 1 illustrates the structure of an exemplary conjugate of the present disclosure, comprising a peptide, a linker, and a metal chelator. Figure 1 discloses SEQ ID NOs: 296, 433, 424, 434, 435, 436, and 437, respectively, in order of appearance. [Figure 1-3] Figure 1 illustrates the structure of an exemplary conjugate of the present disclosure, comprising a peptide, a linker, and a metal chelator. Figure 1 discloses SEQ ID NOs: 296, 433, 424, 434, 435, 436, and 437, respectively, in order of appearance. [Figure 1-4] Figure 1 illustrates the structure of an exemplary conjugate of the present disclosure, comprising a peptide, a linker, and a metal chelator. Figure 1 discloses SEQ ID NOs: 296, 433, 424, 434, 435, 436, and 437, respectively, in order of appearance. [Figure 2-1] Figure 2 illustrates the structure of an exemplary conjugate of the present disclosure, comprising a peptide, a linker, a metal chelator, and cold lutetium. Figure 2 discloses SEQ ID NOS: 292, 330, 283, 328, 334, 360, and 361, respectively, in order of appearance. [Figure 2-2] Figure 2 illustrates the structure of an exemplary conjugate of the present disclosure, comprising a peptide, a linker, a metal chelator, and cold lutetium. Figure 2 discloses SEQ ID NOS: 292, 330, 283, 328, 334, 360, and 361, respectively, in order of appearance. [Figure 2-3] Figure 2 illustrates the structure of an exemplary conjugate of the present disclosure, comprising a peptide, a linker, a metal chelator, and cold lutetium. Figure 2 discloses SEQ ID NOS: 292, 330, 283, 328, 334, 360, and 361, respectively, in order of appearance. [Figure 2-4]Figure 2 illustrates the structure of an exemplary conjugate of the present disclosure, comprising a peptide, a linker, a metal chelator, and cold lutetium. Figure 2 discloses SEQ ID NOS: 292, 330, 283, 328, 334, 360, and 361, respectively, in order of appearance. [Figure 3-1] FIG. 3 illustrates the structure of an exemplary conjugate of the present disclosure, comprising a peptide, a linker, and a metal chelator. [Figure 3-2] FIG. 3 illustrates the structure of an exemplary conjugate of the present disclosure, comprising a peptide, a linker, and a metal chelator. [Figure 4A] FIG. 4A illustrates an exemplary metal chelator of the present disclosure, wherein: [ka] represents the attachment point where the metal chelator is attached to the remaining conjugate. [Figure 4B] FIG. 4B illustrates the same metal chelator as FIG. 4A, except that the portion of the linker or peptide covalently connected to the metal chelator is shown as a dashed circle. [ka] Except as indicated in [Figure 5A] FIG. 5A illustrates an exemplary metal chelator of the present disclosure, wherein: [ka] represents the attachment point where the metal chelator is attached to the remaining conjugate. [Figure 5B] FIG. 5B illustrates the same metal chelator as FIG. 5A, except that the portion of the linker or peptide covalently connected to the metal chelator is shown as a dashed circle. [ka] Except as indicated in [Figure 6A] FIG. 6A illustrates an exemplary metal chelator of the present disclosure, wherein: [ka] represents the attachment point where the metal chelator is attached to the remaining conjugate. [Figure 6B] FIG. 6B illustrates the same metal chelator as FIG. 6A, except that the portion of the linker or peptide covalently connected to the metal chelator is shown as a dashed circle. [ka] Except as indicated in [Figure 7A] FIG. 7A illustrates an exemplary metal chelator of the present disclosure, wherein: [ka] represents the attachment point where the metal chelator is attached to the remaining conjugate. [Figure 7B] FIG. 7B illustrates the same metal chelator as FIG. 7A, except that the portion of the linker or peptide covalently connected to the metal chelator is shown as a dashed circle. [ka] Except as indicated in [Figure 8] FIG. 8 illustrates the structures of representative metal chelators. [Figure 9] FIG. 9 illustrates the structures of representative metal chelators. [Figure 10-1] FIG. 10 illustrates the structures of representative metal chelators. [Figure 10-2] FIG. 10 illustrates the structures of representative metal chelators. [Figure 11-1] FIG. 11 illustrates the structures of representative metal chelators. [Figure 11-2] FIG. 11 illustrates the structures of representative metal chelators. [Figure 12-1] FIG. 12 illustrates the structures of representative metal chelators. [Figure 12-2]FIG. 12 illustrates the structures of representative metal chelators. [Figure 13] FIG. 13 illustrates the structures of representative metal chelators. [Figure 14-1] FIG. 14 illustrates the structures of representative metal chelators. [Figure 14-2] FIG. 14 illustrates the structures of representative metal chelators. [Figure 15] FIG. 15 illustrates the structures of representative metal chelators. [Figure 16-1] FIG. 16 illustrates the structures of representative metal chelators. [Figure 16-2] FIG. 16 illustrates the structures of representative metal chelators. [Figure 17] FIG. 17 illustrates the structures of representative metal chelators. [Figure 18] FIG. 18 illustrates the structures of representative metal chelators. [Figure 19] FIG. 19 illustrates the structures of representative metal chelators. [Figure 20] FIG. 20 illustrates the structures of representative metal chelators. [Figure 21] FIG. 21 illustrates the structures of representative metal chelators. [Figure 22] FIG. 22 illustrates the structures of representative metal chelators. [Figure 23] FIG. 23 illustrates the cell binding and binding EC50 of biotinylated compounds EphA2-biotin-21 and EphA2-biotin-88 tested in HCT116 cells. [Figure 24A] FIG. 24A illustrates the cellular competitive binding of PDC_EphA2-00007196-C302, PDC_EphA2-00019440-C302, and PDC_EphA2-00019443-C302 tested against 50 nM EphA2-biotin-88 in HCT116 cells. [Figure 24B]FIG. 24B illustrates the cellular competitive binding of PDC_EphA2-00001417-C307 with a biotinylated form of the bicyclic reference peptide in H1299 cells. [Figure 25] FIG. 25 illustrates the internalization rates of biotinylated compounds EphA2-biotin-21 and EphA2-biotin-88 measured at 10 nM and 100 nM in PC3 cells at 2 hours. [Figure 26] Figure 26 illustrates the results of SPR peptide binding studies for PDC_EphA2-00007196-C302, PDC_EphA2-00019443-C302, PDC_EphA2-00019440-C302, and PDC_EphA2-00008010-C302. The X-axis represents time (seconds) and the Y-axis is response units (RU). [Figure 27-1] Figure 27 illustrates the structures of exemplary conjugates containing covalently bound radionuclides of the present disclosure. Figure 27 discloses SEQ ID NOS: 88, 171, 114, 55, and 438-440, respectively, in order of appearance. [Figure 27-2] Figure 27 illustrates the structures of exemplary conjugates containing covalently bound radionuclides of the present disclosure. Figure 27 discloses SEQ ID NOS: 88, 171, 114, 55, and 438-440, respectively, in order of appearance. [Figure 27-3] Figure 27 illustrates the structures of exemplary conjugates containing covalently bound radionuclides of the present disclosure. Figure 27 discloses SEQ ID NOS: 88, 171, 114, 55, and 438-440, respectively, in order of appearance. [Figure 27-4] Figure 27 illustrates the structures of exemplary conjugates containing covalently bound radionuclides of the present disclosure. Figure 27 discloses SEQ ID NOS: 88, 171, 114, 55, and 438-440, respectively, in order of appearance. [Figure 28-1]Figure 28 illustrates the structure of an exemplary conjugate comprising a covalently attached radionuclide of the present disclosure. Figure 28 discloses SEQ ID NOs: 441-443, respectively, in order of appearance. [Figure 28-2] Figure 28 illustrates the structure of an exemplary conjugate comprising a covalently attached radionuclide of the present disclosure. Figure 28 discloses SEQ ID NOs: 441-443, respectively, in order of appearance. [Figure 29-1] FIG. 29 illustrates the structure of an exemplary conjugate comprising a covalently attached radionuclide of the present disclosure, including a peptide, a linker, and a radionuclide. [Figure 29-2] FIG. 29 illustrates the structure of an exemplary conjugate comprising a covalently attached radionuclide of the present disclosure, including a peptide, a linker, and a radionuclide. DETAILED DESCRIPTION OF THE INVENTION

[0049] The following description and examples illustrate the embodiments of the present disclosure in detail. It should be understood that the present disclosure is not limited to the specific embodiments described herein and may therefore vary. Those skilled in the art will recognize that some variations and modifications of the present disclosure exist and are encompassed within its scope.

[0050] While various features of the present disclosure may be described in the context of a single embodiment, the features may also be provided separately or in any suitable combination. Conversely, although the present disclosure may, for clarity, be described herein in the context of separate embodiments, the present disclosure may also be implemented in a single embodiment.

[0051] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0052] It is intended that all terms be understood as they would be understood by one of ordinary skill 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 this disclosure belongs.

[0053] The following definitions are for the assistance of those skilled in the art and are directed to this application, and should not be attributed to any related or unrelated cases, such as any commonly owned patents or patent applications.Any method and material similar to or equivalent to those described herein can be used in the implementation of the present disclosure for testing, but preferred materials and methods are described herein.Therefore, the terms used herein are only for describing specific embodiments and are not intended to be limiting.

[0054] I. Definition As used in this specification and the appended claims, unless specified to the contrary, the following terms have the meanings indicated below.

[0055] 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, a reference to "an agent" includes a plurality of such agents, a reference to "the cell" includes a reference to one or more cells (or cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formula, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included.

[0056] The term "about" or "approximately" means within an acceptable range of error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" may mean within one or more standard deviations, per practice in the art. Alternatively, "about" may mean within 20%, 15%, 10%, 5%, or 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term may mean within an order of magnitude, within 5-fold, or within 2-fold of a value.

[0057] The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is to be interpreted in an open, inclusive sense, i.e., "including, but not limited to." The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in certain other embodiments, embodiments, such as, for example, any composition of matter, composition of matter, method, or process described herein, "consist of" or "consist essentially of" the described features.

[0058] "Amino" refers to the -NH2 radical.

[0059] "Cyano" refers to the -CN radical.

[0060] "Nitro" refers to the -NO2 radical.

[0061] "Oxo" refers to the =O radical.

[0062] "Imino" refers to the =NH radical.

[0063] "Oximo" refers to the =N-OH radical.

[0064] "Hydrazino" refers to the =N-NH2 radical.

[0065] "Hydroxy" or "hydroxyl" refers to the --OH radical.

[0066] "Hydroxyamino" refers to the -NH-OH radical.

[0067] "Acyl" refers to a substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted heterocycloalkylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted heteroarylcarbonyl, amide, or ester, where the carbonyl atom of the carbonyl group is the point of attachment. Unless otherwise specifically stated herein, the alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkylcarbonyl, amide, or ester group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc.

[0068] "Alkyl" refers to an optionally substituted straight-chain or optionally substituted branched-chain saturated hydrocarbon monoradical. An alkyl group can have 1 to about 20 carbon atoms, 1 to about 10 carbon atoms, or 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, as well as longer alkyl groups such as heptyl and octyl. Wherever a numerical range such as "C1-C6 alkyl" appears herein, it means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses occurrences of the term "alkyl" where no numerical range is specified. In some embodiments, alkyl is any of C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkyl, C3-C6 alkyl, C4-C6 alkyl, C5-C6 alkyl, C6-C6 alkyl, C7-C6 alkyl, C8-C6 alkyl, C9-C6 alkyl, C10-C6 alkyl, C11-C6 alkyl, C12-C6 alkyl, C13-C6 alkyl, C14-C6 alkyl, C15-C6 alkyl, C16-C6 alkyl, C17-C6 alkyl, C18-C6 alkyl, C19-C6 alkyl, C20-C6 alkyl, C21-C6 alkyl, C22-C6 alkyl, C23-C6 alkyl, C24-C6 alkyl, C25-C6 alkyl, C26-C6 alkyl, C27-C6 alkyl, C28-C6 alkyl, C29-C6 alkyl, C30-C6 alkyl, C31-C6 alkyl, C32-C6 alkyl, C33-C6 alkyl, C34-C6 alkyl, C35-C6 alkyl, C36-C6 alkyl, C37-C6 alkyl, C38-C6 alkyl, C39-C6 alkyl, C39-C6 alkyl, C39-C6 alkyl, C38-C6 alkyl, C39-C6 alkyl, C40-C6 alkyl, C41-C6 alkyl, C42-C6 alkyl, C43-C6 alkyl, C44-C6 alkyl, C45-C6 alkyl, C46-C6 alkyl, C47-C6 alkyl, C48-C6 alkyl, C49-C6 alkyl, C49 10 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 stated otherwise specifically in the specification, an alkyl group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkyl may be optionally substituted with oxo, halogen, —CN, —CF3, —OH, —OMe, —NH2, —NO2, or —C≡CH. In some embodiments, an alkyl may be optionally substituted with oxo, halogen, —CN, —CF3, —OH, or —OMe. In some embodiments, an alkyl may be optionally substituted with halogen.

[0069] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, alkylene groups can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkylene can be optionally substituted with oxo, halogen, -CN, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, alkylene can be optionally substituted with oxo, halogen, -CN, -CF, -OH, or -OMe. In some embodiments, alkylene can be optionally substituted with halogen. In some embodiments, alkylene is -CH-, -CHCH-, -CHCHCH-, or -CHCH(CH)CH-. In some embodiments, alkylene is -CH-. In some embodiments, alkylene is -CHCH-. In some embodiments, the alkylene is —CH 2 CH 2 CH 2 —.

[0070] "Alkenyl" refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon double bonds. In some embodiments, an alkenyl group has 2 to about 10 carbon atoms, or 2 to about 6 carbon atoms. The group may be in either the cis or trans configuration about the double bond and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH), 1-propenyl (-CHCH=CH), isopropenyl [-C(CH)=CH], butenyl, 1,3-butadienyl, and the like. Whenever a numerical range such as "C2-C6 alkenyl" appears herein, it means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses occurrences of the term "alkenyl" where no numerical range is specified. In some embodiments, alkenyl refers to a C2-C6 alkenyl. 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 stated otherwise specifically in the specification, alkenyl groups can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkenyl can be optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkenyl can be optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, alkenyl can be optionally substituted with halogen.

[0071] The term "alkenylene" or "alkenylene chain" refers to an optionally substituted straight or branched divalent hydrocarbon chain having at least one carbon-carbon double bond connecting the remainder of the molecule to a radical group. In some embodiments, the alkenylene is -CH=CH-, -CHCH=CH-, or -CH=CHCH-. In some embodiments, the alkenylene is -CH=CH-. In some embodiments, the alkenylene is -CHCH=CH-. In some embodiments, the alkenylene is -CH=CHCH-. In some embodiments, the alkenylene is -CH=CHCH-.

[0072] "Alkynyl" refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon triple bonds. In some embodiments, alkynyl groups have from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Whenever a numerical range such as "C2-C6 alkynyl" appears herein, it means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses occurrences of the term "alkynyl" where no numerical range is specified. In some embodiments, alkynyl refers to a C2-C6 alkynyl group. 10 alkynyl, 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 stated otherwise specifically in the specification, alkynyl groups can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkynyl can be optionally substituted with oxo, halogen, —CN, —CF3, —OH, —OMe, —NH2, or —NO2. In some embodiments, alkynyl can be optionally substituted with oxo, halogen, —CN, —CF3, —OH, or —OMe. In some embodiments, alkynyl can be optionally substituted with halogen. "Alkynylene" refers to an optionally substituted straight-chain or optionally substituted branched-chain divalent hydrocarbon having one or more carbon-carbon triple bonds.

[0073] "Alkylamino" means a group of the formula -N(R a )2(wherein, R a is a defined alkyl radical or two R arefers to a radical of the formula (which, together with the nitrogen atom, may form a substituted or unsubstituted C2-C7 heterocycloalkyl ring). Unless stated otherwise specifically in the specification, an alkylamino group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkylamino may be optionally substituted with oxo, halogen, —CN, —CF3, —OH, —OMe, —NH2, or —NO2. In some embodiments, an alkylamino may be optionally substituted with oxo, halogen, —CN, —CF3, —OH, or —OMe. In some embodiments, an alkylamino may be optionally substituted with halogen.

[0074] "Alkoxy" means a group of the formula -OR a (In the formula, R a is an alkyl radical as defined above). Unless stated otherwise specifically in the specification, alkoxy groups may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkoxy may be optionally substituted with oxo, halogen, —CN, —CF, —OH, —OMe, —NH, or —NO. In some embodiments, an alkoxy may be optionally substituted with oxo, halogen, —CN, —CF, —OH, or —OMe. In some embodiments, an alkoxy may be optionally substituted with halogen.

[0075] "Aminoalkyl" refers to an alkyl radical, as defined above, substituted with one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Hydroxyalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the hydroxyalkyl is aminomethyl.

[0076] The term "aryl" refers to a radical containing at least one aromatic ring, where each atom forming the ring is a carbon atom. An aryl group may be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. In some embodiments, an aryl is phenyl. Depending on the structure, an aryl group may be a monoradical or a diradical (i.e., an arylene group). Unless otherwise specifically stated herein, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals that may be optionally substituted. In some embodiments, an aryl group includes a partially reduced cycloalkyl group as defined herein (e.g., 1,2-dihydronaphthalene). In some embodiments, an aryl group includes a fully reduced cycloalkyl group as defined herein (e.g., 1,2,3,4-tetrahydronaphthalene). When an aryl includes a cycloalkyl group, the aryl is attached to the remainder of the molecule via an aromatic ring carbon atom. An aryl radical can be a monocyclic or polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) ring system and can include fused, spiro, or bridged ring systems. Unless stated otherwise specifically in the specification, an aryl can be optionally substituted with, for example, halogen, amino, alkylamino, aminoalkyl, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -S(O)NH-C1-C6 alkyl, etc. In some embodiments, an aryl can be 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), -S(O)2N(CH3), or -S(O)2NHC(CH3). In some embodiments, aryl can be optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, aryl can be optionally substituted with halogen.In some embodiments, the aryl is substituted with an 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.

[0077] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic radical in which the atoms forming the ring (i.e., skeletal atoms) are each carbon atoms. In some embodiments, the cycloalkyl is saturated or partially unsaturated. In some embodiments, the cycloalkyl is a spirocyclic or bridged compound. In some embodiments, the cycloalkyl is fused to an aromatic ring (in which case the cycloalkyl is attached through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having 3 to 10 ring atoms. Representative cycloalkyls include, but are not limited to, cycloalkyls having 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3 to 5 carbon atoms. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the monocyclic cycloalkyl is cyclopentyl. In some embodiments, the monocyclic cycloalkyl is cyclopentenyl or cyclohexenyl. In some embodiments, the monocyclic cycloalkyl is cyclopentenyl. Polycyclic radicals include, for example, adamantyl, 1,2-dihydronaphthalenyl, 1,4-dihydronaphthalenyl, tetraynyl, decalinyl, 3,4-dihydronaphthalenyl-1(2H)-one, spiro[2.2]pentyl, norbornyl, and bicyclo[1.1.1]pentyl. Unless stated otherwise specifically in the specification, cycloalkyl groups may be optionally substituted. Representative cycloalkyls include, but are not limited to, cycloalkyls containing 3 to 15 carbon atoms (C3-C6). 15 Cycloalkyl), 3 to 10 carbon atoms (C3 to C 10Examples of cycloalkyl include cycloalkyls having 3 to 8 carbon atoms (C-C cycloalkyl), 3 to 6 carbon atoms (C-C cycloalkyl), 3 to 5 carbon atoms (C-C cycloalkyl), or 3 to 4 carbon atoms (C-C cycloalkyl). In some embodiments, cycloalkyls are 3 to 6-membered cycloalkyls. In some embodiments, cycloalkyls are 5 to 6-membered cycloalkyls. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyls or carbocycles include adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Examples of partially saturated cycloalkyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specifically stated herein, cycloalkyls may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, cycloalkyl may be optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, cycloalkyl may be optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, cycloalkyl may be optionally substituted with halogen.

[0078] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, the halogen is fluoro or chloro. In some embodiments, the halogen is fluoro.

[0079] "Haloalkyl" refers to an alkyl radical, as defined above, substituted with one or more halogens. In some embodiments, the alkyl is substituted with one, two, or three halogens. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six halogens. Haloalkyl may include, for example, iodoalkyl, bromoalkyl, chloroalkyl, and fluoroalkyl. For example, "fluoroalkyl" refers to an alkyl radical, as defined above, substituted with one or more fluoro radicals, as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl radical may be optionally substituted as defined above for an alkyl group.

[0080] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from atoms other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C1-C6 heteroalkyl, where the heteroalkyl contains 1-6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof, and the heteroalkyl is attached to the remainder 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-, -OCH2CHO-, -OCH2CHOCH2CHO-, or -OCH2CHOCH2CHOCH2CHO-. Unless stated otherwise specifically in the specification, a heteroalkyl may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heteroalkyl may be optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, a heteroalkyl may be optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, a heteroalkyl may be optionally substituted with halogen. As used herein, "heteroalkylene" refers to a divalent heteroalkyl group. Examples of such heteroalkylenes are, for example, -CH2-O-CH2-, -CH2-N(alkyl)-CH2-, -CH2-N(aryl)-CH2-, -OCH2CHO-, -OCH2CHOCH2CH2O-, or -OCH2CHOCH2CH2OCH2CH2OCH2CH2O-. Unless otherwise stated, heteroalkylenes may be optionally substituted.

[0081] The term "heterocycloalkyl" refers to a cycloalkyl group containing at least one heteroatom, such as a heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specifically stated herein, a heterocycloalkyl radical may be a monocyclic or bicyclic ring system, which may include fused ring systems (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is attached through a non-aromatic ring atom) or bridged ring systems. The nitrogen, carbon, or sulfur atoms in the heterocyclyl radical may be optionally oxidized. The nitrogen atom may be optionally quaternized. The heterocycloalkyl radical may be partially or fully saturated. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. The term heterocycloalkyl also includes carbohydrates of all ring forms, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Unless otherwise noted, heterocycloalkyls have 2-12 carbons in the ring. In some embodiments, heterocycloalkyls have 2-10 carbons in the ring. In some embodiments, heterocycloalkyls have 2-10 carbons and 1 or 2 N atoms in the ring. In some embodiments, heterocycloalkyls have 2-10 carbons and 3 or 4 N atoms in the ring. In some embodiments, heterocycloalkyls have 2-12 carbons, 0-2 N atoms, 0-2 O atoms, 0-2 P atoms, and 0-1 S atoms in the ring.In some embodiments, a heterocycloalkyl has 2 to 12 carbons, 1 to 3 N atoms, 0 to 1 O atoms, and 0 to 1 S atoms in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, it is understood that the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) comprising the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring). Unless otherwise specifically stated herein, a heterocycloalkyl may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heterocycloalkyl may be optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, a heterocycloalkyl may be optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, heterocycloalkyl can be optionally substituted with halogen.

[0082] "Heteroaryl" refers to a ring system radical containing carbon atoms and one or more ring heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, heteroaryl is monocyclic, bicyclic, or polycyclic. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, furazanyl, indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, thiazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Illustrative examples of bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, heteroaryl is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl, or furyl. In some embodiments, heteroaryls contain 0 to 6 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 4-6 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, 0-1 P atoms, and 0-1 S atoms. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring.In some embodiments, heteroaryl is a C1-C9 heteroaryl. In some embodiments, monocyclic heteroaryl is a C1-C5 heteroaryl. In some embodiments, monocyclic heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, bicyclic heteroaryl is a C6-C9 heteroaryl. In some embodiments, heteroaryl groups include partially reduced cycloalkyl or heterocycloalkyl groups as defined herein (e.g., 7,8-dihydroquinoline). In some embodiments, heteroaryl groups include fully reduced cycloalkyl or heterocycloalkyl groups as defined herein (e.g., 5,6,7,8-tetrahydroquinoline). When heteroaryl includes a cycloalkyl or heterocycloalkyl group, the heteroaryl is attached to the remainder of the molecule through a heteroaromatic ring carbon or heteroatom. Heteroaryl radicals can be monocyclic or polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) ring systems and can include fused, spiro, or bridged ring systems. Unless stated otherwise specifically in the specification, a heteroaryl may be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heteroaryl may be optionally substituted with halogen, methyl, ethyl, -CN, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, a heteroaryl may be optionally substituted with halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, a heteroaryl may be optionally substituted with halogen.

[0083] The term "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is a well-recognized chemical entity embedded in or appended to a molecule.

[0084] As used herein, the terms "treat," "prevent," "ameliorate," and "inhibit," as well as words derived therefrom, do not necessarily mean 100% or complete treatment, prevention, amelioration, or inhibition. Rather, there are various degrees of treatment, prevention, amelioration, and inhibition that one of ordinary skill in the art would recognize as having potential benefit or therapeutic effect. In this regard, the disclosed methods can provide any amount of any level of treatment, prevention, amelioration, or inhibition of a disorder in a mammal. For example, a 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%. Furthermore, the treatment, prevention, amelioration, or inhibition provided by the methods disclosed herein can include treatment, prevention, amelioration, or inhibition of one or more conditions or symptoms of a disorder, e.g., cancer or inflammatory disease. As used herein, "treating" includes the concept of "alleviating," which refers to reducing the frequency of occurrence or recurrence, or the severity, of any symptoms or other pathological effects associated with a disorder and / or related side effects. The term "treating" also encompasses the concept of "managing," which refers to reducing the severity of a particular disease or disorder in a patient or delaying its recurrence, for example, increasing the duration of remission in a patient afflicted with a disease.

[0085] In certain embodiments, the term "prevent" or "preventing" in relation to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in a treated sample compared to an untreated control sample, or delays the onset of or reduces the severity of one or more symptoms of the disorder or condition compared to an untreated control sample.

[0086] As used herein, the term "therapeutically effective amount" refers to an amount effective at the dosage and duration necessary to achieve the desired therapeutic result. The therapeutically effective amount of a composition may vary depending on factors such as the condition, age, sex, and weight of the individual, and the ability of the protein to elicit the desired response in the individual. A therapeutically effective amount may also be an amount that exceeds any toxic or harmful effects of the composition that have a beneficial effect on treatment.

[0087] The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances in which the event or circumstance occurs and instances in which it does not occur. For example, "optionally substituted alkyl" means either "alkyl" or "substituted alkyl," as defined above. Furthermore, optionally substituted groups may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level between fully and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.).

[0088] As used herein, the term "substituent" refers to a position 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 substitution does not exceed the normal valence of the specified atom and results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. Those skilled in the art should note that any carbon and heteroatom having a valence that is not considered satisfied as described or shown herein is assumed to have a sufficient number of hydrogen atoms to satisfy the valence described or shown. In certain instances, one or more substituents having a double bond as a point of attachment (e.g., "oxo" or "=O") may be described, shown, or listed herein within a substituent, and the structure may show only a single bond as the point of attachment to the core structure. Those skilled in the art will understand that although only a single bond is shown, a double bond is intended for these substituents.

[0089] The term "optionally substituted" or "substituted" means that the referenced group may be optionally substituted with one or more further groups individually and independently selected from D, halogen, -CN, -NH, -NH(alkyl), -N(alkyl), -OH, oxo, -COH, -COalkyl, -C(=O)NH, -C(=O)NH(alkyl), -C(=O)N(alkyl), -S(=O)NH, -S(=O)NH(alkyl), -S(=O)N(alkyl), alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, optional substituents are independently selected from D, halogen, —CN, —NH, —NH(CH), —N(CH), —OH, oxo, —COH, —CO(C-C alkyl), —C(═O)NH, —C(═O)NH(C-C alkyl), —C(═O)N(C-C alkyl), —S(═O)NH, —S(═O)NH(C-C alkyl), —S(═O)N(C-C alkyl), C-C alkyl, C-C cycloalkyl, C-C fluoroalkyl, C-C heteroalkyl, C-C alkoxy, C-C fluoroalkoxy, —SC-C alkyl, —S(═O)C-C alkyl, and —S(═O)C-C alkyl. In some embodiments, optional substituents are independently selected from D, halogen, -CN, -NH, -OH, -NH(CH), -N(CH), -NH(cyclopropyl), -CH, -CHCH, -CF, -OCH, and -OCF. In some embodiments, substituted groups are substituted with one or two of said groups. In some embodiments, optional substituents (acyclic or cyclic) on aliphatic carbon atoms include oxo (=O). When referring to the number of substituents, the term "one or more" means from one substituent to the maximum number of substituents possible, i.e., from replacement of one hydrogen to replacement of all hydrogens by substituents.

[0090] The term "unsubstituted" means that the particular group bears no substituents.

[0091] Certain compounds described herein may exist in tautomeric forms, and all such tautomeric forms of the compounds are within the scope of the disclosure.

[0092] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure, i.e., the R and S configurations for each asymmetric center. Accordingly, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0093] As used herein, the term "peptide" refers to a compound containing two or more amino acids. The peptides described herein may contain one or more unnatural amino acids. The term "peptide" also encompasses peptidomimetics. In this disclosure, the term "amino acid" is used in its broadest sense, and it encompasses not only natural amino acids, but also their derivatives and artificial amino acids. For example, the term "amino acid" encompasses unnatural amino acids.

[0094] As used herein, the term "unnatural amino acid" refers to an amino acid other than the 20 standard amino acids: 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).

[0095] As used herein, the term "protein" refers to a polypeptide (i.e., a series of at least three amino acids linked together by peptide bonds). A protein may include moieties other than amino acids (e.g., may be a glycoprotein, proteoglycan, etc.) and / or may be otherwise processed or modified. A protein may be an entire polypeptide (with or without a signal sequence) produced by and / or active in a cell. In some embodiments, a protein is or includes a characteristic portion, such as a polypeptide, produced by 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 linked by other means.

[0096] The term "peptidomimetic" or "mimetics" refers to biologically active compounds that mimic the biological activity of peptides or proteins but are no longer entirely peptidic in chemical nature; for example, they may contain non-peptide bonds (bonds other than 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 peptidic in nature, such as pseudopeptides, semi-peptides, and peptoids. Whether completely non-peptide or partially non-peptide, the peptidomimetics described herein can provide a spatial arrangement of reactive chemical moieties that closely resembles the three-dimensional arrangement of active groups in the target amino acid sequence or molecule on which the peptidomimetic is based. As a result of this similar active site shape, peptidomimetics can have effects on biological systems that are similar to the biological activity of the target entity.

[0097] In some embodiments, the peptide mimetic is substantially similar in both three-dimensional shape and biological activity to the target amino acid sequence or target molecule on which the peptide mimetic is based. An example is described in the paper "Tritiated D-ala1-Peptide T Binding", Smith CS et al., Drug Development Res., 15, pp. 371-379 (1988). A second method is to modify the cyclic structure for stability, such as N-to-C interchain imides and lactams (Ede et al. in Smith and Rivier (Eds.) "Peptides: Chemistry and Biology", Escom, Leiden (1991), pp. 268-270). An example of this is provided in conformationally restricted thymopentin-like compounds, such as those disclosed in US 4,457,489. A third method is to replace the peptide bond in the target entity with a pseudopeptide bond that confers resistance to proteolysis.

[0098] Ranges provided herein are understood to be shorthand for all values ​​within that range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or subrange from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, as well as all intervening decimal values ​​between the above integers, such as, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. With respect to subranges, "nested subranges" extending from either end of the range are specifically contemplated. For example, nested subranges of the exemplary range of 1 to 50 could include 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction.

[0099] As used herein, C1-C x (or C 1~x ) is C1~C2, C1~C3...C1~C x By way of example only, a group designated "C1-C4" indicates that there are 1 to 4 carbon atoms in the moiety, i.e., a group containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. Thus, by way of example only, "C1-C4 alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Also, by way of example, C0-C2 alkylene includes a direct bond, -CH2-, and -CH2CH2- linkages.

[0100] As used herein, the term "cyclized" or "cyclization" means that two amino acids separated from each other by at least one amino acid are directly or indirectly linked to each other in a peptide to form a ring structure within the molecule. In some cases, the two amino acids are linked via a linker or the like.

[0101] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, any member of the mammalian class: non-human primates such as humans, chimpanzees, and other ape and monkey species; agricultural animals such as cows, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. In one aspect, the mammal is a companion animal, such as a dog or cat. In one aspect, the mammal is a human.

[0102] As used herein, the term "therapeutically effective amount" refers to an amount effective at a dosage to achieve a desired therapeutic result. The therapeutically effective amount of a composition may 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).

[0103] Percent sequence identity can be calculated using computer program or direct sequence comparison.Preferred computer program method for determining the identity between two sequences includes but is not limited to GCG program package, FASTA, BLASTP and TBLASTN (see, for example, DW Mount, 2001, Bioinformatics: Sequence and Genome Analysis, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY).BLASTP and TBLASTN programs are publicly available from NCBI and other sources.Percent identity can also be determined using Smith Waterman's algorithm. Exemplary parameters for amino acid sequence comparison include: 1) the Needleman and Wunsch algorithm (J. Mol. Biol., 48:443-453 (1970)); 2) Hentikoff and Hentikoff's BLOSSUM62 comparison matrix (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 may be publicly available as the "Gap" program (Genetics Computer Group, Madison, Wis.). The above parameters are the default parameters for polypeptide comparisons (there is no penalty for end gaps). Alternatively, polypeptide sequence identity can be calculated using the following formula: % identity - (number of identical residues) / (length of alignment in amino acid residues) * 100. For purposes of this calculation, the length of the alignment includes internal gaps but not terminal gaps.

[0104] It will be appreciated that certain features of the present disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the present disclosure, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. For example, a conjugate of the present disclosure may include any peptide ligand described herein (e.g., a peptide ligand of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), or (Ic), or Table 1), any metal chelator described herein (e.g., a metal chelator selected from Figures 4A, 5A, 6A, 7A, 4B, 5B, 6B, 7B, and 8-22), optionally a linker described herein (e.g., a linker of formula (II-1), (II-1a), (II-1b), or (II-2)), and optionally a radionuclide described herein (e.g., a radionuclide of a labeled "chelator" of Table 7). As another example, a conjugate of the present disclosure may include any peptide ligand described herein (e.g., a peptide ligand of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), or (Ic), or Table 1), any covalently bound radionuclide described herein (e.g., a labeled "covalently bound" radionuclide of Table 7), and optionally a linker described herein (e.g., a linker of formula (II-1), (II-1a), (II-1b), or (II-2) or Table 6) connecting the covalently bound radionuclide to the peptide. As another example, a peptide of Formula (I) (or any other formula, such as (III-1), (III-2), (III-1-RI), and (III-2-RI)) may include the X1 through X12 amino acids described herein, with any combination of amino acid embodiments being encompassed by the present disclosure (even though in some cases they are described in the context of separate embodiments).

[0105] II. Radiopharmaceutical conjugates Provided herein are radiopharmaceutical conjugates with avidity for Ephrin type-A receptor 2 (EphA2) and pharmaceutical compositions comprising the conjugates. The conjugates and compositions may be useful for treating cancer. The conjugates and compositions may also be useful in imaging and disease diagnosis.

[0106] In one aspect, described herein is a conjugate comprising a peptide having avidity for Ephrin type-A receptor 2 (EphA2) and a metal chelator configured to bind to a radionuclide. In some embodiments, the EphA2 is human EphA2. In some embodiments, the conjugate or peptide described herein does not have avidity 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 may be cyclic or acyclic, and may be monocyclic, bicyclic, or polycyclic. In one aspect, described herein is a conjugate comprising 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 conjugates described herein may further comprise a linker that covalently attaches the peptide to the metal chelator. In some embodiments, the conjugate comprises a linker attached to the metal chelator. 225 Contains radionuclides such as Ac.

[0107] In another aspect, described herein is a conjugate comprising a peptide having avidity for Ephrin type-A receptor 2 (EphA2) and a covalently bound radionuclide. In some embodiments, EphA2 is human EphA2. In some embodiments, the conjugate or peptide described herein does not have avidity 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 may be cyclic or acyclic, and may be monocyclic, bicyclic, or polycyclic. In one aspect, described herein is a conjugate comprising a cyclic peptide and a covalently bound radionuclide. In some embodiments, the peptide (such as a cyclic peptide) is configured to bind to a target. The conjugates described herein may further comprise a linker that covalently attaches the peptide to the radionuclide. 131 Contains covalently bound radionuclides such as I.

[0108] In one aspect, (a) a peptide having avidity for ephrin type-A receptor 2 (EphA2), the peptide being represented by SEQ ID NO: 1: A peptide comprising an amino acid sequence containing one or more amino acid deletions, substitutions, and / or additions in the amino acid sequence of da-MeF-NL-Hgl-MeF-W1Me-V-W1Me-TEC (SEQ ID NO: 1), or a pharmaceutically acceptable salt thereof; and (b) (i) a metal chelator configured to bind a radionuclide, the metal chelator being conjugated to the peptide; or (ii) a covalently bound radionuclide (or a radionuclide covalently bound to the peptide). Described herein are radiopharmaceutical conjugates comprising: 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, the metal chelator being conjugated to the peptide. In some embodiments, the metal chelator is covalently attached 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.

[0109] 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 of SEQ ID NO: 1 with no more than two amino acid deletions. In some embodiments, one to two amino acids selected from the group consisting of T at position 10 and E at position 11 of SEQ ID NO: 1 are deleted. 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.

[0110] In one aspect, (a) A peptide having avidity for ephrin type-A receptor 2 (EphA2), the peptide having formula (I): X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) [In the formula, X1 is an amino acid; X2 is an aromatic ring-containing amino acid, an N-methylated amino acid thereof, or a variant thereof; X3 is a hydrophilic amino acid (e.g., N, Q, Cit, K or a variant thereof), glycine (G), alanine (A) or a variant thereof (e.g., da, 2-aminoisobutyric acid (Aib)); X4 is a hydrophobic amino acid (e.g., leucine (L)), a hydrophilic amino acid (e.g., citrulline (Cit)), or a variant thereof; X5 is a hydrophilic amino acid or variant thereof; X6 is a hydrophilic amino acid, an amino acid containing an aromatic ring, 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, an N-methylated amino acid, or a variant thereof; X9 is an amino acid containing an aromatic ring (e.g., W or a variant thereof); X10 is absent or a hydrophilic amino acid (e.g., threonine (T) or a variant thereof); X11 is absent or a hydrophilic amino acid; X12 is cysteine ​​(C) or a variant thereof. or a pharmaceutically acceptable salt thereof; and (b) (i) a metal chelator configured to bind a radionuclide, the metal chelator conjugated to the peptide, or (ii) a covalently bound radionuclide. Described herein are radiopharmaceutical conjugates comprising: 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, the metal chelator conjugated to the peptide. In some embodiments, the metal chelator is covalently attached 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 cyclic peptide. In some embodiments, the peptide is a monocyclic peptide.

[0111] In one aspect, (a) A peptide having avidity for ephrin type-A receptor 2 (EphA2), the peptide having formula (I): X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) [In the formula, X1 is an amino acid; X2 is an aromatic ring-containing amino acid, an N-methylated amino acid thereof, or a variant thereof; X3 is absent, a hydrophilic amino acid (e.g., N, Q, Cit, K, or a variant thereof), glycine (G), alanine (A), or a variant thereof (e.g., da, 2-aminoisobutyric acid (Aib)); X4 is absent, a hydrophobic amino acid (e.g., leucine (L)), a hydrophilic amino acid (e.g., citrulline (Cit)), or a variant thereof; X5 is absent or a hydrophilic amino acid or variant thereof; X6 is absent, a hydrophilic amino acid, an amino acid containing an aromatic ring, or an N-methylated version 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, an N-methylated amino acid, or a variant thereof; X9 is an amino acid containing an aromatic ring (e.g., W or a variant thereof); X10 is absent or a hydrophilic amino acid (e.g., threonine (T) or a variant thereof); X11 is absent or a hydrophilic amino acid; X12 is cysteine ​​(C) or a variant thereof. or a pharmaceutically acceptable salt thereof; and (b) (i) a metal chelator configured to bind a radionuclide, the metal chelator conjugated to the peptide; or (ii) a covalently bound radionuclide Described herein are radiopharmaceutical conjugates comprising: 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, the metal chelator conjugated to the peptide. In some embodiments, the metal chelator is covalently attached 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 a peptide.

[0112] In one aspect, (a) A peptide having avidity for ephrin type-A receptor 2 (EphA2), the peptide having formula (I): X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) [In the formula, X1, X2, X3, X4, X5, X6, and X8 are each independently an amino acid; X7 is W1Me or a variant thereof; X9 is W1Me or a variant thereof; X10 and X11 are each independently absent or an amino acid; X12 is cysteine ​​(C) or a variant thereof. or a pharmaceutically acceptable salt thereof; (b) (i) a metal chelator configured to bind a radionuclide; or (ii) a covalently bound radionuclide; and (c) (i) a linker connecting the peptide to a metal chelator; or (ii) a linker connecting the peptide to a covalently bound radionuclide. Described herein are radiopharmaceutical conjugates comprising: In some embodiments, the radiopharmaceutical conjugate comprises a metal chelator configured to bind to a radionuclide and a linker connecting the peptide to the metal chelator. In some embodiments, the metal chelator is covalently attached to the peptide. In some embodiments, the radiopharmaceutical conjugate comprises a covalently bound radionuclide and a linker connecting the peptide to the covalently bound radionuclide.

[0113] In some embodiments, the metal chelator is conjugated to the N-terminus of the peptide. In some embodiments, the conjugate further comprises a linker connecting 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 is attached to the peptide via a non-terminal amino acid residue of the peptide. In some embodiments, the linker is attached to amino acid X1. In some embodiments, the linker is attached to amino acid X2. In some embodiments, the linker is attached to amino acid X3. In some embodiments, the linker is attached to amino acid X4. In some embodiments, the linker is attached to amino acid X5. In some embodiments, the linker is attached to amino acid X6. In some embodiments, the linker is attached to amino acid X7. In some embodiments, the linker is attached to amino acid X8. In some embodiments, the linker is attached to amino acid X9. In some embodiments, the linker is attached to amino acid X10. In some embodiments, the linker is attached to amino acid X11. In some embodiments, the linker is attached to amino acid X12. In some embodiments, the linker is attached to amino acid X5, X8, or X11. In some embodiments, the linker is attached to a lysine of the peptide. In some embodiments, the linker comprises one or more amino acid residues. In some embodiments, the linker comprises a lysine residue, an alanine residue, or both.

[0114] In one aspect, [ka] (In the formula, [ka] represents the linker) Described herein are radiopharmaceutical conjugates having the structure:

[0115] In one aspect, [ka] (In the formula, [ka] represents a linker attached to the C-terminus of the peptide) Described herein are radiopharmaceutical conjugates having the structure:

[0116] In some embodiments, the radiopharmaceutical conjugate comprises a covalently bound radionuclide. In some embodiments, the covalently bound radionuclide is attached to the N-terminus of the peptide. In some embodiments, the conjugate further comprises a linker connecting the peptide to the covalently bound radionuclide. In some embodiments, the linker covalently connects the peptide to the covalently bound radionuclide. In some embodiments, the linker covalently attaches the covalently bound radionuclide to the N-terminus of the peptide. In some embodiments, the linker covalently attaches the covalently bound radionuclide to the C-terminus of the peptide. In some embodiments, the linker is attached to the peptide via a non-terminal amino acid residue of the peptide. In some embodiments, the linker is attached to amino acid X1. In some embodiments, the linker is attached to amino acid X2. In some embodiments, the linker is attached to amino acid X3. In some embodiments, the linker is attached to amino acid X4. In some embodiments, the linker is attached to amino acid X5. In some embodiments, the linker is attached to amino acid X6. In some embodiments, the linker is attached to amino acid X7. In some embodiments, the linker is attached to amino acid X8. In some embodiments, the linker is attached to amino acid X9. In some embodiments, the linker is attached to amino acid X10. In some embodiments, the linker is attached to amino acid X11. In some embodiments, the linker is attached to amino acid X12. In some embodiments, the linker is attached to amino acid X5, X8, or X11. In some embodiments, the linker is attached to a lysine of the peptide. In some embodiments, the linker comprises one or more amino acid residues. In some embodiments, the linker comprises a lysine residue, an alanine residue, or both.

[0117] In some embodiments, the covalently bound radionuclide is directly bound to the peptide. In some embodiments, the covalently bound radionuclide is directly bound to the peptide via a non-terminal amino acid residue of the peptide. In some embodiments, the covalently bound radionuclide is bound to an aromatic amino acid in the peptide. In some embodiments, the covalently bound radionuclide is bound to amino acid X1. In some embodiments, the covalently bound radionuclide is bound to amino acid X2. In some embodiments, the covalently bound radionuclide is bound to amino acid X3. In some embodiments, the covalently bound radionuclide is bound to amino acid X4. In some embodiments, the covalently bound radionuclide is bound to amino acid X5. In some embodiments, the covalently bound radionuclide is bound to amino acid X6. In some embodiments, the covalently bound radionuclide is bound to amino acid X7. In some embodiments, the covalently bound radionuclide is bound to amino acid X8. In some embodiments, the covalently bound radionuclide is bound to amino acid X9. In some embodiments, the covalently bound radionuclide is bound to amino acid X10. In some embodiments, the covalently bound radionuclide is attached to amino acid X11. In some embodiments, the covalently bound radionuclide is attached to amino acid X12. In some embodiments, the covalently bound radionuclide is attached to amino acid X2, X6, X7, or X9.

[0118] In one aspect, [ka] (In the formula, [ka] represents a linker; R * represents a radionuclide) Described herein are radiopharmaceutical conjugates having the structure:

[0119] In one aspect, [ka] (In the formula, [ka] represents a linker connected to the C-terminus of the peptide; R * represents a radionuclide) Described herein are radiopharmaceutical conjugates having the structure:

[0120] In one aspect, [ka] (In the formula, [ka] represents a persister or non-persister; Linker represents a linker; and R * represents a radionuclide) Described herein are radiopharmaceutical conjugates having the structure:

[0121] In one aspect, [ka] (In the formula, [ka] represents a persister or non-persister; Linker represents a linker connected to the C-terminus of the peptide; R * represents a radionuclide) Described herein are radiopharmaceutical conjugates having the structure:

[0122] In some embodiments, conjugates are described herein that include (a) a targeting moiety comprising a monocyclic peptide having avidity 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, conjugates are described herein that include (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, conjugates are described herein that include (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 by a non-disulfide bond. In some embodiments, the monocyclic peptide does not include 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 cyclic peptide to a metal chelator or a covalently attached radionuclide. In some embodiments, the conjugate comprises a linker that covalently attaches the cyclic peptide to a metal chelator or a covalently attached radionuclide. 225 In some embodiments, the conjugate comprises a radionuclide such as Ac. 18 F, 74 As, 76 Br, 123 I, 124 I, 125 I, 131 I, and 211 In some embodiments, the covalently bound radionuclide is attached to the peptide or linker via a residualizing or non-residualizing agent.

[0123] In some embodiments, the conjugates described herein comprise two or more peptides (i.e., a first peptide, a second peptide, etc.). For example, a conjugate may comprise two different peptides, where both peptides are configured to bind to the same target (e.g., EphA2), either at the same binding site or at different binding sites. As another example, a conjugate may comprise two different peptides, where the two peptides are configured to bind to different targets (including EphA2). As yet another example, a conjugate may comprise two identical peptides.

[0124] In some embodiments, the conjugates described herein are in salt form. In some embodiments, the conjugates described herein are in free base form.

[0125] In one aspect, (a) a peptide having avidity for ephrin type-A receptor 2 (EphA2), comprising SEQ ID NO: 1: Described herein are a peptide, or a pharmaceutically acceptable salt thereof, that competes for binding to human EphA2 with a peptide having an amino acid sequence comprising one or more amino acid deletions, substitutions, and / or additions in the amino acid sequence of da-MeF-NL-Hgl-MeF-W1Me-V-W1Me-TEC (SEQ ID NO: 1); and (b) (i) a metal chelator configured to bind to a radionuclide; or (ii) a conjugate comprising a covalently bound radionuclide. In one aspect, described herein is a conjugate comprising: (a) a peptide having avidity for Ephrin type-A receptor 2 (EphA2), wherein the peptide competes for binding to human EphA2 with a peptide having the structure of Formula (I) described herein (e.g., Formula (I-1), (I-2), (I-3), or (I-4)), 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 for binding to human EphA2 at one or more amino acid residues selected from Asp53, Met55, Asn57, Met59, Met66, Thr101, Arg103, Phe156, Glu157, Arg159, Val161, Val189, and Ala190. In some embodiments, the peptide competes for binding to human EphA2 at one or more amino acid residues selected from Asp53, Phe156, and Glu157. In some embodiments, the peptide competes for binding to human EphA2 at Asp53, Glu157, or both. In some embodiments, the peptide is a cyclic peptide. In some embodiments, the peptide is a monocyclic peptide.

[0126] In some embodiments, the metal chelator is conjugated to the peptide directly or indirectly via a linker. In some embodiments, the metal chelator is conjugated to the peptide by a covalent or non-covalent bond. In some embodiments, the radionuclide is covalently attached to the peptide directly or indirectly via a linker.

[0127] The conjugates described herein have suitable plasma half-lives (T 1 / 2In some embodiments, the plasma half-life of the conjugate, as determined in vitro in human plasma at 37° C., is at least 50 minutes, 100 minutes, 150 minutes, 200 minutes, 250 minutes, 300 minutes, 350 minutes, 400 minutes, 450 minutes, or 500 minutes. In some embodiments, the plasma half-life of the conjugate, as determined in vitro in human plasma at 37° C., is at least 280 minutes. In some embodiments, the plasma half-life of the conjugate, as determined in vitro in human plasma at 37° C., is at least 250 minutes. In some embodiments, the plasma half-life of the conjugate, as determined in vitro in human plasma at 37° C., is at most 30 days, 14 days, 7 days, 2 days, 1 day, or 500 minutes. In some embodiments, the plasma half-life of the conjugate, as determined in vivo in humans, is at least 50 minutes, 100 minutes, 150 minutes, 200 minutes, 250 minutes, 300 minutes, 350 minutes, 400 minutes, 450 minutes, or 500 minutes. In some embodiments, the plasma half-life, as determined in vivo in humans, is at least 280 minutes. In some embodiments, the plasma half-life, as determined in vivo in humans, is at least 250 minutes. In some embodiments, the plasma half-life of the conjugate, as determined in vivo in humans, is at most 30 days, 14 days, 7 days, 2 days, 1 day, or 500 minutes. In some embodiments, the plasma half-life of the conjugate, as determined in vitro in mouse plasma at 37° C., is at least 50 minutes, 100 minutes, 150 minutes, 200 minutes, 250 minutes, 300 minutes, 350 minutes, 400 minutes, 450 minutes, or 500 minutes. In some embodiments, the plasma half-life of the conjugate, as determined in vitro in mouse plasma at 37° C., is at least 280 minutes. In some embodiments, the plasma half-life of the conjugate, as determined in vitro in mouse plasma at 37° C., is at least 250 minutes. In some embodiments, the plasma half-life of the conjugate, as determined in vitro in mouse plasma at 37° C., is at most 30 days, 14 days, 7 days, 2 days, 1 day, or 500 minutes.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. Plasma half-life can be determined by any suitable method known in the art, for example, the method described in Example C1. In some embodiments, the conjugate has a plasma half-life (T) of at least 250 minutes, as determined in vitro in human plasma at 37° C. 1 / 2 In some embodiments, the plasma half-life is determined by the percent remaining of the test compound after incubation in plasma.

[0128] The conjugates described herein may have an uptake ratio between tumor and intestine. In some embodiments, the uptake ratio is determined between tumor uptake of the radiopharmaceutical conjugate and kidney uptake of the radiopharmaceutical conjugate in a subject. 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 mouse (such as a xenograft model). In some embodiments, the uptake ratio between tumor uptake and kidney uptake for the radiopharmaceutical conjugate (i.e., tumor uptake / kidney uptake) is at least 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, or 2.0 in a human prostate xenograft mouse model. In some embodiments, the uptake ratio is determined 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 tumor uptake and kidney uptake for the radiopharmaceutical conjugate is at least 1.2. In some embodiments, the uptake ratio between tumor uptake and kidney uptake for the radiopharmaceutical conjugate is at least 1.5, hi some embodiments, the tumor uptake of a radiopharmaceutical conjugate described herein is at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% greater than the kidney uptake of the radiopharmaceutical conjugate in the same subject.

[0129] In some embodiments, uptake of the radiopharmaceutical conjugate is determined about 4 hours, 12 hours, 24 hours, or 48 hours after administration of the radiopharmaceutical conjugate to the subject. In some embodiments, uptake of the radiopharmaceutical conjugate is determined about 4 hours after administration. In some embodiments, uptake of the radiopharmaceutical conjugate is determined about 12 hours after administration. In some embodiments, uptake of the radiopharmaceutical conjugate is determined about 24 hours. In some embodiments, uptake of the radiopharmaceutical conjugate is determined about 48 hours after administration.

[0130] In some embodiments, the conjugates described herein are designed to have a predetermined elimination profile. The elimination profile can be designed by adjusting the peptide sequence and length, linker characteristics, radionuclide type, etc. In some embodiments, the conjugate has an elimination half-life of about 30 minutes to 120 hours. In some embodiments, the conjugate has an elimination half-life of about 1 to 120 hours. In some embodiments, the conjugate has an elimination half-life of at least 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 7 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours. In some embodiments, the conjugate has an elimination half-life of at most 120 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 conjugate has an elimination half-life of about 2-24 hours. In some embodiments, the conjugate has an elimination half-life of about 3-9 hours. In some embodiments, the conjugate has an elimination half-life of about 2-12 hours. In some embodiments, the conjugate has an elimination half-life of about 2-8 hours. In some embodiments, the conjugate has an elimination half-life of about 2-5 hours. In some embodiments, the conjugate has an elimination half-life of about 3-4 hours. In some embodiments, the elimination half-life is determined in rats. In some embodiments, the elimination half-life is determined in humans.

[0131] The conjugates described herein may have an elimination half-life in tumor and non-tumor tissues of a subject. The elimination half-life in tumors may be the same as or different from (longer or shorter than) the elimination half-life in non-tumor tissues. In some embodiments, the elimination half-life of the conjugate in tumors is about 3 hours to 14 days, about 2 to 10 days, about 7 to 10 days, or about 4 to 7 days. In some embodiments, the elimination half-life of the conjugate in tumors is greater than 14 days. In some embodiments, the elimination half-life of the conjugate in non-tumor tissues is about 1 hour to 14 days, about 12 hours to 2 days, about 1 day to 3 days, about 2 to 10 days, about 7 to 10 days, or about 4 to 7 days. In some embodiments, the elimination half-life of the conjugate in the tumor is at least 1.1, 1.2, 1.3, 1.4, 1.5, 2.0, 2.5, 3.0, 4.0, or 5.0 times the elimination half-life of the conjugate in a non-tumor tissue of the subject.

[0132] As used herein, "elimination half-life" refers to the time taken from maximum concentration to half-maximum concentration after administration. 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 pharmaceutical in a biological 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 biological system taking into account the half-life of the radionuclide.

[0133] In some cases, the excretion profile of the conjugate can be adjusted by reversible binding between the conjugate and a plasma protein, such as albumin. Suitable affinity between the conjugate and a plasma protein allows the plasma protein to be used as a reservoir for the conjugate, improving the excretion profile by binding and retaining the conjugate at high concentrations and releasing the conjugate at low concentrations. 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.

[0134] In some embodiments, the conjugate of the present disclosure is selected from Tables 2A-Lu, 2A-Lu177, 2A-Ac255, 2B, 2BLu, 2B-Lu177, 2B-Ac255, and 2C. In some embodiments, the conjugate of the present disclosure is selected from Tables 2A-Ac255 and 2B-Ac255. In some embodiments, the conjugate of the present disclosure comprises a peptide from Table 1, a chelator selected from Figures 4-22, and a labeled "chelator" radionuclide from Table 7. In some embodiments, the conjugate of the present disclosure comprises a conjugate from Figures 1-3. In some embodiments, the conjugate of the present disclosure comprises a peptide from Table 1 and a labeled "covalently bound" radionuclide from Table 7. In some embodiments, the conjugate of the present disclosure comprises a peptide from Table 1, a linker, and a marked "covalently bound" radionuclide from Table 7. In some embodiments, the conjugates of the present disclosure include the conjugates of Figures 27-29.

[0135] EphA2 EPH receptor A2 (ephrin type A receptor 2) is a protein encoded by the EPHA2 gene in humans. EphA2 is upregulated in multiple cancers and is often correlated with disease progression, metastasis, and poor prognosis in solid tumors such as breast cancer, lung cancer, gastric cancer, pancreatic cancer, prostate cancer, liver cancer, and glioblastoma.

[0136] Eph receptor tyrosine kinases (Ephs) belong to a large group of receptor tyrosine kinases (RTKs), kinases that phosphorylate proteins on tyrosine residues. Ephs and their membrane-bound ephrin ligands (ephrins) can control cell positioning and tissue structure. Functional and biochemical Eph responses can occur at higher ligand oligomerization states.

[0137] Among other patterning functions, various Ephs and ephrins have been shown to play a role in vascular development. Knockout of EphB4 and ephrinB2 can result in the inability to remodel capillary beds into blood vessels and embryonic lethality. Persistent expression of some Eph receptors and ephrins has also been observed in newly formed, adult microvessels (Brantley-Sieders et al. (2004) Curr Pharm Des 10, 3431-42). The deregulated reappearance of some ephrins and their receptors in adults may contribute to tumor invasion, metastasis, and neovascularization. Furthermore, some Eph family members can be overexpressed on tumor cells derived from various human tumors (Booth et al. (2002) Nat Med 8, 1360-1).

[0138] Human EphA2 is identified as follows: SEQ ID NO: 276 (isoform 1, P29317-1): It may have the sequence set forth in (SEQ ID NO: 276).

[0139] Human EphA2 is identified as follows: SEQ ID NO: 277 (isoform 2, P29317-2): MELQAARACFALLWGCALAAAAAAQGKEVVLLDFAAAGGELGWLTHPYGKGWDLMQNIMNDMPIYMYSVCNVMSGDQDNWLRTNWVYRGEAERIFIELKFTVRDCNSFPGGASSCKETFNLYYAESDLDY GTNFQKRLFTKIDTIAPDEITVSSDFEARHVKLNVEERSVGPLTRKGFYLAFQDIGACVALLSVRVYYKKCPELLQGLAHFPETIAGSDAPSLATVAGTCVDHAVVPPGGEEPRMHCAVDGEWLVPIGQC LCQAGYEKVEDACQACSPGFFKFEASESPCLECPEHTLPSPEGATSCECEEGFFRAPQDPASMPCTRPPSAPHYLTAVGMGAKVELRWTPPQDSGGREDIVYSVTCEQCWPESGECGPCEASVRYSEPPHGLTRTSVTVSDLEPHMNYTFTVEARNGVSGLVTSRSFRTASVSINQTEPPKVRLEGRSTTSLSVSWSIPPPQQSRVWKYEVTYRKKVTPRGAGLALAGPTAGDRLVT (SEQ ID NO: 277).

[0140] As used herein, the phrase "having avidity for EphA2" or "binding to EphA2" refers to 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 can bind to any location on the EphA2 protein. Binding to EphA2 can be measured by any known method for measuring intermolecular binding. In a non-limiting manner, this can be determined by, for example, surface plasmon resonance (SPR) assay, scattering analysis and / or radioimmunoassay (RIA), enzyme immunoassay (EIA), and competitive binding assays such as sandwich and competitive assays, as well as by any suitable manner known in the art, including different variants of the given examples.

[0141] In some embodiments, the peptide or 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.

[0142] As used herein, the term "EphA2" refers to any form of EphA2 and its variants that retain at least some of the activity of EphA2. Unless otherwise specifically described as human EphA2 (hEphA2), EphA2 includes all native sequences of EphA2 in mammals, such as humans, dogs, cats, horses, and cows. One example of EphA2 is human EphA2, hEphA2 (gene ID: 1969), a protein with the amino acid sequence (SEQ ID NO: 276, isoform 1, P29317-1).

[0143] Peptide Ligands In one aspect, the conjugates described herein comprise a peptide (e.g., a binding peptide) having avidity 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 conjugates comprise two or more peptides, which can be the same or different. The peptides can be linear or cyclic. In some embodiments, the peptides are monocyclic. The peptides can comprise any suitable number of amino acids. In some embodiments, the peptides comprise 5-50, 6-40, 7-30, 8-25, 12-25, or 9-20 amino acid residues. In some embodiments, the peptides comprise 5-14 amino acid residues. In some embodiments, the peptides comprise 7-12 amino acid residues. In some embodiments, the peptides comprise 8-12 amino acid residues. In some embodiments, the peptides comprise 8-10 amino acid residues. In some embodiments, the peptide comprises 7-13 amino acid residues. In some embodiments, the peptide comprises 12-15 amino acid residues. In some embodiments, the peptide comprises 13-14 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 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 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 may be binding peptides that bind to EphA2. In some embodiments, the binding peptide consists of 6-20 amino acid residues. In some embodiments, the binding peptide consists of 7-12 amino acid residues. In some embodiments, the binding peptide consists of 10-12 amino acid residues. In some embodiments, the binding peptide consists of 8-12 amino acid residues. In some embodiments, the binding peptide is monocyclic. In some embodiments, the peptides of the present technology are isolated peptides. In some embodiments, the peptides of the present technology are purified peptides.

[0144] In one embodiment, a peptide (e.g., a cyclic peptide) having avidity for Ephrin type-A receptor 2 (EphA2) is provided, comprising: Described herein is a peptide comprising an amino acid sequence of da-MeF-NL-Hgl-MeF-W1Me-V-W1Me-TEC (SEQ ID NO: 1) containing one or more (e.g., 1 to 6) amino acid deletions, substitutions, and / or additions, or a pharmaceutically acceptable salt thereof.

[0145] In some embodiments, the (cyclic) peptide consists of 10 to 12 amino acid residues.

[0146] In some embodiments, the peptide comprises an amino acid sequence that includes a total of at most six deletions, substitutions, and / or additions of one or more amino acids in the amino acid sequence of SEQ ID NO: 1. In some embodiments, the peptide comprises an amino acid sequence that includes a total of at most five deletions, substitutions, and / or additions of one or more amino acids in the amino acid sequence of SEQ ID NO: 1. In some embodiments, the peptide comprises an amino acid sequence that includes a total of at most four deletions, substitutions, and / or additions of one or more amino acids in the amino acid sequence of SEQ ID NO: 1. In some embodiments, the peptide comprises an amino acid sequence that includes a total of at most three deletions, substitutions, and / or additions of one or more amino acids in the amino acid sequence of SEQ ID NO: 1. In some embodiments, the peptide comprises an amino acid sequence that includes a total of at most two deletions, substitutions, and / or additions of one or more amino acids in the amino acid sequence of SEQ ID NO: 1. In some embodiments, the peptide comprises an amino acid sequence that includes a total of at most one deletion, substitution, and / or addition of one or more amino acids in the amino acid sequence of SEQ ID NO: 1. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. The deletions, additions, or substitutions may be at the termini or in the middle of the peptide. In some embodiments, one to five amino acids selected from the group consisting of 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, and may not have any further 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 of SEQ ID NO: 1 in which two or fewer amino acids have been deleted, and may not have any further additions and / or substitutions. In some embodiments, one to two amino acids selected from the group consisting of T at position 10 and E at position 11 of SEQ ID NO: 1 are deleted, and may not have any further additions and / or substitutions. In some embodiments, V at position 8 is substituted. In some embodiments, E at position 11 is substituted.

[0147] For the purposes of this disclosure, one event of "substitution" of an amino acid or amino acid sequence is not considered to be two separate events: one deletion and one addition. Thus, for the avoidance of doubt, by way of example, a sequence change of "up to 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, one deletion only, one substitution only, one addition only, two deletions, two substitutions, two additions, etc. The locations of the deletions, additions, or substitutions may be at one or both termini of the peptide, or in the middle of the peptide.

[0148] In some embodiments, the peptide comprises an amino acid sequence in which 1 to 5 amino acids selected from the group consisting of N at position 3, L at position 4, Hgl at position 5, MeF at position 6, T at position 10, and E at position 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 group consisting of N at position 3, L at position 4, Hgl at position 5, MeF at position 6, T at position 10, and E at position 11 of SEQ ID NO: 1 are deleted in the peptide. In some embodiments, the N at position 3 is deleted. In some embodiments, the L at position 4 is deleted. In some embodiments, the Hgl at position 5 is deleted. In some embodiments, the MeF at position 6 is deleted. In some embodiments, the E at position 11 is deleted. In some embodiments, the peptide comprises an amino acid sequence in which 1 to 5 amino acids selected from the group consisting of 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 group consisting of the amino acids at positions 3, 4, 5, 6, 10, and 11 of SEQ ID NO: 1 have been deleted in the peptide. In some embodiments, the 3rd amino acid has been deleted. In some embodiments, the 4th amino acid has been deleted. In some embodiments, the 5th amino acid has been deleted. In some embodiments, the 6th amino acid has been deleted. In some embodiments, the 10th amino acid has been deleted. In some embodiments, the 11th amino acid has been deleted. In certain embodiments, the peptide has a deletion of 1 to 5 amino acids of SEQ ID NO: 1 and no additional residue additions. In certain embodiments, the peptide has a deletion of 1 to 5 amino acids of SEQ ID NO: 1 and no additional residue substitutions. In certain embodiments, the peptide has a deletion of 1 to 5 amino acids of SEQ ID NO: 1 and no additional residue additions or substitutions. In certain embodiments, the peptide has a deletion of 1 to 5 amino acid residues of SEQ ID NO: 1 and no additional residue additions. In certain embodiments, the peptide has a deletion of 1 to 5 amino acid residues of SEQ ID NO:1 and no residue substitutions.In certain embodiments, the peptide has a deletion of 1 to 5 amino acid residues of SEQ ID NO:1 and no residue substitutions.

[0149] In one embodiment, there is provided a peptide having avidity for ephrin type-A receptor 2 (EphA2), comprising the formula (I): X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) [In the formula, X1 is an amino acid; X2 is an aromatic ring-containing amino acid, an N-methylated amino acid thereof, or a variant thereof; X3 is a hydrophilic amino acid (e.g., N, Q, Cit, K or a variant thereof), glycine (G), alanine (A) or a variant thereof (e.g., da, 2-aminoisobutyric acid (Aib)); X4 is a hydrophobic amino acid (e.g., leucine (L)), a hydrophilic amino acid (e.g., citrulline (Cit)), or a variant thereof; X5 is a hydrophilic amino acid or variant thereof; X6 is a hydrophilic amino acid, an amino acid containing an aromatic ring, 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, an N-methylated amino acid, or a variant thereof; X9 is an amino acid containing an aromatic ring (e.g., W or a variant thereof); X10 is absent or a hydrophilic amino acid (e.g., threonine (T) or a variant thereof); X11 is absent or a hydrophilic amino acid; X12 is cysteine ​​(C) or a variant thereof. Described herein are peptides having the amino acid sequence set forth in: or a pharmaceutically acceptable salt thereof.

[0150] In some embodiments of Formula (I), X10 and X11 are both present. In some embodiments of Formula (I), X10 and X11 are both absent.

[0151] In one embodiment, there is provided a peptide having avidity for ephrin type-A receptor 2 (EphA2), comprising the formula (I): X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) [In the formula, X1 is an amino acid; X2 is F or an unsubstituted phenyl ring of F, (i) -OH, -CN, amino, halogen, -C 1~3 Haloalkyl, and -C 1~3 a phenyl ring substituted with 1 or 2 substituents each independently selected from alkyl (e.g., —CH3), or (ii) -OH, -CN, amino, halogen, -C 1~3 Haloalkyl, and -C 1~3 a 6-membered heteroaryl ring optionally substituted with 1 or 2 substituents each independently selected from alkyl; Here is a variant of that where you replace wherein F or a variant thereof may be 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 four or more carbon atoms in its side chain, including a linear, branched, or cyclic carbon chain), and X4 may be N-methylated (e.g., Cit or a variant thereof); X5 is an amino acid (e.g., a hydrophilic amino acid; or an amino acid with a functional side chain (e.g., not glycine)); X6 is the N-methylated amino acid; X7 is W, Y, or variants thereof (e.g., 6-, 9-, and 10-membered heteroaryls having 1 to 3 heteroatoms (e.g., N), and 6-, 9-, and 10-membered aryls or heteroaryls optionally substituted (e.g., —OH, —CN, amino, halogen, —C 1~3 Haloalkyl, and -C 1~3 alkyl), a 6-membered aryl or heteroaryl, or an amino acid having a 9- or 10-membered bicyclic aryl or heteroaryl linked to the alpha carbon through a carbon (e.g., a methylene group); X8 is an amino acid having an -H on the alpha amino group (e.g., X8 is not an N-alkylated amino acid); X9 is W or Y or a variant thereof (e.g., W or a variant thereof); X10 is absent or a polar amino acid (e.g., T or a variant thereof); X11 is absent or 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)); X12 is C or a variant thereof] Described herein are peptides having the amino acid sequence set forth in: or a pharmaceutically acceptable salt thereof.

[0152] In some embodiments, X2 is F or an unsubstituted phenyl ring of F, selected from the group consisting of -OH, -CN, and -C 1~3 In some embodiments, X2 replaces the phenyl ring with one or two substituents independently selected from alkyl (e.g., -CH3). In some embodiments, X2 replaces the unsubstituted phenyl ring of F with one or two substituents independently selected from -OH, -CN, amino, halogen, -C 1~3 Haloalkyl, and -C 1~3and variants thereof, where F is replaced by a 6-membered heteroaryl ring, optionally substituted with 1 or 2 substituents independently selected from alkyl. In some embodiments, F or variants thereof may be 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.

[0153] 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 linked to the alpha carbon via a carbon (e.g., a methylene group), wherein the 6-, 9-, and 10-membered heteroaryl has one heteroatom (e.g., N), and the 6-, 9-, and 10-membered aryl or heteroaryl may optionally be substituted with one or two substituents independently selected from -CH3, -ethyl, -Cl, and -F).

[0154] In one embodiment, there is provided a peptide having avidity for ephrin type-A receptor 2 (EphA2), comprising the formula (I): X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) [In the formula, X1 is any amino acid (e.g., a D-amino acid); X2 is an amino acid containing an aromatic ring or a substitution thereof, an N-methylated amino acid, or a substitution thereof; X3 is absent or N or a substitution thereof; X4 is absent or any hydrophobic amino acid or substitution thereof; X5 is absent, a hydrophilic amino acid or a substitution thereof, or an amino acid having a functional side chain (e.g., Dab, Dap, K); X6 is absent, a hydrophilic amino acid, an amino acid having an aromatic ring, an N-methylated amino acid thereof, or a substitution thereof; X7 is W or a substitution thereof; X8 is V, a hydrophilic amino acid or a substitution thereof, an N-methylated amino acid, or an amino acid having a functional side chain; X9 is W or a substitution thereof; X10 is absent, T or a substitution thereof; X11 is absent, any hydrophilic amino acid, or an amino acid with a functional side chain; X12 is C or a variant thereof] Described herein are peptides having the amino acid sequence set forth in: or a pharmaceutically acceptable salt thereof.

[0155] 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 or variant thereof containing an aromatic ring, or an N-methylated amino acid thereof; X3 is absent, N or a variant thereof; X4 is absent or any hydrophobic amino acid or variant thereof; X5 is absent, 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, a hydrophilic amino acid, an amino acid containing 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 variant thereof, an N-methylated amino acid, or an amino acid having a functional side chain; X9 is W or a variant thereof; X10 is absent, T or a variant thereof; X11 is absent, any hydrophilic amino acid, or an amino acid with a functional side chain; X12 is C or a substitution thereof.

[0156] In some embodiments, the peptide of formula (I), or a pharmaceutically acceptable salt thereof, X1 is any amino acid; X2 is an amino acid containing an aromatic ring or an N-methylated amino acid thereof; X3 is absent, a hydrophilic amino acid (e.g., N, Q, Cit, K, or a variant thereof), G, Aib, Hgn, or Ala, or a variant thereof (e.g., da); X4 is absent, a hydrophobic amino acid, or a hydrophilic amino acid (e.g., Cit or a variant thereof); X5 is absent, a hydrophilic amino acid, or an amino acid having a functional side chain; X6 is absent, a hydrophilic amino acid, 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 a polar amino acid (e.g., T or a variant thereof); X11 is absent, a hydrophilic amino acid, or an amino acid having a functional side chain; X12 is C or a variant thereof.

[0157] In some embodiments, the peptide of formula (I), or a pharmaceutically acceptable salt thereof, 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, a hydrophilic amino acid (e.g., N, Q, Cit, K, or a variant thereof), G, Aib, Hgn, or Ala, or a variant thereof (e.g., da); X4 is a hydrophobic amino acid or a hydrophilic amino acid (e.g., Cit or a variant thereof); X5 is a hydrophilic amino acid (e.g., Dab, Dap, R, E, or a variant thereof); X6 is absent, a hydrophilic amino acid, an amino acid containing an aromatic ring (e.g., W), or an N-methylated version 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 a hydrophilic amino acid (e.g., T or a variant thereof); X11 is absent or a hydrophilic amino acid; X12 is C or a variant thereof.

[0158] In some embodiments, the peptide of formula (I), or a pharmaceutically acceptable salt thereof, 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, N, Q, Cit or a variant thereof, G, Aib, Hgn, K or a variant thereof, Ala, or da; X4 is absent or linear or branched C 1~5 Alkyl-substituted G, C 3~7 A substituted with cycloalkyl, or Cit or a variant thereof; X5 is absent, a hydrophilic amino acid, or an amino acid having a functional side chain (e.g., Dab, Dap, R, E), where hydrophilic amino acids include L-amino acids including -NH2, -C(O)OH, -NHC(NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3; X6 is absent, a hydrophilic amino acid, F or a variant thereof, Y or a variant thereof, W or a variant thereof, or 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 one or two linear or branched C 1~5 Alkyl-substituted G, C 3~7 A substituted with cycloalkyl, or a hydrophilic amino acid, wherein the hydrophilic amino acid comprises an L-amino acid containing -NH, one or more -OH, -C(O)OH, -NHC(NH)NH, -NHC(O)NH, -C(O)NH, -NHC(O)CH, or the hydrophilic amino acid comprises a zwitterion; X9 is F or a variant thereof, or W or a variant thereof; X10 is absent, Q, Hgn, S or a variant thereof, T or a variant thereof (e.g., linear or branched C 1~5 T, optionally substituted with alkyl, K or a variant thereof, Cit or a variant thereof, or an L-amino acid substituted with -NHC(NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3; X11 is absent, E, Hgn, R or a variant thereof, Cit or a variant thereof, Hgl, K or a variant thereof, D, N, or Q; X12 is C or a variant thereof.

[0159] In some embodiments, a cyclic peptide having avidity for ephrin type-A receptor 2 (EphA2) is provided, comprising the formula (I): X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) [In the formula, X1, X2, X3, X4, X5, X6, and X8 are each independently an amino acid; X7 is W1Me or a variant thereof; X9 is W1Me or a variant thereof; X10 and X11 are each independently absent or an amino acid; X12 is cysteine ​​(C) or a variant thereof. or a pharmaceutically acceptable salt thereof.

[0160] In some embodiments of a peptide of formula (I), or a pharmaceutically acceptable salt thereof, X7 is W1Me, W1MeCl, W1MeBr, Na1, Na12, W1Et, 3Bzf, 3Bzt, F23dC, W1Me7N, or F23dMe; X8 is V, KCOpipzaa, Hse, N, Cit, hCit, KAc, DapAc, OrnAc, T, alT, Aib, Alb, Qglucamine, Hgl, E, Hgn, MeF, 3Py6NH2, W1Me, A, Q, or K; X9 is W1Me, Na11, W1Et, Na121N, 3Bzf, 3Bzt, Na118N, F23dMe, or F23dC.

[0161] In some embodiments of a peptide of formula (I), or a pharmaceutically acceptable salt thereof, X7 is W1Me; X8 is V; and X9 is W1Me.

[0162] In some embodiments of a peptide of formula (I), or a pharmaceutically acceptable salt thereof, 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, N, Q, Cit, G, Aib, Hgn, hCit, norCit, LysAc, OrnAc, Ala, or da; X4 is L, Cbg, Chg, Cba, Cha, Ahx, Dahp, Cit, I, V, norleucine, or norvaline; X5 is Hgl, Hgn, Dab, Dap, DabAc, DapAc, R, hArg, E, or D; X6 is absent, MeF, MeE, Me3Py, Me4Py, MeF4F, MeF4F, MeF4C, or MeY; X7 is W1Me, W1Me7Cl, W1Me7N, W, F, 7-AzaTrp, W7Me, or W1Et; X8 is V, KCOpipzaa, Cit, Qglucamine, hCit, Aib, norleucine, or norvaline; X9 is W1Me, W1Me7Cl, W1Me7N, F23dMe, W1Et, W7Me, W, F, or 7-AzaTrp; X10 is absent, T, Q, S, Hgn, alpha-methylserine, hSer, hThr, N, OrnAc, LysAc, Cit, or hCit; X11 is absent or E, Hgn, R, hArg, Cit, hCit, Hgl, Orn, D, N, Q, DapAc, OrnAc, DabAc, norCit; X12 is C, hCys, CdMe, C3RMe, C3SMe, selenocysteine, dc, or penicillamine.

[0163] In some embodiments, the peptide of formula (I), or a pharmaceutically acceptable salt thereof, X7 is W1Me; X9 is W1Me.

[0164] In some embodiments, a compound of formula (I): X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) or a pharmaceutically acceptable salt thereof, During the ceremony, X1 is any amino acid; X2 is an amino acid or variant thereof containing an aromatic ring, or an N-methylated amino acid thereof; X3 is absent, N or a variant thereof; X4 is any hydrophobic amino acid or variant thereof; X5 is a hydrophilic amino acid or variant thereof; X6 is absent, a hydrophilic amino acid, 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 variant thereof, or an N-methylated amino acid; X9 is W or a variant thereof; X10 is absent, T or a variant thereof; X11 is absent or any hydrophilic amino acid; X12 is C or a variant thereof.

[0165] In one aspect, (a) A cyclic peptide having avidity for ephrin type-A receptor 2 (EphA2), comprising the formula (I): X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) [In the formula, X1 is any D- or L-amino acid; X2 is [ka] (In the formula, Ring A2 is phenyl or a 6-membered heteroaryl (e.g., heteroaryl with 1 or 2 N); 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; where alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally independently selected from one or more R XA may be substituted with; 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 point of attachment to X1; *X3 indicates the point of attachment to X3) having the structure X3 is [ka] (In the formula, 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 point of attachment to X2; and * X4 indicates the point of attachment to X4) having the structure X4 is a hydrophobic amino acid (e.g., an amino acid having four or more carbon atoms in its side chain, including a straight, branched, or cyclic carbon chain), and X4 is C 1~3 may be N-alkylated with an alkyl group; The X5 is [ka] (In the formula, R NX5 is H, —CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; where alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, or heteroalkyl is selected from the group consisting of one or more R XA may optionally be independently substituted with; R X5 -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 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, or heteroalkyl is selected from the group consisting of one or more R XA may be optionally and independently substituted with However, R NX5 and R X5 at least one of which is a moiety selected from -OH, -NH, and -NH- (e.g., -NH-C(=NH)-NH, -CO-NH, -NH, -COOH, -C(OH)-C 0~6 Alkyl, -NH-CO-C 1~6 alkyl); * X4 indicates the point of attachment to X4; * X6 indicates the point of attachment to X6) is a hydrophilic L-amino acid, such as an amino acid having the structure: The X6 is [ka] (e.g., N, F) (In the formula, R NX6is H, C1-C6 alkyl, or C1-C6 haloalkyl; R X6 -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 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is selected from the group consisting of one or more R XA may optionally be independently substituted with; * X5 indicates the point of attachment to X5; * X7 indicates the point of attachment to X7) and; The X7 is [ka] (In the formula, 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 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is selected from the group consisting of one or more R XA may optionally be independently substituted with; kx7 is 0, 1, 2, or 3; mx7 is 0, 1, 2, 3, 4 or 5; * X6 indicates the point of attachment to X6; * X8 indicates the point of attachment to X8) having the structure X8 is an L-amino acid with an -H on the alpha amino group; X9 is [ka] (In the formula, 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 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is selected from the group consisting of one or more RXA may optionally be independently substituted with; kx9 is 0, 1, 2, or 3; mx9 is 0, 1, 2, 3, 4, or 5; * X8 indicates the point of attachment to X8; * XC indicates the point of attachment to (i) X10 or (i) X12 if X10 and X11 are absent. having the structure X10 is absent or an L-amino acid; X11 is absent or is an L-amino acid, with the proviso that if X10 is absent then X11 is also absent; X12 is an L-amino acid with a reactive thiol group, such as Cys and Cys variants; R a are each 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 optionally and independently substituted with one or more R; R bare each 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 optionally and independently substituted with one or more R; R c and R d are each 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 optionally and independently 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; R and R XA are each independently 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 Rd , -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. a peptide having an amino acid sequence of (b) (i) a metal chelator configured to bind a radionuclide; or (ii) a covalently bound radionuclide; and (c) (i) optionally, a linker connecting the peptide to a metal chelator; or (ii) optionally, a linker connecting the peptide to a covalently bound radionuclide. Described herein is a radiopharmaceutical conjugate comprising:

[0166] In some embodiments, X3 is [ka] wherein the definitions for the groups are provided herein. In some embodiments, A2 has the structure: In some embodiments, A2 is phenyl. In some embodiments, A2 is 6-membered heteroaryl. In some embodiments, R X2 are each independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -SH, -S(=O)2NR 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; wherein alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, or heteroalkyl is selected from the group consisting of 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.

[0167] In some embodiments, X3 is [ka] wherein the definitions for the groups are provided herein. In some embodiments, kx3 is 0. In some embodiments, kx3 is 1. In some embodiments, kx3 is 2. In some embodiments, kx3 is 3. In some embodiments, 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.

[0168] In some embodiments, X5 is [ka] wherein the definitions for the groups are provided herein. In some embodiments, R NX5is H. In some embodiments, R NX5 is methyl. In some embodiments, R X5 -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 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, or heteroalkyl is selected from the group consisting of one or more R XA In some embodiments, R NX5 and R X5 At least one of the groups is --NH-C(=NH)-NH2, --CO-NH2, --NH2, --COOH, --C(OH)-C 0~6 Alkyl, -NH-CO-C 1~6 In some embodiments, R NX5 and R X5 At least one of the groups comprises a moiety selected from -CO-NH2.

[0169] In some embodiments, X6 is [ka] wherein the definitions for the groups are provided herein. In some embodiments, R NX6 is H. In some embodiments, R NX6 is methyl. In some embodiments, R X6is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; where alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, or heteroalkyl is selected from the group consisting of one or more R XA In some embodiments, R X6 is an optionally substituted C1-C6 alkyl.

[0170] In some embodiments, X7 is [ka] wherein the definitions for the groups are provided herein. In some embodiments, ring A7 is a 6-membered aryl or heteroaryl. In some embodiments, ring A7 is a 9- or 10-membered bicyclic aryl or heteroaryl. In some embodiments, ring A7 is an optionally substituted bicyclic heteroaryl. In some embodiments, the 6-, 9-, or 10-membered heteroaryl has one heteroatom selected from N, O, and S. In some embodiments, ring A7 is 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, R X7 are each independently halogen, -CN, -NO2, -OH, -OR a , amino, C1-C6 alkyl, or C1-C6 haloalkyl. X7 are each independently 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 Rd , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; wherein alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, or heteroalkyl is selected from the group consisting of one or more R XA In some embodiments, R X7 are each 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.

[0171] In some embodiments, X7 is W1Me, Na11, Na12, W1Et, Na121N, 3Bzf, 3Bzt, Na115N, Na114N, Na124N, Na128N, F23dMe, F23dC, W1Me7N, or W1Me7Cl. In some embodiments, X7 is W1Me, F23dMe, or W1Me7Cl.

[0172] In some embodiments, X9 is [ka] wherein the definitions for the groups are provided herein. In some embodiments, X9 has the structure: [ka] (In the formula, R X9 are each independently selected from -OH, CN, NH, C-C alkyl, -Cl, -F, -Br, -CONH, and -SOF. is.

[0173] In some embodiments, ring A9 is an optionally substituted bicyclic heteroaryl. 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, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, mx9 is 0. In some embodiments, mx9 is 1. In some embodiments, mx9 is 2.

[0174] In some embodiments, R X9 are each 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 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. X9 are each independently halogen, -CN, -NO2, -OH, -ORa , amino, C1-C6 alkyl, or C1-C6 haloalkyl. 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.

[0175] In some embodiments, X9 is W1Me, W, Na11, W1Et, Na121N, 3Bzf, 3Bzt, Na114N, Na118N, F23dMe, F23dC, or W1Et. In some embodiments, X9 is W1Me or F23dMe.

[0176] In some embodiments, ring A2 is a 6-membered heteroaryl containing 1 or 2 N.

[0177] In some embodiments, 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 It is alkyl.

[0178] In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (III-1), (III-2), (III-1-RI), and (III-2-RI), X1 is any amino acid (e.g., a D-amino acid). In some embodiments, X1 is any one of the standard amino acids. In some embodiments, X1 is an unnatural 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-5F. In some embodiments, a metal chelator or linker is attached to X1. In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (III-1), (III-2), (III-1-RI), and (III-2-RI), X1 is any amino acid. In some embodiments, X1 is an amino acid (e.g., a D-amino acid). In some embodiments, X1 is da, df3CON, dkCOpipzaa, dahp, dDab-NH2-Ph3-SO2F, dDap-NH2-Ph3-SO2F, dDap-NH2-Ph4-SO2F, dCit, Aib, G, norvaline, norleucine, or dhAla. X1 is da. X1 is df3CON. X1 is dkCOpipzaa. X1 is dahp. X1 is dDab-NH2-Ph3-SO2F. X1 is dDap-NH2-Ph3-SO2F. X1 is dCit. X1 is Aib. X1 is G. X1 is norvaline. X1 is norleucine. X1 is dhAla. In some embodiments, X1 is F. In some embodiments, X1 is chloroacetylated. In some embodiments, X1 is bromoacetylated. In some embodiments, X1 comprises a chloroacetyl group.In some embodiments, X 1 comprises a bromoacetyl group. In some embodiments, in the cyclic peptide, the chloroacetyl or bromoacetyl group has reacted and is no longer present in X 1 .

[0179] 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 standard amino acid. In some embodiments, X2 is an unnatural amino acid. In some embodiments, X2 is an aromatic amino acid or variant thereof. In some embodiments, X2 is V. In some embodiments, X2 is an N-methylated amino acid or variant thereof. In some embodiments, X2 is an N-alkylated amino acid or variant thereof. In some embodiments, X2 is an amino acid comprising an aryl group. In some embodiments, X2 is an amino acid comprising an optionally substituted phenyl group. In some embodiments, X2 is an amino acid comprising an optionally substituted naphthyl group. In some embodiments, X2 is an amino acid comprising a heteroaryl group. In some embodiments, X2 is an amino acid comprising an optionally substituted monocyclic heteroaryl group. In some embodiments, X2 is an amino acid comprising an optionally substituted bicyclic heteroaryl group. In some embodiments, the aryl or heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from -CH3, -ethyl, -Cl, and -F. In some embodiments, the aryl or heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from -OH, oxo, halogen, CN, amino, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl. In some embodiments, X2 is F, or an unsubstituted phenyl ring of F is optionally substituted with (i) -OH, -CN, -C 1~3 a phenyl ring substituted by one or two substituents each independently selected from alkyl, or (ii) —OH, —CN, —C 1~3and variants thereof, where X2 is replaced by a 6-membered heteroaryl ring optionally substituted by 1 or 2 substituents independently selected from alkyl, wherein F or variants thereof may be N-methylated. In some embodiments, X2 is Me3Py. 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 aryl or heteroaryl. In some embodiments, X2 is histidine (H). In some embodiments, X2 is phenylalanine, tryptophan, tyrosine, or variants thereof. In some embodiments, X2 is phenylalanine or variants thereof. In some embodiments, X2 is tryptophan or a variant thereof. In some embodiments, X2 is W1Me. In some embodiments, X2 is tyrosine or a variant thereof. In some embodiments, X2 is absent. In some embodiments, a metal chelator or linker is attached to X2. In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (Ia), (Ib), (Ic), (III-2), (III-1-RI), and (III-2-RI), X2 is an amino acid comprising an aromatic ring or an N-methylated amino acid thereof. In some embodiments, X2 is an N-methylated amino acid. In some embodiments, X2 is an amino acid comprising an aromatic ring. In some embodiments, X2 is an N-methylated amino acid comprising an aromatic ring. In some embodiments, X2 is F or a variant thereof, Y or a variant thereof, or W or a variant thereof, or an N-methylated amino acid thereof. In some embodiments, X2 is F or a variant thereof. In some embodiments, X2 is N-methyl F or a variant thereof.In some embodiments, X2 is Y or a variant thereof. In some embodiments, X2 is N-methyl Y or a variant thereof. In some embodiments, X2 is W or a variant thereof. In some embodiments, X2 is N-methyl W or a variant thereof. In some embodiments, X2 is MeF, Me3Py, MeF3CON, MeF3F, Me4Py, or MeY(Me). In some embodiments, X2 is MeF. In some embodiments, X2 is Me3Py. In some embodiments, X2 is MeF3CON. In some embodiments, X2 is MeF3F. In some embodiments, X2 is Me4Py. In some embodiments, X2 is MeY. In some embodiments, X2 is MeY(Me).

[0180] In some embodiments of Formula (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 standard amino acid. In some embodiments, X3 is an unnatural 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 asparagine. In some embodiments, X3 is absent. In some embodiments of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (Ia), (III-2), (III-1-RI), and (III-2-RI), X3 is absent. In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (Ia), (III-2), (III-1-RI), and (III-2-RI), X3 is a hydrophilic amino acid (e.g., N, Hgn, Q, Cit, K, or a variant thereof), glycine (G), alanine (A), or a variant thereof (e.g., da, 2-aminoisobutyric acid (Aib)). In some embodiments, X3 is a hydrophilic amino acid. In some embodiments, X3 is an amino acid 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 comprising a charged side chain (e.g., K or a variant thereof), an amino acid comprising a polar, uncharged side chain (e.g., Q, Cit, N, or a variant thereof), or G, A, or a variant thereof. In some embodiments, X3 is an amino acid comprising a charged side chain. In some embodiments, X3 is an amino acid comprising a polar, uncharged side chain.In some embodiments, X3 has a zwitterionic (e.g., KCOpipzaa) side chain. In some embodiments, X3 is zwitterionic. In some embodiments, X3 comprises an -OH, -COOH, -NH-, or NH2 moiety. In some embodiments, X3 comprises -OH, -C(O)OH, -NHC(=NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3. In some embodiments, X3 is C1-C6 hydroxyl, 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 1~6and a variant thereof, including an alkyl side chain. In some embodiments, X3 is absent, a hydrophilic amino acid (e.g., N, Q, Cit, K, or a variant thereof), G, Ala, or a variant thereof (e.g., da, Aib). In some embodiments, X3 is a D-amino acid such as N, Q, K, G, S, T, E, Aib, Hcit, Cit, Hgn, KCOpipzaa, Har, Nmm, Ndm, Ala, Hgl, 3Py6NH2, or da, and a variant thereof, including variations such as Qglucamine. In some embodiments, X3 is absent, N, Q, Cit, or a variant thereof, G, Aib, Hgn, K, or a variant thereof, or Ala or a variant thereof (e.g., da). In some embodiments, X3 is absent, N, Q, Cit, G, Aib, Hgn, hCit, norCit, LysAc, OrnAc, Ala, or da. In some embodiments, X3 is N or a variant thereof. In some embodiments, X3 is N. In some embodiments, X3 is Q or a variant thereof. In some embodiments, X3 is Q. In some embodiments, X3 is Cit or a variant thereof. In some embodiments, X3 is Cit, hCit, or norCit. In some embodiments, X3 is Cit. In some embodiments, X3 is hCit. In some embodiments, X3 is norCit. In some embodiments, X3 is K or a substitution 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 X. In some embodiments, a covalently attached radionuclide or linker is attached to X. In some embodiments, X is directly attached to X.

[0181] 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 variant thereof. In some embodiments, X4 is an unnatural amino acid. In some embodiments, X4 is a standard amino acid. In some embodiments, X4 is leucine. In some embodiments, X4 comprises four or more carbon atoms in its side chain, including a linear, branched, or cyclic carbon chain. In some embodiments, X4 comprises four or more consecutive carbon atoms in its side chain. In some embodiments, X4 comprises an ethylene, propylene, or butylene group in its 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 substitutions thereof. In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (III-1), (III-2), (III-1-RI), and (III-2-RI), X4 is an amino acid comprising a hydrophobic side chain (e.g., L), an amino acid comprising a polar, uncharged side chain (e.g., Cit or a variant thereof). In some embodiments, X4 is an amino acid comprising a hydrophobic side chain. In some embodiments, X4 is an amino acid comprising a polar, uncharged side chain. In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (III-1), (III-2), (III-1-RI), and (III-2-RI), X4 is absent, a hydrophobic amino acid, or a hydrophilic amino acid (e.g., Cit or a variant thereof). In some embodiments, X4 is absent, a linear or branched C1~5 Alkyl-substituted G, C 3~7 In some embodiments, X4 is A substituted with cycloalkyl, or Cit or a variant thereof. In some embodiments, X4 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 a linear or branched C 1~5 In some embodiments, X4 is G substituted with alkyl. In some embodiments, X4 is G substituted with methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, or isopentyl. In some embodiments, X4 is C 3~7X4 is A substituted with cycloalkyl. 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 may be N-methylated. In some embodiments, a metal chelator or linker is attached to X4. In some embodiments, X1 is directly attached to X4. In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (III-1), (III-2), (III-1-RI), and (III-2-RI), X4 is a hydrophilic amino acid. In some embodiments, X4 is an amino acid containing an -OH, -NH2, -C(O)OH, -NHC(=NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3 group. 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 a zwitterion. In some embodiments, X4 comprises an -OH, -COOH, -NH-, or NH2 moiety.In some embodiments, X4 comprises -OH, -C(O)OH, -NHC(=NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3. In some embodiments, X4 comprises C1-C6 hydroxyl, 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 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 hydrophobic amino acid. In some embodiments, X4 is linear or branched and comprises at least 4 consecutive carbon atoms. In some embodiments, X4 is linear or branched and comprises at least 5 consecutive carbon atoms. In some embodiments, X4 comprises a propylene moiety in the side chain. In some embodiments, X4 comprises a butylene moiety in the side chain.

[0182] 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-naturally occurring 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 standard 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 a D-amino acid such as N, Q, K, G, S, T, E, Aib, Hcit, Cit, Hgn, KCOpipzaa, Har, Nmm, Ndm, Ala, Hgl, 3Py6NH2, or da, and variants thereof, including variations such as Qglucamine. In some embodiments, X5 is Hgn, N, Qglucamine, KCOpipzaa, Hgl, Nmm, Ndm, KCOpipzaa, K, S, T, or E. In some embodiments, X5 is Hgn. In some embodiments, X5 is asparagine (N). In some embodiments, X5 is Qglucamine. In some embodiments, X5 is Hgl. In some embodiments, X5 is Nmm. In some embodiments, X5 is Ndm. In some embodiments, X5 is KCOpipzaa. In some embodiments, X5 is Dab. In some embodiments, X5 is S. In some embodiments, X5 is K. In some embodiments, X5 is absent. In some embodiments of 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), X5 is an amino acid comprising a charged side chain (e.g., E, Hgl, D, or a variant thereof) or an amino acid comprising a polar, uncharged side chain (e.g., Q, Cit, Hgn, N, or a variant thereof).In some embodiments, X5 is an amino acid comprising a charged side chain. In some embodiments, X5 is an amino acid comprising a polar, uncharged side chain. In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (Ia), (Ib), (III-2), (III-1-RI), and (III-2-RI), X5 is absent, a hydrophilic amino acid, or a variant thereof. In some embodiments, X5 is absent, a hydrophilic amino acid, or an amino acid having a functional side chain (e.g., Dab, Dap, R, E), where hydrophilic amino acids include L-amino acids comprising -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 comprising -NH2, -C(O)OH, -NHC(NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3. In some embodiments, X5 is an L-amino acid comprising -NH2, -C(O)OH, -NHC(NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3. In some embodiments, X5 is Hgl. In some embodiments, X5 is Hgn. In some embodiments, X5 is Dab. In some embodiments, X5 is Dap. In some embodiments, X5 is DabAc. In some embodiments, X5 is DapAc. In some embodiments, X5 is R or a variant thereof. In some embodiments, X5 is R or hArg. In some embodiments, X5 is R. In some embodiments, X5 is hArg. In some embodiments, X5 is E. In some embodiments, X5 is hCit. In some embodiments, X5 is G. In some embodiments, X5 is D. In some embodiments, a metal chelator or linker is attached to X5. In some embodiments, a covalently attached radionuclide or linker is attached to X5.In some embodiments, X1 is directly linked to X5.

[0183] In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ic), (III-1), (III-2), (III-1-RI), and (III-2-RI), X6 is any amino acid. In some embodiments, X6 is a standard amino acid. In some embodiments, X6 is an unnatural amino acid. In some embodiments, X6 is a hydrophilic amino acid or an amino acid having an aromatic ring, an N-methylated amino acid thereof, or a substitution thereof. In some embodiments, X6 is an amino acid having an aromatic ring or a substitution thereof. In some embodiments, X6 is an amino acid comprising an aryl group. In some embodiments, X6 is an amino acid comprising an optionally substituted phenyl group. In some embodiments, X6 is an amino acid comprising an optionally substituted naphthyl group. In some embodiments, X6 is an amino acid comprising a heteroaryl group. In some embodiments, X6 is an amino acid comprising an optionally substituted monocyclic heteroaryl group. In some embodiments, X6 is an amino acid comprising an optionally substituted bicyclic heteroaryl group. In some embodiments, the aryl or heteroaryl is optionally substituted with one, two, or three substituents independently selected from -CH3, -ethyl, -Cl, and -F. In some embodiments, the aryl or heteroaryl is optionally substituted with one, two, or three substituents independently selected from -OH, oxo, 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 substitution thereof. In some embodiments, X6 is an amino acid having an aromatic ring or a substitution thereof. In some embodiments, X6 is an N-methylated amino acid or a substitution thereof. In some embodiments, X6 is MeE. In some embodiments, X6 is N. In some embodiments, X6 is MeN. In some embodiments, X6 is Me3Py. In some embodiments, X6 is MeF. In some embodiments, X6 is Qglucamine. In some embodiments, X6 is MeF4C.In some embodiments, X6 is absent. In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ic), (III-1), (III-2), (III-1-RI), and (III-2-RI), X6 is an amino acid comprising a charged side chain (e.g., E, Hgl, D, or a variant thereof) or an amino acid comprising a polar, uncharged side chain (e.g., Q, Cit, Hgn, N, or a variant). In some embodiments, X6 is an amino acid comprising a charged side chain. In some embodiments, X6 is an amino acid comprising a polar, uncharged side chain. In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (Ia), (Ic), (III-2), (III-1-RI), and (III-2-RI), X6 is absent, a hydrophilic amino acid, an amino acid containing an aromatic ring, or an N-methylated amino acid thereof. In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (III-1), (III-2), (III-1-RI), and (III-2-RI), X6 is a hydrophilic amino acid. In some embodiments, X6 is an amino acid comprising an -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 comprises an -OH, -COOH, -NH-, or NH2 moiety. In some embodiments, X6 comprises -OH, -C(O)OH, -NHC(=NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3. In some embodiments, X6 is C1-C6 hydroxyl, 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 1~6In some embodiments, X6 is absent, a hydrophilic amino acid, F or a variant thereof, Y or a variant thereof, W or a variant thereof, or 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. In some embodiments, X6 is absent, MeF, MeE, Me3Py, Me4Py, MeF4F, MeF4C, or MeY. In some embodiments, X6 is MeE, MeN, Me3Py, MeF, MeF4C, or N. In some embodiments, X6 is absent. In some embodiments, X6 is a hydrophilic amino acid. In some embodiments, X6 is an amino acid comprising -NH2, -C(O)OH, -NHC(NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3. In some embodiments, X6 is E or an N-methylated amino acid thereof. In some embodiments, X6 is E. In some embodiments, X6 is MeE. In some embodiments, X6 is an aromatic ring-containing amino acid or an N-methylated amino acid thereof. In some embodiments, X6 is an optionally substituted phenyl-containing amino acid. In some embodiments, X6 is an optionally substituted heteroaryl-containing amino acid. 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 X. In some embodiments, X is attached directly to X.

[0184] 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 standard amino acid. In some embodiments, X7 is an unnatural 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 substitution thereof. In some embodiments, X7 is an amino acid comprising an aryl group. In some embodiments, X7 is an amino acid comprising an optionally substituted phenyl group. In some embodiments, X7 is an amino acid comprising an optionally substituted naphthyl group. In some embodiments, X7 is an amino acid comprising a heteroaryl group. In some embodiments, X7 is an amino acid comprising an optionally substituted monocyclic heteroaryl group. In some embodiments, X7 is an amino acid comprising an optionally substituted bicyclic heteroaryl group. In some embodiments, the aryl or heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from -CH3, -ethyl, -Cl, and -F. In some embodiments, the aryl or heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from -OH, oxo, halogen, CN, amino, C1-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 alpha carbon via a carbon (e.g., a methylene group), where the 6-, 9-, and 10-membered heteroaryl has one heteroatom (e.g., N), and the 6-, 9-, and 10-membered aryl or heteroaryl may optionally be substituted with one or two substituents independently selected from -CH3, -ethyl, -Cl, and -F).In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (III-1), (III-2), (III-1-RI), and (III-2-RI), X7 is an amino acid comprising an aromatic ring. In some embodiments, X7 is an amino acid comprising an aromatic ring (e.g., W or a variant thereof). In some embodiments, X7 is F or a variant thereof, or W or a variant thereof. In some embodiments, X7 is W1Me, W1Me7Cl, W1Me7N, W, F, 7-AzaTrp, W7Me, or W1Et. In some embodiments, X7 is F or a variant thereof. In some embodiments, X7 is F. In some embodiments, X7 is W or a variant thereof. In some embodiments, X7 is Na11, Na12, W1Et, Na121N, 3Bzf, 3Bzt, Na15N, Na14N, Na124N, Na128N, 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 attached radionuclide or linker is attached to X7. In some embodiments, X1 is directly attached to X7.

[0185] In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (III-1), (III-2), (III-1-RI), and (III-2-RI), X8 is any amino acid. In some embodiments, X8 is any one of the standard amino acids. In some embodiments, X8 is an unnatural amino acid. In some embodiments, X8 is V, a hydrophilic amino acid, an N-methylated amino acid, or a substitution 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 substitution thereof. In some embodiments, X8 is an N-alkylated amino acid or a substitution thereof. In some embodiments, X8 is KCOpipzaa. In some embodiments, X8 is K. In some embodiments, X8 is valine (V). In some embodiments, X8 is Qglucamine. In some embodiments, X8 is Cit. In some embodiments, X8 is hCit. In some embodiments, X8 is absent. In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (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 having a functional side chain. In some embodiments, X8 is one or two linear or branched C 1~5 Alkyl-substituted G, C 3~7X8 is a cycloalkyl-substituted A or a hydrophilic amino acid, where the hydrophilic amino acid comprises an L-amino acid comprising one or more of -NH2, -OH, -C(O)OH, -NHC(NH)NH2, -NHC(O)NH2, -C(O)NH2, -NHC(O)CH3, or the hydrophilic amino acid comprises a zwitterion. In some embodiments, X8 is V, A, E, N, K, Qglucamine, KCOpipzaa, Q, Hse, N, Cit, Hcit, Kac, DapAc, OrnAc, T, a1T, Aib, Alb, or 3Py6NH2. In some embodiments, X8 is A, E, N, K, Qglucamine, KCOpipzaa, Q, Hse, N, Cit, Hcit, Kac, DapAc, OrnAc, T, a1T, Aib, Alb, or 3Py6NH2. In some embodiments, X8 is KCOpipzaa, N, Cit, Qglucamine, hCit, K, KAc, Aib, Alb, DapAc, OrnAc, A, T, a1T, norleucine, norvaline, Hgl, E, Hgn, Q, I, or L. In certain embodiments, X8 is KCOpipzaa, V, Qglucamine, Cit, Hcit, K, or 3Py6NH2. In certain embodiments, X8 is KCOpipzaa, Qglucamine, Cit, Hcit, K, or 3Py6NH2. In some embodiments, X8 is V, KCOpipzaa, Cit, Qglucamine, hCit, Aib, Alb, norleucine, or norvaline. In some embodiments, X8 is KCOpipzaa, Cit, Qglucamine, hCit, Aib, Alb, norleucine, or norvaline. In some embodiments, X8 is KCOpipzaa, N, Cit, hCit, KAc, DapAc, OrnAc, A, T, a1T, Aib, Alb, Qglucamine, Hgl, Q, E, Hgn, or K. In some embodiments, X8 is a hydrophobic amino acid. In some embodiments, X8 is a linear or branched C 1~5 In some embodiments, X8 is G substituted with methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and isopentyl. In some embodiments, X8 is C3~7 X8 is A 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 a zwitterion. In some embodiments, X8 is Cit or a variant thereof. In some embodiments, X8 is Cit or hCit. In some embodiments, X8 is KCOpipzaa. In some embodiments, X8 is Qglucamine. In some embodiments, a metal chelator or linker is attached to X8. In some embodiments, a covalently attached radionuclide or linker is attached to X8. In some embodiments, X1 is directly linked to X8.

[0186] 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), X is W or a variant thereof. In some embodiments, X is a standard amino acid. In some embodiments, X is an unnatural amino acid. In some embodiments, X is an N-alkylated amino acid. In some embodiments, X is WMe, WMeCl, FdMe, NaI, NaI, WIEt, NaIIN, 3Bzf, 3Bzt, NaIIN, NaIIN, NaIIN, NaIIN, NaIIN, FdC, or WMeN. In some embodiments, X is WMe or FdMe. 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 substitution 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, X is an amino acid containing an optionally substituted monocyclic heteroaryl group. In some embodiments, X is an amino acid containing an optionally substituted bicyclic heteroaryl group. In some embodiments, the aryl or heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from -CH, -ethyl, -Cl, and -F.In some embodiments, the aryl or heteroaryl may be optionally substituted with one, two, or three substituents independently selected from -OH, oxo, 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 a 6-, 9-, or 10-membered aryl or heteroaryl, or an amino acid having a 9- or 10-membered bicyclic aryl or heteroaryl linked to the alpha carbon via a carbon (e.g., a methylene group), where the 6-, 9-, and 10-membered heteroaryl has one heteroatom (e.g., N), and the 6-, 9-, and 10-membered aryl or heteroaryl may be optionally substituted with one or two substituents independently selected from -CH3, -ethyl, -Cl, and -F). In some embodiments, X9 is an amino acid containing an aromatic ring (e.g., W or a variant thereof). In some embodiments, X9 is F or a variant thereof, or W or a variant thereof. In some embodiments, X9 is W1Me, W1Me7Cl, W1Me7N, F23dMe, W1Et, W7Me, W, F, or 7-AzaTrp. In some embodiments, X9 is F or a variant thereof. In some embodiments, X9 is F or F23dMe. In some embodiments, X9 is F. In some embodiments, X9 is F23dMe. In some embodiments, X9 is W or a variant thereof. In some embodiments, X9 is W1Me, W1Me7Cl, W1Me7N, W, 7-AzaTrp, W7Me, or W1Et. In some embodiments, X9 is W1Me or F23dMe. In some embodiments, X9 is W1Me. In some embodiments, X9 is W1Me7Cl. In some embodiments, X9 is W1Me7N. In some embodiments, X9 is W. In some embodiments, X9 is 7-AzaTrp. In some embodiments, X9 is W7Me. In some embodiments, X9 is W1Et. In some embodiments, a metal chelator or linker is attached to X9. In some embodiments, a covalently attached radionuclide or linker is attached to X9. In some embodiments, X1 is directly attached to X9.

[0187] 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 standard amino acid. In some embodiments, X10 is an unnatural amino acid. In some embodiments, X10 is threonine (T). In some embodiments, X10 is absent. In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (III-1-RI), and (III-2-RI), X10 is absent or is a polar amino acid (e.g., T or a variant thereof). In some embodiments, X10 is absent, Q, Hgn, S or a variant thereof, linear or branched C 1~5 X is an L-amino acid substituted with -NHC(NH)NH, -NHC(O)NH, -C(O)NH, or -NHC(O)CH, optionally substituted with alkyl. In some embodiments, X is absent, T, Q, S, Hgn, alpha-methylserine, hSer, hThr, N, OrnAc, LysAc, Cit, or hCit. In some embodiments, X is absent. In some embodiments, X is a polar amino acid. In some embodiments, X is Q. In some embodiments, X is Hgn. In some embodiments, X is S or a variant thereof. In some embodiments, X is S, alpha-methylserine, or hSer. In some embodiments, X is S. In some embodiments, X is alpha-methylserine. In some embodiments, X is hSer. In some embodiments, X10 is a linear or branched C 1~5X10 is T or a variant thereof, optionally substituted with alkyl. 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 X 10. In some embodiments, X 1 is attached directly to X 10.

[0188] In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (III-1-RI), and (III-2-RI), X11 is absent, a hydrophilic amino acid, or a substitution thereof. In some embodiments, X11 is serine, threonine, tyrosine, asparagine, glutamine, or a substitution thereof. In some embodiments, X11 is a standard amino acid. In some embodiments, X11 is an unnatural amino acid. In some embodiments, X11 is Hgn. In some embodiments, X11 is K. In some embodiments, X11 is 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 Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (III-1-RI), and (III-2-RI), X11 is absent, a hydrophilic amino acid, or an amino acid having a functional side chain. In some embodiments, X11 is a hydrophilic amino acid. In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (III-1-RI), and (III-2-RI), X11 is an amino acid comprising a charged side chain (e.g., E, Hgl, D, R, hArg, K, or a variant thereof) or an amino acid comprising a polar, uncharged side chain (e.g., Q, Cit, Hgn, N, or a variant thereof). In some embodiments, X11 is an amino acid comprising a charged side chain. In some embodiments, X11 is an amino acid comprising a polar, uncharged side chain.In some embodiments, X11 is an amino acid comprising an -OH, -NH2, -C(O)OH, -NHC(=NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3 group. 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 a zwitterion. In some embodiments, X11 comprises 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 is C1-C6 hydroxyl, 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 1~6In some embodiments, X11 is absent, E, Hgn, R or a variant thereof, Cit or a variant thereof, Hgl, K or a variant thereof, D, N, or Q. In some embodiments, X11 is absent, E, Hgn, R, hArg, Cit, hCit, Hgl, Orn, D, N, Q, DapAc, OrnAc, DabAc, or norCit. In some embodiments, X11 is absent, arginine (R), asparagine (N), aspartic acid (D), glutamine (Q), lysine (K), or a non-natural hydrophilic amino acid. In some embodiments, X11 is absent, Hgn, R, hArg, Cit, hCit, Hgl, Orn, D, N, Q, DapAc, OrnAc, DabAc, or norCit. In some embodiments, X11 is Hgn, R, hArg, Cit, hCit, Hgl, Orn, D, N, Q, DapAc, OrnAc, DabAc, or norCit. In some embodiments, X11 is a D-amino acid such as Q, K, G, S, T, E, Aib, Hcit, Cit, Hgn, KCOpipzaa, Har, Nmm, Ndm, Ala, Hgl, 3Py6NH2, or da, and variants thereof, including variations such as Qglucamine. In some embodiments, X11 is a D-amino acid such as Q, K, G, S, T, Aib, Hcit, Cit, Hgn, KCOpipzaa, Har, Nmm, Ndm, Ala, Hgl, 3Py6NH2, or da, and variants thereof, including variations such as Qglucamine. In some embodiments, X11 is Hgn, N, R, Har, Nmm, Ndm, E, or K. In some embodiments, X11 is Hgn, N, R, Har, Nmm, Ndm, or K. In some embodiments, X11 is absent. In some embodiments, X11 is a hydrophilic amino acid. In some embodiments, X11 is E. In some embodiments, X11 is Hgn. In some embodiments, X11 is R or a variant thereof. In some embodiments, X11 is R or hArg. In some embodiments, X11 is R. In some embodiments, X11 is hArg.In some embodiments, X11 is Cit or a variant thereof. In some embodiments, X11 is Cit, hCit, or norCit. In some embodiments, X11 is Cit. In some embodiments, X11 is hCit. In some embodiments, X11 is norCit. In some embodiments, X11 is Hgl. In some embodiments, X11 is K or a variant thereof. In some embodiments, X11 is K, Orn, OrnAc, DabAc, or DapAc. In some embodiments, X11 is K. In some embodiments, X11 is Orn. ​​In some embodiments, X11 is OrnAc. In some embodiments, X11 is DabAc. In some embodiments, X11 is DapAc. In some embodiments, X11 is D, N, or Q. In some embodiments, X11 is D. In some embodiments, X11 is N. In some embodiments, X11 is Q. In some embodiments, a metal chelator or linker is attached to X11. In some embodiments, a covalently attached radionuclide or linker is attached to X11. In some embodiments, X1 is attached directly to X11.

[0189] In some embodiments of Formula (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 standard amino acid. In some embodiments, X12 is an unnatural amino acid. In some embodiments, X12 is cysteine. In some embodiments, X12 is a cysteine ​​substitute. 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 Formula (I), (I-5), (Ia), (Ib), (Ic), (III-2), and (III-2-RI), X12 is C or a variant thereof. In some embodiments, 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 attached radionuclide or linker is attached to X12. In some embodiments, X1 is directly attached to X12.

[0190] In some embodiments, the peptide of formula (I) has the formula (I-1): [ka] (In the formula, R 1 is selected from the group consisting of NH2 and OH; R 2 is H or C 1~3 selected from the group consisting of alkyl; R 3 is H or C 1~3 selected from the group consisting of alkyl; The points of attachment to the metal chelator or linker are not shown; X1-X11 are as described in formula (I). or a pharmaceutically acceptable salt thereof.

[0191] In some embodiments, the peptide of formula (I-1) is a peptide of formula (I-2): [ka] or a pharmaceutically acceptable salt thereof.

[0192] In some embodiments, the peptide of formula (I-1) is a peptide of formula (I-3): [ka] or a pharmaceutically acceptable salt thereof.

[0193] In some embodiments, the peptide of formula (I-1) is a peptide of formula (I-4): [ka] or a pharmaceutically acceptable salt thereof.

[0194] 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 In some embodiments of formula (I-1), (I-2), (I-3), or (I-4), R 1 is attached to the linker or metal chelator. In some embodiments, the linker or metal chelator is attached to the group R 1 The peptide is bound via

[0195] In some embodiments of formula (I-1), (I-2), (I-3), or (I-4), R2 is H. In some embodiments of formula (I-1), (I-2), (I-3) or (I-4), R 2 is C 1~3 In some embodiments of formula (I-1), (I-2), (I-3), or (I-4), R 2 is methyl.

[0196] 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), R3 is C1-3 alkyl. In some embodiments of Formula (I-1), (I-2), (I-3) or (I-4), R 3 is methyl.

[0197] In some embodiments, the peptide of formula (I) has the formula (I-5): [ka] (wherein X1 to X12 have the definitions described above, and Lcyc is a ring-closing group that covalently connects X1 to X12). or a pharmaceutically acceptable salt thereof.

[0198] In some embodiments, Lcyc is a group selected from Table 4B. In some embodiments, Lcyc is formed by reacting a first and second functional group in Table 4C.

[0199] In some embodiments, a compound of formula (I): X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) or a pharmaceutically acceptable salt thereof, During the ceremony, X1 is any amino acid (e.g., a D-amino acid); X2 is an amino acid or variant thereof containing an aromatic ring, or an N-methylated amino acid thereof; X3 is N or a variant thereof; X4 is any hydrophobic amino acid or variant thereof; X5 is a hydrophilic amino acid or variant thereof; X6 is a hydrophilic amino acid or an amino acid having an aromatic ring, or an N-methylated version thereof; X7 is W or a variant thereof; X8 is V or a hydrophilic amino acid or variant thereof; X9 is W or a variant thereof; X10 is T or a variant thereof; X11 is any hydrophilic amino acid; X12 is C or a variant thereof.

[0200] In some embodiments of formula (I), X1 is a D-amino acid (such as da, df3CON, dahp, or dkCOpipzaa); X2 is an N-methylated phenylalanine or a variant thereof (e.g., 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), Qglucamine, KCOpipzaa, Hgl, Nmm, Ndm, or lysine (K); X6 is asparagine (N) or N-methylated glutamic acid (E), N-methylated asparagine, N-methylated phenylalanine (F) or a substitution thereof (such as Qglucamine, MeE, MeN, Me3Py, MeF, MeF4C, or N); X7 is W1Me, W1Me7Cl, or W1Me7N; X8 is KCOpipzaa, V, Qglucamine, Cit, Hcit, or K; X9 is W1Me or F23dMe; X10 is T; X11 is hArg, hCit, citrulline (Cit), A Hgn, asparagine (N), arginine (R), Har, Nmm, Ndm, glutamic acid (E), lysine (K); X12 is a cysteine.

[0201] In some embodiments, the amino acid of formula (I) has formula (Ia): X1-X2-X3-X4-X5-X6-X7-X8-X9-X12 Formula (Ia) or a pharmaceutically acceptable salt thereof.

[0202] In some embodiments, the amino acid of formula (I) has formula (Ib): X1-X2-X4-X5-X7-X8-X9-X12 Formula (Ib) or a pharmaceutically acceptable salt thereof.

[0203] In some embodiments, the amino acid of formula (I) has formula (Ic): X1-X2-X6-X7-X8-X9-X12 Formula (Ic) or a pharmaceutically acceptable salt thereof.

[0204] In some embodiments, the peptides described herein have the formula (Ia): X1-X2-X3-X4-X5-X6-X7-X8-X9-X12 Formula (Ia) [In the formula, X1 is any amino acid (e.g., a D-amino acid); X2 is an amino acid or variant thereof containing an aromatic ring, or an N-methylated amino acid thereof; X3 is N or a variant thereof; X4 is any hydrophobic amino acid or variant thereof; X5 is a hydrophilic amino acid or variant thereof; X6 is a hydrophilic amino acid or an amino acid having an aromatic ring, or an N-methylated version thereof; X7 is W or a variant thereof; X8 is any hydrophilic amino acid or variant thereof; X9 is W or a variant thereof; X12 is C or a variant thereof] or a pharmaceutically acceptable salt thereof.

[0205] In some embodiments, the peptides described herein have the formula (Ib): X1-X2-X4-X5-X7-X8-X9-X12 Formula (Ib) [In the formula, X1 is any amino acid (e.g., a D-amino acid); X2 is an amino acid or variant thereof containing an aromatic ring, or an N-methylated amino acid thereof; X4 is any hydrophobic amino acid or variant thereof; X5 is a hydrophilic amino acid or variant thereof; X7 is W or a variant thereof; X8 is an N-methylated amino acid; X9 is W or a variant thereof; X12 is C or a variant thereof] or a pharmaceutically acceptable salt thereof.

[0206] In some embodiments, the peptides described herein have the formula (Ic): X1-X2-X6-X7-X8-X9-X12 Formula (Ic) (In the formula, X1 is any amino acid (e.g., a D-amino acid); X2 is an amino acid or variant thereof containing an aromatic ring, 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; X12 is C or a variant of it) or a pharmaceutically acceptable salt thereof.

[0207] In some embodiments, the peptide of Formula (I), (Ia), (Ib), and / or (Ic) is monocyclic. In some embodiments, the amino acid and cysteine ​​or cysteine ​​substitution at X1 are linked.

[0208] In some embodiments, peptides of the present disclosure bind to the ligand binding domain (LBD) of human EphA2.

[0209] In some embodiments, peptides of the present disclosure make good contact with Asp53 and / or Glu157 of human EphA2 as set forth in SEQ ID NO: 276. In some embodiments, peptides of the present disclosure interact with Asp53 and / or Glu157 of human EphA2 as set forth in SEQ ID NO: 276. In some embodiments, peptides of the present disclosure interact with Asp53 and / or Glu157 of human EphA2 as set forth in SEQ ID NO: 501. The interaction may be the formation of one or more hydrogen bonds, van der Waals interactions, dipole-dipole interactions, or pi-pi stacking interactions. In some embodiments, peptides of the present disclosure interact with human EphA2 at one or more residues selected from Asp53, Met55, Asn57, Met59, Met66, Thr101, Arg103, Phel56, 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, amino acid residue X5 of Formula (I) interacts with Glu157 of human EphA2. In some embodiments, amino acid residue X6 of Formula (I) interacts with Arg159 of human EphA2. In some embodiments, amino acid residue X7 of Formula (I) interacts with one or more of Phe156, Thr101, Asn57, Val161, Met59, Ala190, and Met66 of human EphA2. In some embodiments, amino acid residue X9 of Formula (I) interacts with one or more of Phe156, Arg103, and Val189. In some embodiments, amino acid residue X11 of Formula (I) interacts with Asp53 of human EphA2. In some embodiments, amino acid residue X7 of Formula (I) forms a pi-pi stacking interaction with Phe156 of human EphA2. In some embodiments, amino acid residue X9 of Formula (I) forms a pi-pi stacking interaction with Phe156 of human EphA2. In some embodiments, amino acid residue X2 of Formula (I) interacts with the backbone carbonyl of C70 of human EphA2 protein via an intermolecular aromatic H-bonding interaction.

[0210] In some embodiments, when a peptide of Formula (I) or a conjugate comprising the peptide binds to human EphA2, amino acid residue X2 of Formula (I) is located less than 15 Å from C70 of human EphA2. In some embodiments, X2 is located less than 10 Å from C70. In some embodiments, X2 is located less than 6 Å from C70. In some embodiments, X2 is located less than 4 Å from C70.

[0211] In some embodiments, when a peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, amino acid residue X7 of formula (I) is located less than 10 Å from Phe156 of human EphA2. In some embodiments, X7 is located less than 6 Å from Phe156. In some embodiments, X7 is located less than 4 Å from Phe156.

[0212] In some embodiments, when a peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, amino acid residue X7 of formula (I) is located less than 20 Å from Thr101 of human EphA2. In some embodiments, X7 is located less than 15 Å from Thr101. In some embodiments, X7 is located less than 10 Å from Thr101. In some embodiments, X7 is located less than 6 Å from Thr101. In some embodiments, X7 is located less than 4 Å from Thr101.

[0213] In some embodiments, when a peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, amino acid residue X7 of formula (I) is located less than 20 Å from Asn57 of human EphA2. In some embodiments, X7 is located less than 15 Å from Asn57. In some embodiments, X7 is located less than 10 Å from Asn57. In some embodiments, X7 is located less than 6 Å from Asn57. In some embodiments, X7 is located less than 4 Å from Asn57.

[0214] In some embodiments, when a peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, amino acid residue X7 of formula (I) is located less than 20 Å from Val161 of human EphA2. In some embodiments, X7 is located less than 15 Å from Val161. In some embodiments, X7 is located less than 10 Å from Val161. In some embodiments, X7 is located less than 6 Å from Val161. In some embodiments, X7 is located less than 4 Å from Val161.

[0215] In some embodiments, when a peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, amino acid residue X7 of formula (I) is located less than 20 Å from Met59 of human EphA2. In some embodiments, X7 is located less than 15 Å from Met59. In some embodiments, X7 is located less than 10 Å from Met59. In some embodiments, X7 is located less than 6 Å from Met59. In some embodiments, X7 is located less than 4 Å from Met59.

[0216] In some embodiments, when a peptide of Formula (I) or a conjugate comprising the peptide binds to human EphA2, amino acid residue X7 of Formula (I) is located less than 20 Å from Ala190 of human EphA2. In some embodiments, X7 is located less than 15 Å from Ala190. In some embodiments, X7 is located less than 10 Å from Ala190. In some embodiments, X7 is located less than 6 Å from Ala190. In some embodiments, X7 is located less than 4 Å from Ala190.

[0217] In some embodiments, when a peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, amino acid residue X7 of formula (I) is located less than 20 Å from Met66 of human EphA2. In some embodiments, X7 is located less than 15 Å from Met66. In some embodiments, X7 is located less than 10 Å from Met66. In some embodiments, X7 is located less than 6 Å from Met66. In some embodiments, X7 is located less than 4 Å from Met66.

[0218] In some embodiments, when a peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, amino acid residue X9 of formula (I) is located less than 10 Å from Phe156 of human EphA2. In some embodiments, X9 is located less than 6 Å from Phe156. In some embodiments, X9 is located less than 4 Å from Phe156.

[0219] In some embodiments, when a peptide of Formula (I) or a conjugate comprising the peptide binds to human EphA2, amino acid residue X9 of Formula (I) is located less than 15 Å from Asn3 of human EphA2. In some embodiments, X9 is located less than 10 Å from Asn3. In some embodiments, X9 is located less than 6 Å from Asn3. In some embodiments, X9 is located less than 4 Å from Asn3.

[0220] In some embodiments, when a peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, amino acid residue X9 of formula (I) is located less than 15 Å from Arg103 of human EphA2. In some embodiments, X9 is located less than 10 Å from Arg103. In some embodiments, X9 is located less than 6 Å from Arg103. In some embodiments, X9 is located less than 4 Å from Arg103.

[0221] In some embodiments, when a peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, amino acid residue X9 of formula (I) is located less than 15 Å from Val189 of human EphA2. In some embodiments, X9 is located less than 10 Å from Val189. In some embodiments, X9 is located less than 6 Å from Val189. In some embodiments, X9 is located less than 4 Å from Val189.

[0222] In some embodiments, when a peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, amino acid residue X8 of formula (I) is located less than 10 Å from Phe156 of human EphA2. In some embodiments, X8 is located less than 6 Å from Phe156. In some embodiments, X8 is located less than 4 Å from Phe156.

[0223] In some embodiments, when a peptide of Formula (I) or a conjugate comprising the peptide binds to human EphA2, amino acid residue X2 of Formula (I) is located less than 15 Å from C70 of human EphA2. In some embodiments, X2 is located less than 10 Å from C70. In some embodiments, X2 is located less than 7 Å from C70. In some embodiments, X2 is located less than 4 Å from C70.

[0224] In some embodiments, when a peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, amino acid residue X7 of formula (I) is located less than 10 Å from Phe156 of human EphA2. In some embodiments, X7 is located less than 6 Å from Phe156. In some embodiments, X7 is located less than 3 Å from Phe156.

[0225] In some embodiments, when a peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, amino acid residue X9 of formula (I) is located less than 20 Å from Thr101 of human EphA2. In some embodiments, X9 is located less than 15 Å from Thr101. In some embodiments, X9 is located less than 10 Å from Thr101. In some embodiments, X9 is located less than 6 Å from Thr101. In some embodiments, X9 is located less than 5 Å from Thr101.

[0226] In some embodiments, when a peptide of Formula (I) or a conjugate comprising the peptide binds to human EphA2, amino acid residue X8 of Formula (I) is located less than 20 Å from Asn57 of human EphA2. In some embodiments, X8 is located less than 15 Å from Asn57. In some embodiments, X8 is located less than 10 Å from Asn57. In some embodiments, X8 is located less than 6 Å from Asn57. In some embodiments, X8 is located less than 4 Å from Asn57.

[0227] In some embodiments, when a peptide of Formula (I) or a conjugate comprising the peptide binds to human EphA2, amino acid residue X7 of Formula (I) is located less than 20 Å from Val161 of human EphA2. In some embodiments, X7 is located less than 15 Å from Val161. In some embodiments, X7 is located less than 11 Å from Val161. In some embodiments, X7 is located less than 6 Å from Val161. In some embodiments, X7 is located less than 5 Å from Val161.

[0228] In some embodiments, when a peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, amino acid residue X7 of formula (I) is located less than 20 Å from Met59 of human EphA2. In some embodiments, X7 is located less than 15 Å from Met59. In some embodiments, X7 is located less than 11 Å from Met59. In some embodiments, X7 is located less than 6 Å from Met59. In some embodiments, X7 is located less than 4 Å from Met59.

[0229] In some embodiments, when a peptide of Formula (I) or a conjugate comprising the peptide binds to human EphA2, amino acid residue X7 of Formula (I) is located less than 20 Å from Ala190 of human EphA2. In some embodiments, X7 is located less than 15 Å from Ala190. In some embodiments, X7 is located less than 11 Å from Ala190. In some embodiments, X7 is located less than 6 Å from Ala190. In some embodiments, X7 is located less than 4 Å from Ala190.

[0230] In some embodiments, when a peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, amino acid residue X7 of formula (I) is located less than 20 Å from Met66 of human EphA2. In some embodiments, X7 is located less than 15 Å from Met66. In some embodiments, X7 is located less than 10 Å from Met66. In some embodiments, X7 is located less than 6 Å from Met66. In some embodiments, X7 is located less than 4 Å from Met66.

[0231] In some embodiments, when a peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, amino acid residue X2 of formula (I) is located less than 15 Å from Arg103 of human EphA2. In some embodiments, X2 is located less than 10 Å from Arg103. In some embodiments, X2 is located less than 6 Å from Arg103. In some embodiments, X2 is located less than 4 Å from Arg103.

[0232] In some embodiments, when a peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, amino acid residue X9 of formula (I) is located less than 15 Å from Val189 of human EphA2. In some embodiments, X9 is located less than 10 Å from Val189. In some embodiments, X9 is located less than 6 Å from Val189. In some embodiments, X9 is located less than 4 Å from Val189.

[0233] In some embodiments, the conjugate of the present disclosure has formula (III-1): [ka] (wherein -linker- represents a linker) It has the following structure.

[0234] In some embodiments, the conjugate comprising the cyclic peptide of formula (I) has formula (III-2): [ka] (In the formula, X1 to X12 have the definitions described above, and Lcyc is a ring-closing group covalently connecting X1 to X12; -Linker- represents a linker) It has the following structure.

[0235] In some embodiments, the conjugate of the present disclosure has the formula (III-1-RI): [ka] (In the formula, X1 to X12 have the definitions set forth above; -linker- represents a linker; R * represents a covalently bound radionuclide) It has the following structure.

[0236] In some embodiments, the conjugate comprising the cyclic peptide of formula (I) has the formula (III-2-RI): [ka] (In the formula, X1 to X12 have the definitions described above, and Lcyc is a ring-closing group covalently connecting X1 to X12; -linker- represents a linker; R * represents a covalently bound radionuclide) It has the following structure.

[0237] In some embodiments, Lcyc is a group selected from Table 4B. In some embodiments, Lcyc is formed by reacting the first and second functional groups in Table 4C. In some embodiments, Lcyc is -C(=O)-CH2-. In some embodiments, Lcyc is -C(=O)-CH2- formed by reacting a chloroacetylated (or bromoacetylated) amino acid with cysteine. In some embodiments, Lcyc is -C(=O)-CH2-S- formed by reacting a chloroacetylated (or bromoacetylated) amino acid with an amino acid containing an SH group.

[0238] In some embodiments, the peptides disclosed herein, or pharmaceutically acceptable salts thereof, have a cyclic structure in which the chloroacetylated amino acid and the cysteine ​​residue or variant thereof at the first residue X1 are linked to the chloroacetylated amino acid and the cysteine ​​residue or variant thereof at X1. In some embodiments, the peptides disclosed herein, or pharmaceutically acceptable salts thereof, have a cyclic structure in which the chloroacetylated amino acid and the cysteine ​​residue or variant thereof at the first residue X1 are linked to the chloroacetylated amino acid and the cysteine ​​residue or variant thereof at X1. In some embodiments, the peptides disclosed herein, or pharmaceutically acceptable salts thereof, have a cyclic structure in which the bromoacetylated amino acid and the cysteine ​​residue or variant thereof at the first residue X1 are linked to the bromoacetylated amino acid and the cysteine ​​residue or variant thereof at X1.

[0239] 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 with a cysteine ​​residue or variant thereof at the 12th residue (X12). In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NOs: 1-122, 159-163, and 165-171, and the peptide has a cysteine ​​residue or variant thereof at the 12th residue (X12), and the chloroacetylated amino acid and the cysteine ​​residue or variant thereof at the 12th residue form a covalent bond, and the chloroacetyl group may be replaced with a bromoacetyl group.

[0240] In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NOs: 123-149 and 164, wherein the peptide has a cyclic structure with a cysteine ​​residue or variant thereof at the tenth residue (X10). In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NOs: 123-149 and 164, wherein the peptide has a cysteine ​​residue or variant thereof at the tenth residue (X10), wherein the chloroacetylated amino acid and the cysteine ​​residue or variant thereof at the tenth residue form a covalent bond. In some embodiments, the chloroacetyl group may be replaced with a bromoacetyl group.

[0241] In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NOs: 150-157, wherein the peptide has a cyclic structure with a cysteine ​​residue or variant thereof at the eighth residue (X8). In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NOs: 150-157, wherein the peptide has a chloroacetylated amino acid and a cysteine ​​residue or variant thereof at the eighth residue (X8), wherein the chloroacetylated amino acid and the cysteine ​​residue or variant thereof at the eighth residue form a covalent bond, forming a cyclic structure. In some embodiments, the chloroacetyl group may be replaced with a bromoacetyl group.

[0242] In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NO: 158, wherein the peptide has a cyclic structure with a cysteine ​​residue or variant thereof at the seventh residue (X7). In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NO: 158, wherein the peptide has a cyclic structure with a chloroacetylated amino acid and a cysteine ​​residue or variant thereof at the seventh residue, wherein the chloroacetylated amino acid and the cysteine ​​residue or variant thereof at the seventh residue form a covalent bond. In some embodiments, the chloroacetyl group may be replaced with a bromoacetyl group.

[0243] In some embodiments, the peptides disclosed herein or pharmaceutically acceptable salts thereof have a cyclic structure in which the first amino acid is covalently linked to the last amino acid.

[0244] In some embodiments, the peptide or pharmaceutically acceptable salt thereof has a chloroacetylated amino acid in X1 and a cysteine ​​or substituted cysteine ​​residue, and has a cyclic structure to which the chloroacetylated amino acid in X1 and the cysteine ​​or substituted cysteine ​​are bonded. In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NOs: 1-171. In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NOs: 1-171, and has a cyclic structure. In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NOs: 1-171, and has a chloroacetylated amino acid and a cysteine ​​or substituted cysteine ​​residue at the C-terminus, and has a cyclic structure to which the chloroacetylated amino acid and the cysteine ​​or substituted cysteine ​​are bonded. In some embodiments, the peptide has a chloroacetylated amino acid and (i) a cysteine ​​or substituted cysteine ​​residue at residue 12, where the chloroacetylated amino acid and the cysteine ​​or substituted cysteine ​​residue at residue 12 are linked; or (ii) a cysteine ​​or substituted cysteine ​​residue at residue 10, where the chloroacetylated amino acid and the cysteine ​​or substituted cysteine ​​residue at residue 10 are linked, forming a cyclic structure. In some embodiments, the chloroacetyl group may be replaced with a bromoacetyl group.

[0245] For example, the cyclic peptide of formula (I) may have the structure shown below: [ka] For example, the cyclic peptide of formula (I) may have the structure shown below: [ka] may have

[0246] In some embodiments, the conjugate comprising the cyclic peptide of formula (I) is [ka] It has the following structure.

[0247] In some embodiments, the conjugate of the present disclosure comprises: [ka] (In the formula, [ka] represents the linker) It has the following structure.

[0248] In some embodiments, the conjugate comprising the cyclic peptide of formula (I) is [ka] It has the following structure.

[0249] In some embodiments, the conjugate of the present disclosure comprises: [ka] (In the formula, [ka] represents the linker) It has the following structure.

[0250] In some embodiments, the peptide or salt thereof comprises an amino acid sequence that is at least 95% identical to a sequence selected from SEQ ID NOs: (1) X1 to X12 of SEQ ID NOs: 1-122, 159-163, and 165-171, (2) X1 to X10 of SEQ ID NOs: 123-149 and 164, (3) X1 to X8 of SEQ ID NOs: 150-157, and (4) X1 to X7 of SEQ ID NO: 158. In some embodiments, the peptide or salt thereof comprises an amino acid sequence that is at least 90% identical to a sequence selected from SEQ ID NOs: (1) X1 to X12 of SEQ ID NOs: 1-122, 159-163, and 165-171, (2) X1 to X10 of SEQ ID NOs: 123-149 and 164, (3) X1 to X8 of SEQ ID NOs: 150-157, and (4) X1 to X7 of SEQ ID NO: 158. In some embodiments, the peptide or salt thereof comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, or 98% identical to a sequence selected from SEQ ID NOs: (1) X1 to X12 of SEQ ID NOs: 1-122, 159-163, and 165-171, (2) X1 to X10 of SEQ ID NOs: 123-149 and 164, (3) X1 to X8 of SEQ ID NOs: 150-157, and (4) X1 to X7 of SEQ ID NO: 158. In some embodiments, the peptide or salt thereof consists of an amino acid sequence selected from SEQ ID NOs: (1) X1 to X12 of SEQ ID NOs: 1-122, 159-163, and 165-171, (2) X1 to X10 of SEQ ID NOs: 123-149 and 164, (3) X1 to X8 of SEQ ID NOs: 150-157, and (4) X1 to X7 of SEQ ID NO: 158. In some embodiments, the peptide or salt thereof comprises an amino acid sequence having at most 1, 2, 3, 4, or 5 amino acid residues that differ compared to a sequence selected from: (1) X1 to X12 of SEQ ID NOs: 1-122, 159-163, and 165-171; (2) X1 to X10 of SEQ ID NOs: 123-149 and 164; (3) X1 to X8 of SEQ ID NOs: 150-157; and (4) X1 to X7 of SEQ ID NO: 158.In some embodiments, the peptide or salt thereof comprises an amino acid sequence having at most 1, 2, 3, 4, or 5 additions, deletions, and / or substitutions (including conservative substitutions) relative to a sequence selected from: (1) X1 to X12 of SEQ ID NOs: 1 to 122, 159 to 163, and 165 to 171; (2) X1 to X10 of SEQ ID NOs: 123 to 149 and 164; (3) X1 to X8 of SEQ ID NOs: 150 to 157; and (4) X1 to X7 of SEQ ID NO: 158. In some embodiments, the peptide or salt thereof comprises an amino acid sequence having at most one addition, deletion, or substitution (including conservative substitution) relative to a sequence selected from: (1) X1 to X12 of SEQ ID NOs: 1-122, 159-163, and 165-171; (2) X1 to X10 of SEQ ID NOs: 123-149 and 164; (3) X1 to X8 of SEQ ID NOs: 150-157; and (4) X1 to 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.

[0251] Exemplary peptides of the present disclosure include those set forth in Table 1. In some embodiments, the peptides in Table 1 have a -C(=O)-halogen group attached to the N-terminus. In some embodiments, the peptides in Table 1 have a -C(=O)-CH2-halogen group attached to the N-terminus. In some embodiments, the peptides in Table 1 have a -C(=O)-halogen group attached to the residue at position 1 (e.g., X1). In some embodiments, the peptides in Table 1 have a -C(=O)-CH2-halogen group attached to the residue at position 1 (e.g., X1). In some embodiments, the peptides in Table 1 have a -C(=O)-Cl group attached to the N-terminus. In some embodiments, the peptides in Table 1 have a -C(=O)-CH2-Cl group attached to the N-terminus. In some embodiments, the peptides in Table 1 have a -C(=O)-Cl group attached to the residue at position 1 (e.g., X1). In some embodiments, the peptides in Table 1 have a -C(=O)-CH2-Cl group attached to the residue at position 1 (e.g., X1). In some embodiments, the peptides in Table 1 have a -C(=O)-CH2-Br group attached to the residue at position 1 (e.g., X1). In some embodiments, the peptides in Table 1 have a -C(=O)-CH2-Br group attached to the residue at position 1 (e.g., X1).

[0252] 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 to the residue at position 1 (e.g., X1). In some embodiments, the radiopharmaceutical conjugates of the present disclosure have a -C(=O)-CH2-halogen group attached to the residue at 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 to the residue at position 1 (e.g., X1). In some embodiments, the radiopharmaceutical conjugates of the present disclosure have a -C(=O)-CH2-Cl group attached to the residue at position 1 (e.g., X1). In some embodiments, the radiopharmaceutical conjugates of the present disclosure have a -C(=O)-Br group attached to the residue at position 1 (e.g., X1). In some embodiments, the radiopharmaceutical conjugates of the present disclosure have a -C(=O)-CH2-Br group attached to the residue at position 1 (e.g., X1). In some embodiments, the peptide in the radiopharmaceutical conjugate is monocyclic.

[0253] In some embodiments, the peptide of the radiopharmaceutical conjugates described herein is a monocyclic peptide in which the -C(=O)-Cl of residue 1 (e.g., X1) forms a bond with the cysteine ​​of residue 12 (e.g., X12). In some embodiments, the peptide of the radiopharmaceutical conjugates described herein is a monocyclic peptide in which the -C(=O)-CH2-Cl of residue 1 (e.g., X1) forms a bond with the cysteine ​​of residue 12 (e.g., X12). In some embodiments, the peptide in the radiopharmaceutical conjugates described herein is a monocyclic peptide with 12 amino acid residues forming a ring.

[0254] Exemplary peptides of the present disclosure include those set forth in Table 1. In some embodiments, the peptides in Table 1 have a -C(=O)-halogen group attached to the N-terminus. In some embodiments, the peptides in Table 1 have a -C(=O)-halogen group attached to the residue at position 1 (e.g., X1). In some embodiments, the peptides in Table 1 have a -C(=O)-Cl group attached to the N-terminus. In some embodiments, the peptides in Table 1 have a -C(=O)-Cl group attached to the residue at position 1 (e.g., X1). In some embodiments, the peptides in Table 1 have a -C(=O)-Br group attached to the residue at position 1 (e.g., X1).

[0255] In some embodiments, the conjugates described herein are selected from those listed in Table 2A-Lu, Table 2A-Lu177, or Table 2A-Ac255. In some embodiments, the conjugates described herein are selected from those listed in Table 2B, Table 2B-Lu, Table 2B-Lu177, or Table 2B-Ac255. In some embodiments, the conjugates described herein are selected from those listed in Table 2C.

[0256] In some embodiments, provided herein are conjugates having the same peptide sequence and linker as a conjugate 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 the cysteine ​​(e.g., at position 10 or 12) is covalently bonded by a different group. For example, the amino acid residue at position 1 may include a group selected from a maleimide, a halide, a disulfide, an electron-deficient alkyne, a thioester, and an alkene that forms a covalent bond with the cysteine.

[0257] In some embodiments, the peptides in the conjugates of Table 2A-Lu, Table 2A-Lu177, and Table 2A-Ac255 are monocyclic peptides in which the -C(=O)-Cl at residue 1 forms a bond with the cysteine ​​at residue 12. In some embodiments, the -C(=O)-CH2-Cl at residue 1 forms a bond with the cysteine ​​at residue 12. In some embodiments, the peptides in the conjugates of Table 2A-Lu, Table 2A-Lu177, and Table 2A-Ac255 are monocyclic peptides with 12 amino acid residues forming a ring. In some embodiments, the peptides in the conjugates of Table 2B, Table 2B-Lu, Table 2B-Lu177, and Table 2B-Ac255 are monocyclic peptides in which the -C(=O)-Cl at residue 1 forms a bond with the cysteine ​​at residue 10. In some embodiments, the -C(=O)-CH2-Cl at residue position 1 forms a bond with the cysteine ​​at residue position 10. In some embodiments, the peptides in the conjugates of Table 2B, Table 2B-Lu, Table 2B-Lu177, and Table 2B-Ac255 are monocyclic peptides with 10 amino acid residues forming a ring.

[0258] In one embodiment, a peptide having avidity for ephrin type-A receptor 2 (EphA2) is provided, which is represented by SEQ ID NO:1: Described herein is a peptide, or a pharmaceutically acceptable salt thereof, that competes for binding to human EphA2 with a peptide having an amino acid sequence containing one or more amino acid deletions, substitutions, and / or additions in the amino acid sequence of da-MeF-NL-Hgl-MeF-W1Me-V-W1Me-TEC (sequence number 1).

[0259] In one aspect, described herein is a peptide having avidity for Ephrin type-A receptor 2 (EphA2), which competes for binding to human EphA2 with a peptide having the structure of formula (I) described herein (e.g., formulas (I-1) and (I-2)), or a pharmaceutically acceptable salt thereof.

[0260] In some embodiments, the peptides compete for binding to human EphA2 at one or more amino acid residues selected from Asp53, Met55, Asn57, Met59, Met66, Thr101, Arg103, Phe156, Glu157, Arg159, Val161, Val189, and Ala190. In some embodiments, the peptides compete for binding to human EphA2 at one or more amino acid residues selected from Asp53, Phe156, and Glu157. In some embodiments, the peptides compete for binding to human EphA2 at Asp53, Glu157, or both.

[0261] The structures of exemplary unnatural amino acids present in Table 1 can be found in Table 3.

[0262] As set forth in Table 1, 2A, 2B, 2C, or other tables, the abbreviations have the following meanings:

[0263] Lower case d denotes a D-amino acid, for example, dF refers to d-phenylalanine.

[0264] Me refers to a methyl group, for example, MeG represents N-methyl-glycine.

[0265] Ala or A refers to alanine.

[0266] Arg or R refers to arginine.

[0267] Asn or N refers to asparagine.

[0268] Asp or D refers to aspartic acid.

[0269] Cys or C refers to cysteine.

[0270] Gln or Q refers to glutamine.

[0271] Gly or G refers to glycine.

[0272] His or H refers to histidine.

[0273] Ile or I refers to isoleucine.

[0274] Leu or L refers to leucine.

[0275] Lys or K refers to lysine.

[0276] Met or M refers to methionine.

[0277] Phe or F refers to phenylalanine.

[0278] Pro or P refers to proline.

[0279] Ser or S refers to serine.

[0280] Thr or T refers to threonine.

[0281] Trp or W refers to tryptophan.

[0282] Tyr or Y refers to tyrosine.

[0283] Val or V refers to valine.

[0284] Ahp refers to 2-aminoheptanoic acid.

[0285] Nal1 refers to 1-naphthylalanine.

[0286] Chg refers to cyclohexylglycine.

[0287] F3C refers to 3-chlorophenylalanine.

[0288] mBph refers to 3-phenylphenylalanine.

[0289] Cba refers to cyclobutylalanine.

[0290] Hph refers to homophenylalanine.

[0291] W6C refers to 6-chlorotryptophan.

[0292] Har refers to homoarginine (ie, hArg).

[0293] [Table 1]

[0294] [Table 2]

[0295] [Table 3]

[0296] [Table 4]

[0297] [Table 5]

[0298] [Table 6]

[0299] [Table 7]

[0300] [Table 8]

[0301]

Table 9

[0302]

Table 10

[0303]

Table 11

[0304]

Table 12

[0305]

Table 13

[0306]

Table 14

[0307]

Table 15

[0308] Table 16

[0309] Table 17

[0310] Table 18

[0311] Table 19

[0312] Table 20

[0313] Table 21

[0314] Table 22

[0315] Table 23

[0316] Table 24

[0317] Table 25

[0318] Table 26

[0319] Table 27

[0320] Table 28

[0321] Table 29

[0322] Table 30

[0323] Table 31

[0324] Table 32

[0325] Table 33

[0326] Table 34

[0327] Table 35

[0328] Table 36

[0329] Table 37

[0330] Table 38

[0331] Table 39

[0332] The structures and names of exemplary unnatural amino acids of the disclosure are further provided below: Alb (S)-2-amino-3-ureidopropanoic acid (CAS number 1483-07-4) da or Da (2R)-2-aminopropanoic acid; dkCOpipzaa (2R)-2-amino-6-{[4-(carboxymethyl)piperazine-1-carbonyl]amino}hexanoic acid; [ka] Dahp (2R)-2-aminoheptanoic acid; [ka] df3CON (2R)-2-amino-3-(3-carbamoylphenyl)propanoic acid (CAS no. 1217637-40-5); [ka] MeF (2S)-2-(methylamino)-3-phenylpropanoic acid; Me3Py (2S)-2-(methylamino)-3-(pyridin-3-yl)propanoic acid (CAS number 1979173-93-7); [ka] Nal1 1-naphthylalanine; 4Py (2S)-2-amino-3-(pyridin-4-yl)propanoic acid (CAS no. 169555-95-7); [ka] MeHph (2S)-2-(methylamino)-4-phenylbutanoic 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); [ka] QPh (2S)-2-amino-4-(phenylcarbamoyl)butanoic acid (CAS no. 198134-12-2); MeF3CN (2S)-3-(3-cyanophenyl)-2-(methylamino)propanoic acid (CAS number 2642331-80-2); [ka] MeF3H (2S)-3-(3-hydroxyphenyl)-2-(methylamino)propanoic acid; [ka] 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); [ka] tma (R)-2-amino-4,4-dimethylpentanoic acid; [ka] Cbg (S)-2-amino-2-cyclobutylacetic acid (CAS no. 1391630-31-1); [ka] Chg (2S)-2-amino-2-cyclohexylacetic acid (CAS no. 161321-36-4); [ka] Cba (2S)-2-amino-3-cyclobutylpropanoic acid (CAS no. 478183-62-9); [ka] KCOpipzaa (2S)-2-amino-6-{[4-(carboxymethyl)piperazine-1-carbonyl]amino}hexanoic acid; [ka] Hgn (2S)-2-amino-5-carbamoylpentanoic acid (CAS no. 1263046-43-0); [ka] Nmm (2S)-2-amino-3-(methylcarbamoyl)propanoic acid (CAS no. 149204-93-3); [ka] Ndm (2S)-2-amino-3-(dimethylcarbamoyl)propanoic acid (CAS no. 138585-02-1); [ka] Hcit or hCit (2S)-2-amino-6-(carbamoylamino)hexanoic acid (CAS number 201485-17-8); [ka] Qglucamine (2S)-2-amino-4-{[(2S,3R,4R,5R)-2,3,4,5,6 pentahydroxyhexyl]carbamoyl}butanoic acid; [ka] 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 number 1217779-77-5); Hph (2S)-2-amino-4-phenylbutanoic acid; W1Me7N (2S)-2-amino-3-{1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl}propanoic acid (CAS no. 1813528-10-7); [ka] W1Me7Cl (2S)-2-amino-3-(7-chloro-1-methyl-1H-indol-3-yl)propanoic acid; [ka] W6C 6-chlorotryptophan; 3Py6NH2 (2S)-2-amino-3-(6-aminopyridin-3-yl)propanoic acid; [ka] Cit (2S)-2-amino-5-(carbamoylamino)pentanoic acid; [ka] F23dMe (2S)-2-amino-3-(2,3-dimethylphenyl)propanoic acid (CAS no. 1270295-08-3); [ka] F3C 3-chlorophenylalanine; Har (2S)-2-amino-6-carbamimidamidohexanoic acid (CAS no. 776277-76-0); bA 3-aminopropanoic acid; KAc (2S)-2-amino-6-acetamidohexanoic acid (CAS no. 159766-56-0); dkAc (2R)-2-amino-6-acetamidohexanoic acid (CAS no. 320410-22-8); CdMe (R)-2-amino-3-mercapto-3-methylbutanoic acid; C3SMe (2R,3S)-2-amino-3-mercaptobutanoic acid; C3RMe (2R,3R)-2-amino-3-memercaptobutanoic acid; 4Py2NH2 (S)-2-amino-3-(2-aminopyridin-4-yl)propanoic acid; and Hgl (S)-2-aminohexanedioic acid.

[0333] 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) analysis. 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) analysis. 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) analysis. 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) analysis. 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) analysis. 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) analysis.

[0334] 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 surface plasmon resonance (SPR) analysis. In some embodiments, the conjugates described herein have a binding affinity for human EphA2 of at most 100 nM, as determined by Kd in surface plasmon resonance (SPR) analysis. In some embodiments, the conjugates described herein have a binding affinity for human EphA2 of at most 1 nM, as determined by Kd in surface plasmon resonance (SPR) analysis. In some embodiments, the conjugates described herein have a binding affinity for human EphA2 of at most 2 nM, as determined by Kd in surface plasmon resonance (SPR) analysis. In some embodiments, the conjugates described herein have a binding affinity for human EphA2 of at most 5 nM, as determined by Kd in surface plasmon resonance (SPR) analysis. In some embodiments, the conjugates described herein have a binding affinity for human EphA2 of at most 10 nM, as determined by Kd in surface plasmon resonance (SPR) analysis. In one aspect, the binding affinity of a peptide or radiopharmaceutical conjugate of the present disclosure is at most 100 nM, as determined by Kd in surface plasmon resonance (SPR) analysis. In some delivery forms, the Kd of the peptide or radiopharmaceutical conjugate of the present disclosure is less than 100 nM, less than 50 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, less than 1 nM, less than 0.9 nM, less than 0.5 nM, less than 0.4 nM, less than 0.3 nM, less than 0.2 nM, less than 0.1 nM, less than 0.09 nM, less than 0.08 nM, less than 0.07 nM, less than 0.06 nM, less than 0.05 nM, less than 0.04 nM, less than 0.03 nM, less than 0.02 nM, less than 0.01 nM.

[0335] The molecular weight of the described peptides can vary. In some embodiments, the peptides have a molecular weight of about 0.1 to about 25 kDa. In some embodiments, the peptides have a molecular weight of about 0.2 to about 20 kDa, about 0.5 to about 15 kDa, about 0.75 to about 10 kDa, about 0.5 to about 10 kDa, about 0.5 to about 5 kDa, about 0.5 to about 2.5 kDa, about 0.5 to about 2 kDa, about 0.5 to about 1.5 kDa, about 0.5 to about 1 kDa, about 1 to about 10 kDa, about 1 to about 5 kDa, about 1 to about 2.5 kDa, about 1 to about 2 kDa, about 1 to about 1.5 kDa, about 1 to about 1.25 kDa, or about 0.5 to about 1.25 kDa. In some embodiments, the peptides have a molecular weight of about 0.5 to 5 kDa. In some embodiments, the peptide has a molecular weight of about 0.5 to 2 kDa. In some embodiments, the peptide has a molecular weight of about 0.75 to 1.75 kDa. In some embodiments, the peptide has a molecular weight of about 1 to 1.5 kDa. In some embodiments, the peptide is monocyclic.

[0336] The peptides described herein can be cyclized (i.e., macrocyclized). Cyclization can be achieved less ideally through a single disulfide bond, or more ideally through, but not limited to, a peptide bond, alkyl bond, alkenyl bond, ester bond, thioester bond, ether bond, thioether bond, phosphate ether bond, azo bond, CSC bond, CNC bond, C=NC bond, C=NO bond, amide bond, lactam bridge, carbamoyl bond, urea bond, thiourea bond, amine bond, thioamide bond, etc. In some embodiments, the peptide is a cyclic peptide cyclized through a peptide bond, alkyl bond, alkenyl bond, ester bond, thioester bond, ether bond, thioether bond, phosphate ether bond, azo bond, CNC bond, C=NC bond, C=NO bond, amide bond, lactam bridge, carbamoyl bond, urea bond, thiourea bond, amine bond, or thioamide bond. In some embodiments, the cyclic peptide is cyclized through a thioether bond. In some embodiments, cyclic peptides are cyclized via oxime cyclization. Peptide cyclization may stabilize the peptide structure, thereby enhancing affinity for the target. Cyclization may occur between the N-terminus and C-terminus, or 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, peptides are cyclized via oxime cyclization. In some embodiments, peptides are cyclized between cysteine ​​and a haloacyl. In some embodiments, peptides include a haloacetyl group (e.g., chloroacetyl or bromoacetyl) at the N-terminus. In some embodiments, peptides include a haloacetyl group (e.g., chloroacetyl or bromoacetyl) at the C-terminus. In some embodiments, peptides include a Cys at the C-terminus. In some embodiments, peptides include a 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 C-terminus of the peptide.

[0337] For example, amino acids having the following functional group A and amino acids having the corresponding functional group B can be used as amino acids for macrocyclization (see Table 4A). Either functional group A or functional group B can be located on the N-terminus. The amino acid having functional group A and the amino acid having functional group B can be the N-terminal amino acid, the C-terminal amino acid, or a non-terminal amino acid, respectively. In some embodiments, the amino acid having functional group A is located at the N-terminus. In some embodiments, the amino acid having functional group A is located at the C-terminus. In some embodiments, the amino acid having functional group A is located at a non-terminal amino acid. In some embodiments, the amino acid having functional group B is located at the N-terminus. In some embodiments, the amino acid having functional group B is located at the C-terminus. In some embodiments, the amino acid having functional group B is located at a non-terminal amino acid.

[0338] [Table 40]

[0339] In some embodiments, for example, a chloroacetylated amino acid can be used as the amino acid (IA). 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-diaminopropanoic acid, γ-N-chloroacetyl-L-diaminopropanoic acid, β-N-chloroacetyl-L-diaminopropanoic acid, γ-N-chloroacetyl-L-alanine, β-N-chloroacetyl-L-diaminopropanoic acid, γ-N-chloroacetyl-L-alanine, β-N-chloroacetyl-L-diaminopropanoic acid, γ-N-chloroacetyl-L-alanine, β-N-chloroacetyl-L-diaminopropanoic acid, γ-N-chloroacetyl-L-alanine, β-N-chloroacetyl-L-diaminopropanoic acid, γ-N-chloroacetyl-L-alanine, β-N-chloroacetyl-L-alanine ... 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, as well as the corresponding D-amino acid derivatives (e.g., N-chloroacetyl-D-alanine, N-chloroacetyl-D-phenylalanine, N-chloroacetyl-D-tyrosine, and N-chloroacetyl-D-tryptophan).

[0340] Examples of amino acids (IB) include, but are not limited to, cysteine, homocysteine, mercaptonorvaline, mercaptonorleucine, 2-amino-7-mercaptoheptanoic acid, 2-amino-8-mercaptooctanoic acid, and amino acids obtained by protecting the SH groups of these amino acids and then removing the protecting groups, as well as the corresponding D-amino acid derivatives.

[0341] The cyclization method can be based on the method described in, for example, 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 WO 2008 / 117833.

[0342] In some embodiments, for example, the amino acid (II-A) can be selected from propargylglycine, homopropargylglycine, 2-amino-6-heptynoic acid, 2-amino-7-octynoic acid, and 2-amino-8-nonynoic acid. In addition, 4-pentynoylated or 5-hexynoylated amino acids can also be used. Examples of 4-pentenoylated 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-pentenoylamido)benzoyl-L-phenylalanine, N-3-(4-pentenoylamido)benzoyl-L-tyrosine, N-3-(4-pentenoylamido)benzoyl-L-tryptophan, β-N-(4-pentenoyl)-L-diaminopropanoic acid, γ-N-(4-pentenoyl)-L-diaminobutyric acid, σ-N-(4-pentenor)-L-ornithine, and ε-N-(4-pentenor)-L-lysine, and the corresponding D-amino acid derivatives.

[0343] In some embodiments, for example, amino acid (II-B) can be selected from azidoalanine, 2-amino-4-azidobutanoic acid, azidoptonorvaline, azidonorleucine, 2-amino-7-azidoheptanoic acid, and 2-amino-8-azidooctanoic acid. In addition, azidoacetylated or 3-azidopentanoylated amino acids can also be used. Examples of azidoacetylated amino acids include N-azidoacetyl-L-alanine, N-azidoacetyl-L-phenylalanine, N-azidoacetyl-L-tyrosine, N-azidoacetyl-L-tryptophan, N-3-(4-pentynoylamido)benzoyl-L-phenylalanine, N-3-(4-pentynoylamido)benzoyl-L-tyrosine, N-3-(4-pentynoylamido)benzoyl-L-tryptophan, β-N-azidoacetyl-L-diaminopropanoic acid, γ-N-azidoacetyl-L-diaminobutyric acid, α-N-azidoacetyl-L-ornithine, and ε-N-azidoacetyl-L-lysine, and the corresponding D-amino acid derivatives.

[0344] The cyclization can be carried out based on the method described in, for example, Sako, Y. et al., Journal of American Chemical Society 130, 7932-7934 (2008), or WO 2008 / 117833.

[0345] Examples of amino acids (III-A) include, but are not limited to, N-(4-aminomethyl-benzoyl)-phenylalanine (AMBF) and 4-3-aminomethyltyrosine.

[0346] Examples of the amino acid (III-B) include, but are not limited to, 5-hydroxytryptophan (WoH). The cyclization method can be carried out based on, for example, the method described in Yamagishi, Y. et al., ChemBioChem 10, 1469-1472 (2009) or WO 2008 / 117833.

[0347] Examples of amino acids (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.

[0348] Examples of amino acid (IV-B) include, but are not limited to, cysteine, homocysteine, mercaptonorvaline, mercaptonorleucine, 2-amino-7-mercaptoheptanoic acid, and 2-amino-8-mercaptooctanoic acid, the amino acids obtained by protecting the SH group of these amino acids and then removing the protecting group, and the corresponding D-amino acid derivatives.Cyclization method can be carried out, for example, based on the method described in WO2012 / 074129.

[0349] Examples of amino acids (VA) include, but are not limited to, N-3-chloromethylbenzoyl-L-phenylalanine, N-3-chloromethylbenzoyl-L-tyrosine, and N-3-chloromethylbenzoyl-L-tryptophan.

[0350] Examples of amino acids (VB) include, but are not limited to, cysteine, homocysteine, mercaptonorvaline, mercaptonorleucine, 2-amino-7-mercaptoheptanoic acid, and 2-amino-8-mercaptooctanoic acid, and amino acids obtained by protecting the SH groups of these amino acids and then removing the protecting groups, and the corresponding D-amino acid derivatives.

[0351] Amino acids IA-VA and IB-VB can be introduced into the peptide in a known manner, by chemical synthesis as described herein, or by translation and synthesis. In some embodiments, the cyclization reaction involves forming a thioether bond using an amino acid containing a sulfanyl group, e.g., cysteine, homocysteine, mercaptonorvaline, mercaptovaline, mercaptonorleucine, 2-amino-7-mercaptoheptanoic acid, and 2-amino-8-mercaptooctanoic acid.

[0352] The peptides described herein may contain 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 contain heteroaryl substituents (e.g., pyridine, imidazole, pyrazole, or triazole with one or more ring nitrogen atoms). Negatively charged amino acids include, for example, amino acids containing additional carboxylic acid groups (e.g., glutamic acid).

[0353] In some embodiments, a cyclic peptide of Formula (I), Formula (I-1), Formula (I-2), Formula (Ia), Formula (Ib), or Formula (Ic) has a net charge of -3 to +1. In some embodiments, a cyclic peptide has a net charge of -3. In some embodiments, a cyclic peptide has a net charge of -2. In some embodiments, a cyclic peptide has a net charge of -1. In some embodiments, a cyclic peptide has a net charge of 0. In some embodiments, a cyclic peptide has a net charge of +1. In some embodiments, a cyclic peptide of Formula (I), Formula (I-1), Formula (I-2), Formula (Ia), Formula (Ib), or Formula (Ic) has a net charge of at most -4. In some embodiments, a cyclic peptide has a net charge of -4. In some embodiments, a cyclic peptide of Formula (I), Formula (I-1), Formula (I-2), Formula (Ia), Formula (Ib), or Formula (Ic) has a net charge of at least +2. In some embodiments, the cyclic peptide has a net charge of +2. In some embodiments, the cyclic peptide has a net charge of +3. The net charge can be determined by adding together the charges of each of the amino acids X1 through X12 (or each amino acid within 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 standard amino acids each have a charge of 0.

[0354] In some embodiments, the cyclic peptide of Formula (I) has a net charge of -3 to +1. In some embodiments, the cyclic peptide has a net charge of -3. In some embodiments, the cyclic peptide has a net charge of -2. In some embodiments, the cyclic peptide has a net charge of -1. In some embodiments, the cyclic peptide has a net charge of 0. In some embodiments, the cyclic peptide has a net charge of +1. The net charge can be determined by adding together the charges of each of the amino acids of the cyclic peptide.

[0355] In some embodiments, a cyclic peptide described herein (e.g., a cyclic peptide of Formula (I), Formula (I-1), Formula (I-2), Formula (Ia), Formula (Ib), or Formula (Ic)) is configured to bind to EphA2 with a specified affinity, e.g., as measured as plasma protein albumin binding (PPB) percentage. The binding percentage (%) can be determined by HSA-HPLC (immobilized human serum albumin-HPLC drug-protein binding measurement). PPB can be determined in vitro by HPLC (e.g., Example B3) or 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 under 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.

[0356] In some embodiments, a conjugate described herein (e.g., a conjugate comprising a cyclic peptide of Formula (I), Formula (I-1), Formula (I-2), Formula (Ia), Formula (Ib), or Formula (Ic)) is configured to bind to a plasma protein with a defined affinity, e.g., as measured as plasma protein albumin binding (PPB) percentage. PPB can be determined in vitro by HPLC (e.g., Example B3) or 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 under 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 conjugates bind to HSA in vitro. In some embodiments, about 40% to about 80% of the conjugates bind to HSA in vitro. In some embodiments, about 40% to about 60% of the conjugates bind to HSA in vitro. In some embodiments, about 60% to about 99% of the conjugates bind to HSA in vitro. In some embodiments, about 60% to about 95% of the conjugates bind to HSA in vitro. In some embodiments, about 60% to about 80% of the conjugates bind to HSA in vitro. In some embodiments, about 60% to about 70% of the conjugates bind to HSA in vitro. In some embodiments, about 40% to about 50% of the conjugates bind 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.

[0357] In some embodiments, the cyclic peptide of formula (I), formula (I-1), formula (I-2), formula (Ia), formula (Ib), or formula (Ic) does not contain any S—S bonds.

[0358] In some embodiments, peptides of the present disclosure may be cyclized by forming groups such as those illustrated in Table 4B.

[0359] [Table 41]

[0360] 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.

[0361] In some embodiments, peptides of the present disclosure, such as 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.

[0362] [Table 42]

[0363] In some embodiments, a conjugate comprising any one of the peptides in Table 1 may further comprise an amino acid residue at the N-terminus and / or C-terminus of the peptide that is not part of a 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 (e.g., Ac-225 or lutetium-177, etc.). In some embodiments, the conjugate further comprises a covalently bound radionuclide and, optionally, a linker connecting the peptide and the covalently bound radionuclide. In some embodiments, the conjugate further comprises a covalently bound radionuclide (e.g., 18 F, 74 As, 76 Br, 123 I, 124 I, 125 I, 131 I, or 211 At etc.)

[0364] The peptides described herein may be peptidomimetics. For example, peptides may contain non-peptide bonds, but may also contain one or more non-natural amino acids. Unless otherwise specified, each amino acid (except the natural amino acid glycine) in the peptides described herein may independently exist in its D-form or L-form. Both D-form and L-form are encompassed by the present disclosure.

[0365] In the present disclosure, the term amino acid includes amino acid derivatives. Derivatives include, for example, amino acids obtained by modifying natural amino acids that make up proteins produced by biological entities encoded by cellular DNA. Examples of such unnatural amino acids include hydroxyproline and hydroxylysine (amino acids with a hydroxyl group introduced therein), and diaminopropionic acid (an amino acid with an amino group introduced therein).

[0366] The peptides described herein may contain N-substituted amino acids. In some embodiments, the N-substituted amino acids are derivatives of tryptophan, phenylalanine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, or valine. In some embodiments, the N-substituted amino acids are N-alkyl (e.g., N-methyl and N-ethyl, etc.). In some embodiments, the N-substituted amino acids are N-methyl. In some embodiments, the N-substituted amino acids are N-aryl (e.g., N-phenyl or N-biphenyl, etc.). In some embodiments, the N-substituted amino acids are N-heteroaryl (e.g., N-pyridyl, etc.). In some embodiments, the N-substituted amino acids are present at the N-terminus of the peptide. In some embodiments, the N-substituted amino acids are non-terminal amino acids.

[0367] In some embodiments, the peptides described herein comprise one or more amino acids in Tables 5A-5F.

[0368] [Table 43]

[0369] [Table 44]

[0370] [Table 45]

[0371] [Table 46]

[0372] Exemplary alkyl groups in Table 5D include methyl, ethyl, and propyl groups.

[0373] [Table 47]

[0374] [Table 48]

[0375] An amino acid used in the disclosed peptides may be substituted with a similar amino acid. In some embodiments, an amino acid may be substituted with another amino acid having similar hydrophobicity. In some embodiments, an amino acid may be substituted with another amino acid having similar hydrophilicity. In some embodiments, an amino acid may be substituted with another amino acid having a similar size. In some embodiments, an amino acid may be substituted with another amino acid having a similar charge. In some embodiments, an amino acid may be substituted with another amino acid having a similar functional group. In some embodiments, an amino acid may be substituted with another amino acid having the same functional group.

[0376] In some embodiments, the amino acids described herein can be replaced with 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 at the C-terminus and / or N-terminus. Additional examples of amino acid / peptide variants include those obtained by modification (e.g., phosphorylation, alkylation (e.g., methylation), acetylation, adenylylation, ADP-ribosylation, glycosylation, etc.) and fusion proteins obtained by fusion with another peptide or protein. These variants can be prepared by those skilled in the art using known methods or methods based thereon. Amino acid variants further include amino acids with the same functional group but different side chain lengths (e.g., LysAc and OrnAc, and cysteine ​​and homocysteine). Amino acid variants further include amino acids with different aromatic moieties compared to standard amino acids (e.g., indole in tryptophan and 7-azaindole in 7-AzaTrp; phenyl in phenylalanine and pyridine in 4Py). Amino acid variants further include amino acids with optional substituents, i.e., optionally substituted amino acids. In some embodiments, optionally substituted amino acids include halogen, hydroxyl, cyano, amino, amido, nitro, ureido, C1-C6 alkyl, C1-C6 alkoxy, C6-C 10In some embodiments, the optionally substituted amino acids may be optionally substituted with one or more substituents independently selected from aryl, C3-C6 cycloalkyl, 6- to 10-membered heterocycloalkyl, and 6- to 10-membered heteroaryl. In some embodiments, the optionally substituted amino acids may be optionally substituted with one or more substituents independently selected from halogen, -CN, -NH, -NH(alkyl), -N(alkyl), oxo, -OH, -COH, -COalkyl, -C(=0)NH, -C(=0)NH(alkyl), -C(=0)N(alkyl), -S(=0)NH, -S(=0)NH(alkyl), -S(=0)N(alkyl), alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some embodiments, a substituent may be any substituent described herein, for example, halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO), imino (=NH), oximo (=N-OH), hydrazino (=N-NH), 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 -OR 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 (wherein t is 1 or 2), -R b -S(O) t R a (wherein 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 (wherein t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, and heterocycle, any of which may be alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oximo (=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 -OR 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(wherein t is 1 or 2), -R b -S(O) t R a (wherein 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 (wherein t is 1 or 2); each R a is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, and heterocycle; and each R a , if valence allows, alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oximo (=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 -OR 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 (wherein t is 1 or 2), -R b -S(O)t R a (wherein 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 (wherein t is 1 or 2); and each R b is independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each R c is a straight or branched alkylene, alkenylene, or alkynylene chain.

[0377] In some embodiments, the amino acid variants are selected from amino acids having one, two, or three substituents based on the amino acid, the substituents being halogen, -CN, -NH, -NH(C-C alkyl), -N(C-C alkyl), oxo, -OH, -COH, -CO-C-C alkyl, -C(=O)NH, -C(=O)NH(C-C alkyl), -C(=O)N(C-C alkyl), -S(=O)NH, -S(=O)NH(C-C alkyl), -S(=O)N(C-C alkyl), C-C alkyl, C-C heteroalkyl, C-C alkoxy, C-C 10 independently selected from aryl, C3-C6 cycloalkyl, 6-10 membered heterocycloalkyl, and 6-10 membered heteroaryl.

[0378] In some embodiments, the variants are selected from amino acids having one or two substituents based on the amino acid, wherein the substituents are independently selected from halogen, -CN, -NH, -NH(C-C alkyl), -N(C-C alkyl), oxo, -OH, -COH, -CO-C-C alkyl, -C(=O)NH, -C(=O)NH(C-C alkyl), -C(=O)N(C-C alkyl), and C-C alkyl. In some embodiments, the variants are selected from amino acids having one or two substituents based on the amino acid, wherein the substituents are independently selected from halogen, -CN, -NH, -NH(C-C alkyl), -N(C-C alkyl), and C-C alkyl. In some embodiments, the variants are selected from amino acids having one or two substituents based on the amino acid, wherein the substituents are independently selected from C-C alkyl.

[0379] In some embodiments, a variant of an amino acid is selected from amino acids that have 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.

[0380] 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 comprises an -OH, COOH, -NH-, or NH2 moiety. In some embodiments, the hydrophilic amino acid comprises an -OH, -C(O)OH, -NHC(=NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3. In some embodiments, the hydrophilic amino acid comprises a C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, -C0-6 alkylene-NH-C(=NH)-NH2, -C0-6 alkylene-CO-NH2, -C0-6 alkylene-COOH, or -NH-CO-C1-6 alkyl side chain.

[0381] In some embodiments, the hydrophobic amino acid is uncharged. In some embodiments, the hydrophobic amino acid contains at least two consecutive carbon atoms. In some embodiments, the hydrophobic amino acid contains at least three consecutive carbon atoms, either linear or branched. In some embodiments, the hydrophobic amino acid contains at least four consecutive carbon atoms, either linear or branched. In some embodiments, the hydrophobic amino acid contains at least five consecutive carbon atoms, either linear or branched. 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.

[0382] In some embodiments, an amino acid variant is selected from an amino acid having the same functional group as the amino acid, where the variant has a side chain of a different length compared to the amino acid. In some embodiments, an amino acid variant is selected from an amino acid having the same functional group as the amino acid, where the variant has a side chain of a different carbon chain length compared to the amino acid (e.g., leucine and (S)-2-amino-5-methylhexanoic acid, or 2-(methylamino)pentanedioic acid and 2-(methylamino)hexanedioic acid). In some embodiments, an amino acid variant is selected from an amino acid having the same charge as the amino acid. In some embodiments, an amino acid variant is selected from an amino acid having the same polarity as the amino acid. In some embodiments, an amino acid containing an aromatic group can be a variant of another amino acid having an aromatic group. In some embodiments, an amino acid containing a phenyl can be a variant of another amino acid having a phenyl. In some embodiments, an amino acid containing a heteroaryl can be a variant of another amino acid having a heteroaryl. In some embodiments, an amino acid containing a heteroaryl can be a variant of another amino acid having a phenyl group. Amino acids with aromatic groups include, but are not limited to, F, W, Me3Py, MeF, MeF3H, MeFCN, MeF4F, MeF3F, MeFCON, F23dMe, df3CON, W1Me, W1Me7Cl, W1Me7N, W1Et, 7-AzaTrp, W1Me7Br, W1Me7Ome, W1Me6O7Cl, d4PyCON, W7Me, dDab-NH2-Ph3-SO2F, dDap-NH2-Ph3-SO2F, dDap-NH2-Ph4-SO2F, MeF4C, 4Py, 3Py6NH2, 4Py2NH2 and Me4Py.Therefore, variants of amino acids containing heteroaryl rings include amino acids containing different heteroaryls.In some embodiments, F or its variants include amino acids in which the phenyl ring is replaced with a heteroaryl (e.g., pyridine). In some embodiments, an amino acid that includes a cycloalkyl group can be a variant of another amino acid that has a cycloalkyl group.In some embodiments, an amino acid that includes a heterocycloalkyl group can be a variant of another amino acid that has a heterocycloalkyl group.

[0383] In some embodiments, the variant of an amino acid is selected from amino acids with a 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, Qglucamine).

[0384] 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.

[0385] In some embodiments, the molecular weight of a variant does not vary by more than 14, 28, 30, 45, or 60 g / mol compared to the amino acid. In some embodiments, the molecular weight of a variant does not vary by more than 14 g / mol compared to the amino acid. In some embodiments, the molecular weight of a variant does not vary by more than 50 g / mol compared to the amino acid. In some embodiments, the molecular weight of a variant does not vary by more than 28 g / mol compared to the amino acid.

[0386] Amino acid variants also include amino acids in which a functional group is replaced with another functional group having similar properties, for example, cysteine ​​can be replaced with homocysteine. In some embodiments, an aryl functional group can be replaced with an aryl or heteroaryl group. In some embodiments, a heteroaryl functional group can be replaced with an aryl or heteroaryl group. In some embodiments, an amino functional group can be replaced with an NH (alkyl) group.

[0387] As used herein, the phrase "conservative amino acid substitution" refers to the substitution of a functionally equivalent or similar amino acid. Conservative amino acid substitutions within a peptide result in a static change to the peptide's amino acid sequence. For example, one or more amino acids with similar polarity have equivalent functional effects and result in a static change to the peptide's amino acid sequence. Generally, substitutions within a particular group can be considered conservative with respect to structure and function. However, as will be apparent to those skilled in the art, the role played by a given amino acid residue can be determined by its significance in the three-dimensional structure of the molecule containing that amino acid. For example, the oxidized form of a cysteine ​​residue (disulfide) can be less polar than the reduced form (thiol). The long aliphatic moiety of the arginine side chain can constitute an important structural and functional feature. Furthermore, side chains containing aromatic rings (tryptophan, tyrosine, phenylalanine) can contribute to ion-aromatic or cation-pi (pi) interactions. In such cases, substitution of amino acids with such side chains with amino acids belonging to acidic or nonpolar groups may be structurally and functionally conservative. Residues (e.g., proline, glycine, cysteine ​​(in disulfide form), etc.) have direct effects on the three-dimensional structure of the main chain and may often not be able to be substituted without causing structural distortion.

[0388] The conservative amino acid substitutions listed below include specific substitutions based on side chain similarity (e.g., substitutions described in Lehninger, Biochemistry, Revised 2nd Edition, published in 1975, pp. 73 to 75: L. Lehninger, Biochemistry, 2nd edition, pp. 73 to 75, Worth Publisher, New York (1975)), which are incorporated herein by reference, and representative substitutions.

[0389] Hydrophobic amino acids include amino acids that exhibit hydrophobicity, including alanine (also known as "Ala" or simply "A"), glycine (also known as "Gly" or simply "G"), valine (also known as "Val" or simply "V"), leucine (also known as "Leu" or simply "L"), isoleucine (also known as "Ile" or simply "I"), proline (also known as "Pro" or simply "P"), phenylalanine (also known as "Phe" or simply "F"), tryptophan (also known as "Trp" or simply "W"), tyrosine (also known as "Tyr" or simply "Y"), and methionine (also known as "Met" or simply "M").

[0390] Exemplary hydrophobic amino acids can be further divided into the following groups: Aliphatic amino acids: amino acids with fatty acids or hydrogens in their side chains (e.g., Ala, Gly, Val, Ile, and Leu) Aliphatic / branched-chain amino acids: amino acids with branched fatty acids in their side chains (e.g., Val, Ile, and Leu) Aromatic amino acids: Amino acids with an aromatic ring in the side chain (e.g., Trp, Tyr, and Phe)

[0391] In some embodiments, a hydrophobic amino acid has four or more carbon atoms in its side chain (linear, branched, or cyclic carbon side chain) (e.g., Leu, Hcit, Cbg, Chg, or Cba), each of which is optionally N-methylated. In some embodiments, a hydrophobic amino acid has 4-5, 4-6, or 4-7 carbon atoms in its side chain.

[0392] Hydrophilic amino acids include, for example, serine (also called "Ser" or simply "S"), threonine (also called "Thr" or simply "T"), cysteine ​​(also called "Cys" or simply "C"), asparagine (also called "Asn" or simply "N"), glutamine (also called "Gln" or simply "Q"), aspartic acid (also called "Asp" or simply "D"), glutamic acid (also called "Glu" or simply "E"), lysine (also called "Lys" or simply "K"), arginine (also called "Arg" or simply "R"), and histidine (also called "His" or simply "H").

[0393] Exemplary hydrophilic amino acids can be further divided into the following groups: Acidic amino acids: amino acids with acidic side chains (Asp and Glu) Basic amino acids: Amino acids with basic side chains (Lys, Arg, and His) Neutral amino acids: amino acids with neutral side chains (Ser, Thr, Asn, Gln, and Cys)

[0394] 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 (including D-amino acids such as da, and variations such as Qglucamine, which have a glucamine moiety attached to the NH2-terminus of the side chain).

[0395] In some embodiments, the peptides described herein include amino acids that influence backbone orientation (e.g., Gly and Pro). In some embodiments, the peptides described herein include sulfur-containing amino acids (e.g., Cys and Met). In some embodiments, the peptides described herein include amino acids that include an aromatic ring (which may be optionally substituted). Amino acids that include an aromatic ring include, for example, F (Phe; phenylalanine), Y (Tyr; tyrosine), and W (Trp; tryptophan).

[0396] In some embodiments, W or a variant thereof can be W, an amino acid having a heteroatom in the indole ring of W in the side chain, an amino acid in which the hydrogen of the NH in the indole ring of W is replaced, or an amino acid having a substituent in the benzene ring of W, etc.

[0397] In some embodiments, F or a variant thereof is F (phenylalanine), (i) the phenyl ring of F is selected from the group consisting of -OH, -CN, -C 1~3 (ii) a 6-membered heteroaryl ring is substituted with one or two substituents each independently selected from -OH, -CN, -C, 1~3 or (iii-1) F has a heteroatom in the phenyl ring in the side chain; or (iii-2) F is a derived amino acid, where the 6-membered heteroaryl ring in the side chain is substituted. In some embodiments, F or a variant thereof is optionally N-methylated.

[0398] In some embodiments, W, Y, or a variant thereof can be W, Y, or an amino acid having either a 6-membered aryl or heteroaryl, or a 9- or 10-membered bicyclic aryl, or a heteroaryl linked to the alpha carbon through a carbon (e.g., a methylene group). In some embodiments, the 6-, 9-, and 10-membered heteroaryl has one heteroatom (e.g., N), in which case the 6-, 9-, and 10-membered aryl or heteroaryl can be optionally substituted with one or two substituents independently selected from -methyl, -ethyl, -Cl, and -F. In certain embodiments, W or Y, or a variant thereof, is W1Me, W1Me7Cl, or F23dMe, Na11, Na12, W1Et, Na121N, 3Bzf, 3Bzt, Na15N, Na14N, Na124N, Na128N, 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.

[0399] Examples of amino acids include naturally occurring L-amino acids, unnatural amino acids, and chemically synthesized compounds having properties known in the art to be characteristic of amino acids. Examples of unnatural amino acids include, but are not limited to, α,α-disubstituted amino acids (e.g., α-methylalanine, etc.), 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 that of natural amino acids (e.g., norleucine and homohistidine, etc.); amino acids with an additional methylene in their side chains (e.g., "homo" amino acids, homophenylalanine, homohistidine, etc.); and amino acids obtained by replacing a carboxylic acid functional amino group in their side chains with a sulfonic acid group (e.g., cysteic acid, etc.).

[0400] 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 alpha-amino group). In certain embodiments, such amino acids are A, E, N, K, Qglucamine, KCOpipzaa, Q, Hse, Cit, Hcit, KAc, DapAc, OrnAc, T, a1T, Aib, or 3Py6NH2, more preferably V, Qglucamine, Cit, Hcit, K, or 3Py6NH2.

[0401] The peptides described herein may contain one or more unnatural amino acids. Unnatural amino acids include, but are not limited to, (1) amino acids corresponding to amino acid residues on polypeptides that have been modified post-expression (e.g., phosphorylated tyrosine, acetylated lysine, or farnesylated cysteine), (2) naturally occurring amino acids that cannot be used in ribosomal expression, and (3) artificial amino acids that do not occur in nature (unnatural amino acids). Non-limiting examples of unnatural amino acids include p-acetyl-L-phenylalanine, p-iodo-L-phenylalanine, p-methoxyphenylalanine, O-methyl-L-tyrosine, p-propargyloxyphenylalanine, p-propargyl-phenylalanine, L-3-(2-naphthyl)alanine, 3-methyl-phenylalanine, O-4-allyl-L-tyrosine, 4-propyl-L-tyrosine, tri-O-acetyl-GlcNAcp-serine, L-Dopa, fluorine, thiamin ... p-L-phenylalanine, isopropyl-L-phenylalanine, p-azido-L-phenylalanine, p-acyl-L-phenylalanine, p-benzoyl-L-phenylalanine, boronophenylalanine, O-propargyltyrosine, L-phosphoserine, phosphonoserine, phosphonotyrosine, p-bromophenylalanine, selenocysteine, p-amino-L-phenylalanine, isopropyl-L-phenylalanine, and azido-lysine (AzK). In some embodiments, the unnatural amino acid is an unnatural 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, alkynl, ether, thiol, sulfonyl, seleno, ester, thioacid, borate, boronate, phospho, phosphono, phosphine, heterocyclic, enone, imine, aldehyde, hydroxylamine, keto, or amino substituted amino acid; or a combination thereof.In some embodiments, the unnatural amino acid is an amino acid with a photoactivatable 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; a keto-containing amino acid; 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 with 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 aminothioacid; 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.

[0402] Non-natural amino acids include, for example, N-alkylamino acids in which the above-mentioned natural amino acids have been N-alkylated, e.g., modified with a lower alkyl group (e.g., C1-C5, C1-C3, and C1) (where the nitrogen forming the peptide bond is branched or unbranched). Exemplary N-alkylamino acids include, for example, N-ethyl amino aci...

Claims

1. (a) A cyclic peptide having avidity for ephrin type-A receptor 2 (EphA2), comprising the formula (I): X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) [In the formula, X1 is an 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 variants thereof), glycine (G), alanine (A) or variants 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 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, an N-methylated amino acid, or a variant thereof; X9 is an amino acid containing an aromatic ring (e.g., W or a variant thereof); X10 is absent or a hydrophilic amino acid (e.g., threonine (T) or a variant thereof); X11 is absent or a hydrophilic amino acid; X12 is cysteine ​​(C) or a variant thereof. or a pharmaceutically acceptable salt thereof; and (b) (i) a metal chelator configured to bind a radionuclide, the metal chelator being conjugated to a peptide, or (ii) a radionuclide covalently attached to a cyclic peptide.

10. A radiopharmaceutical conjugate comprising:

2. (a) a cyclic peptide having avidity for ephrin type-A receptor 2 (EphA2), comprising SEQ ID NO: 1: da-MeF-NL-Hgl-MeF-W1Me-V-W1Me-T-E-C (SEQ ID NO: 1) an amino acid sequence containing one or more (e.g., 1 to 6) amino acid deletions, substitutions, and / or additions in the amino acid sequence of a cyclic peptide consisting of 10 or 12 amino acid residues, or a pharmaceutically acceptable salt thereof; and (b) (i) a metal chelator configured to bind a radionuclide, the metal chelator being conjugated to a peptide, or (ii) a radionuclide covalently attached to a cyclic peptide.

10. A radiopharmaceutical conjugate comprising:

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

4. 3. The radiopharmaceutical conjugate of claim 2, wherein 1 to 5 amino acids selected from the group consisting of 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, and optionally no further additions and / or substitutions are present.

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

6. 6. The radiopharmaceutical conjugate of claim 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. 7. The radiopharmaceutical conjugate of any one of claims 1 or 4 to 6, wherein 1 to 2 amino acids selected from the group consisting of T at position 10 and E at position 11 of SEQ ID NO: 1 are deleted, and optionally have no further additions and / or substitutions.

8. 7. The radiopharmaceutical conjugate of claim 2, wherein the eighth V is substituted.

9. 7. The radiopharmaceutical conjugate of claim 2, wherein the 11th E is substituted.

10. 10. The radiopharmaceutical conjugate of claim 1, wherein the metal chelator is conjugated to the N-terminus of the peptide.

11. 11. The radiopharmaceutical conjugate of claim 1, further comprising a radionuclide bound to a metal chelator.

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

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

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

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

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

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

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

19. The metal chelating agent is 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, PC 19. The radiopharmaceutical conjugate of any one of claims 1 to 18, comprising H-OCTAPA, 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 maleimido-nBu-DOTA.

20. The metal chelating agent 【Chemical 1】 20. The radiopharmaceutical conjugate of claim 19 having the structure:

21. The metal chelating agent 【Chemistry 2】 20. The radiopharmaceutical conjugate of claim 19 having the structure:

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

23. 【Chemical 3】 (In the formula, 【Chemistry 4】 represents a linker) 23. The radiopharmaceutical conjugate of claim 22 having the structure:

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

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

26. 25. The radiopharmaceutical conjugate of claim 24, wherein the linker is attached to the eighth amino acid residue or X8.

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

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

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

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

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

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

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

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

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

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

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

38. The linker is represented by formula (II-1): 【Chemistry 5】 (In the formula, Each L independently represents —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) ２ NR Ｌ -, -C(=O)NR Ｌ S (= O) ２ -, -S(=O) ２ NR Ｌ C(=O)-, substituted or unsubstituted C ３ ~C １５ Cycloalkyl, substituted or unsubstituted C １ ~C １２ Heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C １ ~C ３０ Alkylene, substituted or unsubstituted C ２ ~C ３０ Alkenylene, substituted or unsubstituted C ２ ~C ３０ Alkynylene, substituted or unsubstituted C １ ~C ３０ Heteroalkylene, -(C １ ~C ３０ alkylene)-O-, -O-(C １ ~C ３０ alkylene)-, -(C １ ~C ３０ alkylene)-NR Ｌ -, -NR Ｌ -(C １ ~C ３０ alkylene)-, -(C １ ~C ３０ alkylene)-N(R Ｌ ) ２ -, or -N(R Ｌ ) ２ -(C １ ~C ３０ alkylene)-; Each R Ｌ are independently hydrogen, substituted or unsubstituted C １ ~C ４ Alkyl, substituted or unsubstituted C １ ~C ４ Heteroalkyl, substituted or unsubstituted C ２ ~C ６ Alkenyl, substituted or unsubstituted C ２ ~C ５ Alkynyl, substituted or unsubstituted C ３ ~C ８ Cycloalkyl, substituted or unsubstituted C ２ ~C ７ heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and n is 1 to 20) 31. The radiopharmaceutical conjugate of any one of claims 22 to 30, having the structure:

39. The linker is represented by formula (II-1a): 【Chemistry 6】 (In the formula, L １ and L ３ are each independently —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) ２ NR Ｌ -, -C(=O)NR Ｌ S (= O) ２ - or -S(=O) ２ NR Ｌ C(═O)—; L ２ is absent or is a substituted or unsubstituted C １ ~C ３０ Alkylene, or substituted or unsubstituted C １ ~C ３０ heteroalkylene) 39. The radiopharmaceutical conjugate of claim 38, comprising the structure:

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

41. L ２ is a substituted or unsubstituted C １ ~C ３０ Alkylene, or substituted or unsubstituted C １ ~C ３０ 41. The radiopharmaceutical conjugate of claim 39 or 40, which is a heteroalkylene.

42. L ２ is a substituted or unsubstituted C １ ~C １８ Alkylene, or substituted or unsubstituted C １ ~C １８ 41. The radiopharmaceutical conjugate of claim 39 or 40, which is a heteroalkylene.

43. L ２ -OH, -SH, oxo, amino, C １ ~C ６ Alkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ 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 optionally substituted with one or more substituents selected from １ ~C ６ Alkyl is -OH, -SH, oxo, amino, C ６ ~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 43. The radiopharmaceutical conjugate of any one of claims 39 to 42, optionally further substituted with one or more substituents selected from:

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

45. The linker 【Chemistry 7】 【Chemistry 8】 40. The radiopharmaceutical conjugate of claim 39 having the structure:

46. The linker 【Chemistry 9】 40. The radiopharmaceutical conjugate of claim 39 having the structure:

47. 47. The radiopharmaceutical conjugate of any one of claims 1 to 46, wherein the peptide or a pharmaceutically acceptable salt thereof has a cyclic structure in which the first amino acid (or X1) is covalently linked to the last amino acid (or X12).

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

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

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

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

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

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

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

58. 58. The radiopharmaceutical conjugate of 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 thereof).

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

60. 60. The radiopharmaceutical conjugate of 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. 60. The radiopharmaceutical conjugate of claim 59, wherein X11 is arginine (R), asparagine (N), aspartic acid (D), glutamine (Q), lysine (K), or a non-naturally occurring hydrophilic amino acid.

62. The peptide has the formula (I) X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) (In the formula, X1 is an amino acid; X2 is F or an unsubstituted phenyl ring of F, (i) —OH, —CN, and —C １～３ a phenyl ring substituted by 1 or 2 substituents each independently selected from alkyl, or (ii) —OH, —CN, and —C １～３ a 6-membered heteroaryl ring optionally substituted with 1 or 2 substituents each independently selected from alkyl; Here is a variant of that where you replace wherein F or a variant thereof may be 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 four or more carbon atoms in its side chain, including a linear, branched, or cyclic carbon chain), and X4 may be 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 the N-methylated amino acid; X7 is W, Y, or variants thereof (e.g., 6-, 9-, and 10-membered heteroaryl having one heteroatom (e.g., N), 6-, 9-, and 10-membered aryl or heteroaryl having -CH ３ , -6-membered aryl or heteroaryl, or amino acids having a 9- or 10-membered bicyclic aryl or heteroaryl linked to the alpha carbon through a carbon (e.g., a methylene group), optionally substituted with 1 or 2 substituents independently selected from -ethyl, -Cl, and -F; X8 is an amino acid having an -H on the alpha amino group; X9 is W or Y or a variant thereof (e.g., W or a variant thereof); X10 is absent or is a polar amino acid (e.g., T or a variant thereof); X11 is absent or an amino acid (e.g., a hydrophilic amino acid; Dab, Dap, R, E or a variant thereof; or an amino acid having a functional side chain); X12 is C or a variant thereof.

62. The radiopharmaceutical conjugate of any one of claims 1 to 61, having the amino acid sequence:

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

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

65. The peptide has the formula (Ia) X1-X2-X3-X4-X5-X6-X7-X8-X9-X12 Formula (Ia) (In the formula, 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); X12 is C or a variant thereof.

62. The radiopharmaceutical conjugate of any one of claims 1 to 61, having the amino acid sequence:

66. The peptide has the formula (I) X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) (In the formula, 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; X12 is C or a variant thereof.

62. The radiopharmaceutical conjugate of any one of claims 1 to 61, having the amino acid sequence:

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

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

69. 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., linear or branched C １～５ Alkyl-substituted G, C ３～７ G or C substituted with cycloalkyl ３～７ A) substituted with cycloalkyl; X5 is a hydrophilic L-amino acid, wherein the L-amino acid is -NH ２ , -C(O)OH, -NHC(NH)NH ２ , -NHC(O)NH ２ , —C(O)NH ２ , and —NHC(O)CH ３ comprising a functional group selected from X6 is a hydrophilic amino acid, F, Y, W, an N-methylated amino acid thereof, or a variant thereof, wherein the hydrophilic amino acid is -C(O)OH, -C(O)NH ２ , and —NHC(O)CH ３ comprising a functional group selected from X7 is F, W, or a variant thereof; X8 is one or two straight or branched C １～５ Alkyl-substituted G, C ３～７ Cycloalkyl-substituted G, C ３～７ A substituted with a cycloalkyl, or a hydrophilic L-amino acid, wherein the hydrophilic L-amino acid is -NH ２ , one or more of —OH, —C(O)OH, —NHC(NH)NH ２ , -NHC(O)NH ２ , —C(O)NH ２ , or -NHC(O)CH ３ or the hydrophilic amino acid comprises a zwitterion; X9 is F, W, or a variant thereof; X10 is absent, Q, S, K, Cit, N, T, or a variant thereof (e.g., linear or branched C １～５ Q, S, K, Cit, N, or T, optionally substituted with alkyl, or —NHC(NH)NH ２ , -NHC(O)NH ２ , —C(O)NH ２ , or -NHC(O)CH ３ L-amino acids including: X11 is absent, E, Q, R, Cit, K, D, or N, or a variant thereof; 62. The radiopharmaceutical conjugate of any one of claims 1 to 61, wherein X12 is C or a variant thereof.

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

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

72. The amino acid variants are selected from amino acids having one, two or three substituents based on said amino acid, wherein the substituents are halogen, -CN, -NH ２ , —NH(C １ ~C ３ alkyl), -N(C １ ~C ３ alkyl) ２ , oxo, —OH, —CO ２ H, -CO ２ -C １ ~C ３ Alkyl, —C(═O)NH ２ , -C(=O)NH(C １ ~C ３ alkyl), -C(=O)N(C １ ~C ３ alkyl) ２ , -S(=O) ２ NH ２ , -S(=O) ２ NH (C １ ~C ３ alkyl), -S(=O) ２ N (C １ ~C ３ alkyl) ２ , C １ ~C ６ Alkyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Alkoxy, C ６ ~C １０ Aryl, C ３ ~C ６ 72. The radiopharmaceutical conjugate of any one of claims 1 or 10-71, wherein the aryl is independently selected from cycloalkyl, 6- to 10-membered heterocycloalkyl, and 6- to 10-membered heteroaryl.

73. The variants are selected from amino acids having one or two amino acid-based substituents, where the substituents are halogen, —CN, —NH ２ , —NH(C １ ~C ３ alkyl), -N(C １ ~C ３ alkyl) ２ , oxo, —OH, —CO ２ H, -CO ２ -C １ ~C ３ Alkyl, —C(═O)NH ２ , -C(=O)NH(C １ ~C ３ alkyl), -C(=O)N(C １ ~C ３ alkyl) ２ , and C １ ~C ６ 73. The radiopharmaceutical conjugate of claim 72, wherein:

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

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

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

77. The peptide has the formula (I) X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) (In the formula, X1 is da, df3CON, dkCOpipzaa, dahp, dDab-NH ２ -Ph3-SO ２ F, dDap-NH ２ -Ph3-SO ２ F, dDap-NH ２ -Ph4-SO ２ F, dCit, Aib, G, norvaline, norleucine, d4PyCON, or dhAla; X2 is MeF, Me3Py, MeF3CON, MeF3F, Me4Py, or MeY(Me); X3 is absent, N, Q, Cit, G, Aib, Hgn, hCit, norCit, LysAc, OrnAc, Ala, or da; X4 is L, Cbg, Chg, Cba, Cha, Ahx, Dahp, Cit, I, V, norleucine, or norvaline; X5 is Hgl, Hgn, Dab, Dap, DabAc, DapAc, R, hArg, E, or D; X6 is absent, MeF, MeE, Me3Py, Me4Py, MeF4F, MeF4F, MeF4C, or MeY; X7 is W1Me, W1Me7Cl, W1Me7N, W, F, 7-AzaTrp, W7Me, W1Et, W1Me7Br, W1Me7OMe, or W1Me6O7Cl; X8 is V, KCOpipzaa, N, Cit, Qglucamine, hCit, K, KAc, Aib, Alb, DapAc, OrnAc, A, T, alT, norleucine, norvaline, Hgl, E, Hgn, Q, I, or L; X9 is W1Me, W1Me7Cl, W1Me7N, F23dMe, W1Et, W7Me, W, F, or 7-AzaTrp; X10 is absent, T, Q, S, Hgn, alpha-methylserine, hSer, hThr, N, OrnAc, LysAc, Cit, or hCit; X11 is absent, E, Hgn, R, hArg, Cit, hCit, Hgl, Orn, D, N, Q, DapAc, OrnAc, DabAc, or norCit; X12 is C, hCys, CdMe, C3RMe, C3SMe, selenocysteine, dc, or penicillamine 72. The radiopharmaceutical conjugate of any one of claims 1 to 71, having the amino acid sequence set forth in:

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

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

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

81. X7 is W1Me, W1MeCl, W1MeBr, Na1, Na12, W1Et, 3Bzf, 3Bzt, F23dC, W1Me7N, or F23dMe; X8 is V, KCOpipzaa, N, Cit, hCit, KAc, DapAc, OrnAc, A, T, alT, Aib, Alb, Qglucamine, Hgl, Q, E, Hgn, or K; and X9 is W1Me, Na11, W1Et, Na121N, 3Bzf, 3Bzt, Na118N, F23dMe, or F23dC; 81. The radiopharmaceutical conjugate of any one of claims 62 to 80.

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

83. (a) A cyclic peptide having avidity for ephrin type-A receptor 2 (EphA2), comprising the formula (I): X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) (In the formula, X1, X2, X3, X4, X5, X6, and X8 are each independently an amino acid; X7 is W1Me or a variant thereof; X9 is W1Me or a variant thereof; X10 and X11 are each independently absent or an amino acid; X12 is cysteine ​​(C) or a variant thereof or a pharmaceutically acceptable salt thereof; (b) a metal chelator configured to bind to a radionuclide; and (c) optionally, a linker connecting the peptide to the metal chelator.

10. A radiopharmaceutical conjugate comprising:

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

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

86. (a) A cyclic peptide having avidity for ephrin type-A receptor 2 (EphA2), comprising the formula (I): X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) [In the formula, X1 is any D- or L-amino acid; X2 is, 【Chemistry 10】 (In the formula, Ring A2 is phenyl or a 6-membered heteroaryl (e.g., heteroaryl with 1 or 2 N); R Ｘ２ are each independently a halogen, —CN, or —NO ２ , —OH, —OR ａ , —OC(═O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH,SF ５ , -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR 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) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, or heterocycloalkyl; where alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl, as appropriate, independently represent one or more R ＸＡ may be substituted with; kx2 is 0, 1, 2, or 3; mx2 is 0, 1, 2, 3 or 4; R ＮＸ２ is H, C １ ~C ６ Alkyl, or C １ ~C ６ haloalkyl; ＊ X1 represents the point of attachment to X1; ＊ X3 indicates the point of attachment to X3) having the structure X3 is, 【Chemistry 11】 (In the formula, kx3 is 0, 1, 2, or 3; R ＮＸ３ is H, C １ ~C ６ Alkyl, or C １ ~C ６ haloalkyl; R Ｘ３ is H, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ aminoalkyl, or C １ ~C ６ is heteroalkyl; ＊ X2 indicates the point of attachment to X2; ＊ X4 indicates the point of attachment to X4 having the structure X4 is a hydrophobic amino acid (e.g., an amino acid having four or more carbon atoms in its side chain, including a straight, branched, or cyclic carbon chain), and X4 is C １～３ may be N-alkylated with an alkyl group; The X5 is 【Chemistry 12】 (In the formula, R ＮＸ５ is H, -CN, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ aminoalkyl, or C １ ~C ６ heteroalkyl; where alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, or heteroalkyl is selected from one or more R ＸＡ optionally independently substituted with; R Ｘ５ -CN, -NO ２ , —OH, —OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH,SF ５ , -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR 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) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ aminoalkyl, or C １ ~C ６ heteroalkyl; where alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, or heteroalkyl is selected from one or more R ＸＡ may be independently substituted as appropriate, However, R ＮＸ５ and R Ｘ５ At least one of the groups is —OH, —NH ２ and —NH— (e.g., —NH—C(═NH)—NH ２ , —CO—NH ２ , -NH ２ , -COOH, -C(OH)-C ０～６ Alkyl, —NH—CO—C １～６ alkyl); ＊ X4 indicates the point of attachment to X4; ＊ X6 indicates the point of attachment to X6 is a hydrophilic L-amino acid, such as an amino acid having the structure: The X6 is 【Chemistry 13】 (e.g., N, F) (In the formula, R ＮＸ６ is H, C １ ~C ６ Alkyl, or C １ ~C ６ haloalkyl; R Ｘ６ -CN, -NO ２ , —OH, —OR ａ , —OC(═O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH,SF ５ , -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR 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) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is selected from the group consisting of one or more R ＸＡ optionally independently substituted with; ＊ X5 indicates the point of attachment to X5; ＊ X7 indicates the point of attachment to X7 and The X7 is 【Chemistry 14】 (In the formula, R ＮＸ７ is H, C １ ~C ６ Alkyl, or C １ ~C ６ haloalkyl; Ring A7 is aryl or heteroaryl; R Ｘ７ are each independently a halogen, —CN, or —NO ２ , —OH, —OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH,SF ５ , -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ -halogen, -S(=O) ２ NR 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) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, or heterocycloalkyl, where alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is selected from the group consisting of one or more R ＸＡ optionally independently substituted with; kx7 is 0, 1, 2, or 3; mx7 is 0, 1, 2, 3, 4 or 5; ＊ X6 indicates the point of attachment to X6; ＊ X8 indicates the point of attachment to X8) having the structure X8 is an L-amino acid with an -H on the alpha amino group; The X9 is 【Chemistry 15】 (In the formula, R ＮＸ９ is H, C １ ~C ６ Alkyl, or C １ ~C ６ haloalkyl; Ring A9 is aryl or heteroaryl; R Ｘ９ are each independently a halogen, —CN, or —NO ２ , —OH, —OR ａ , —OC(═O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH,SF ５ , -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR 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) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, or heterocycloalkyl, where alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is selected from the group consisting of one or more R ＸＡ optionally independently substituted with; kx9 is 0, 1, 2, or 3; mx9 is 0, 1, 2, 3, 4, or 5; ＊ X8 indicates the point of attachment to X8; ＊ XC indicates the point of attachment to (i) X10 or (i) X12 if X10 and X11 are absent. having the structure X10 is absent or an L-amino acid; X11 is absent or an L-amino acid, with the proviso that if X10 is absent then X11 is also absent; X12 is an L-amino acid with a reactive thiol group, such as Cys and Cys variants; R ａ are each independently C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ ~C ６ Alkyl (cycloalkyl), C １ ~C ６ Alkyl (heterocycloalkyl), C １ ~C ６ Alkyl (aryl), or C １ ~C ６ alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; R ｂ are each independently hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ ~C ６ Alkyl (cycloalkyl), C １ ~C ６ Alkyl (heterocycloalkyl), C １ ~C ６ Alkyl (aryl), or C １ ~C ６ alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; R ｃ and R ｄ are each independently hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ ~C ６ Alkyl (cycloalkyl), C １ ~C ６ Alkyl (heterocycloalkyl), C １ ~C ６ Alkyl (aryl), or C １ ~C ６ alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; or R ｃ and R ｄ together with the atom to which they are attached form a heterocycloalkyl which may be optionally substituted with one or more R; R and R ＸＡ are each independently a halogen, —CN, —OH, or —OC １ ~C ６ Alkyl, SF ５ , -S(=O)C １ ~C ６ Alkyl, —S(═O) ２ C １ ~C ６ Alkyl, —S(═O) ２ NH ２ , -S(=O) ２ -halogen, -S(=O) ２ NHC １ ~C ６ Alkyl, —S(═O) ２ N (C １ ~C ６ alkyl) ２ , -NH ２ , -NHC １ ~C ６ Alkyl, —N(C １ ~C ６ alkyl) ２ , -NR ｂ C (=NR ｂ ) NR ｃ R ｄ , -NHC(=O)OC １ ~C ６ Alkyl, —C(═O)C １ ~C ６ Alkyl, —C(═O)OH, —C(═O)OC １ ~C ６ Alkyl, —C(═O)NH ２ , -C(=O)N(C １ ~C ６ alkyl) ２ , -C(=O)NHC １ ~C ６ Alkyl, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ aminoalkyl, or C １ ~C ６ heteroalkyl] a peptide having an amino acid sequence of (b) a metal chelator configured to bind to a radionuclide; and (c) optionally, a linker connecting the peptide to the metal chelator.

10. A radiopharmaceutical conjugate comprising:

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

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

89. R Ｘ７ are each independently -CH ３ , -ethyl, -Cl, and -F; and mx7 is 0, 1, or 2.

90. 87. The radiopharmaceutical conjugate of claim 86, wherein X7 is W1Me, Na1, Na12, W1Et, Na1N, 3Bzf, 3Bzt, Na15N, Na14N, Na124N, Na128N, F23dMe, F23dC, W1Me7N, or W1Me7Cl.

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

92. X9, 【Chemistry 16】 and R Ｘ９ are each independently —OH, CN, NH ２ , C １ ~C ３ Alkyl, —Cl, —F, —Br, —CONH ２ , and -SO ２ 92. The radiopharmaceutical conjugate of any one of claims 86 to 91, wherein R is selected from: F.

93. 【Catalog 17】 but, 【Chemistry 18】 93. The radiopharmaceutical conjugate of any one of claims 86 to 92, wherein

94. R Ｘ９ are each independently a halogen, -CN, or -NO ２ , —OH, —OR ａ , -OC(=O)R ａ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR 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 , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ aminoalkyl, or C １ ~C ６ 94. The radiopharmaceutical conjugate of any one of claims 86 to 93, which is heteroalkyl.

95. 92. The radiopharmaceutical conjugate of any one of claims 86 to 91, wherein X9 is W1Me, W, Na11, W1Et, Na121N, 3Bzf, 3Bzt, Na114N, Na118N, F23dMe, F23dC, or W1Et.

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

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

98. R Ｘ５ But C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, -C ０～６ Alkylene-NH-C(=NH)-NH ２ , -C ０～６ Alkylene -CO-NH ２ , -C ０～６ Alkylene -COOH, or -NH-CO-C １～６ 98. The radiopharmaceutical conjugate of any one of claims 86 to 97, wherein said radiopharmaceutical conjugate is alkyl.

99. X7 is W1Me, W1MeCl, W1MeBr, Na1, Na12, W1Et, 3Bzf, 3Bzt, F23dC, W1Me7N, or F23dMe; X8 is V, KCOpipzaa, Hse, N, Cit, hCit, KAc, DapAc, OrnAc, T, alT, Aib, Alb, Qglucamine, Hgl, E, Hgn, MeF, 3Py6NH2, W1Me, A, Q, or K; 87. The radiopharmaceutical conjugate of any one of claims 83 to 86, wherein X9 is W1Me, Na11, W1Et, Na121N, 3Bzf, 3Bzt, Na118N, F23dMe, or F23dC.

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

101. X7 is W1Me; X8 is V; X9 is W1Me; 100. The radiopharmaceutical conjugate of claim 81 or 99.

102. X7 is W1Me; X8 is KCOpipzaa, N, Cit, hCit, KAc, DapAc, OrnAc, A, T, alT, Aib, Alb, Qglucamine, Hgl, Q, E, Hgn, or K; X9 is W1Me; 100. The radiopharmaceutical conjugate of claim 81 or 99.

103. The peptide has the formula (I) X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) (In the formula, 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 variant thereof; X5 is a hydrophilic amino acid or 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 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 (e.g., C) 62. The radiopharmaceutical conjugate of any one of claims 1 to 61, having the amino acid sequence set forth in:

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

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

106. The peptide has the formula (Ia) X1-X2-X3-X4-X5-X6-X7-X8-X9-X12 Formula (Ia) (In the formula, 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 acid or variant thereof; X5 is a hydrophilic amino acid or 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 variant thereof; X9 is W or a variant thereof; X12 is C or a variant thereof. or a pharmaceutically acceptable salt thereof, 62. The radiopharmaceutical conjugate of any one of claims 1 to 61.

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

108. 108. The radiopharmaceutical conjugate of claim 107, wherein said amino acid X1 and said cysteine ​​or variant thereof are linked.

109. The peptide is represented by formula (I-1) 【Chemistry 19】 (In the formula, R １ is NH ２ and OH; R ２ is H or C １～３ selected from the group consisting of alkyl; R ３ is H or C １～３ selected from the group consisting of alkyl; X1-X11 have the definitions set forth in formula (I), with no point of attachment to the radionuclide or linker indicated.

108. The radiopharmaceutical conjugate of claim 107, having the structure:

110. The peptide of formula (I-1) is 【Chemistry 20】 110. The radiopharmaceutical conjugate of claim 109, having the structure:

111. Formula (III-1) 【Chemical 21】 (In the formula, X1 to X11 have the definitions described in formula (I), -Linker- represents a linker connecting the peptide and the metal chelator.

111. The radiopharmaceutical conjugate of any one of claims 22 to 110, having the structure:

112. Formula (III-2) 【Chemical 22】 (In the formula, Lcyc is a ring-closing group covalently connecting X1 to X12; -Linker- represents a linker connecting the peptide and the metal chelator; X1 to X12 have the definitions described in formula (I).

111. The radiopharmaceutical conjugate of any one of claims 22 to 110, having the structure:

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

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

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

282.

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

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

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

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

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

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

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

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

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

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

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

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

130. 129. The radiopharmaceutical conjugate of 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. 84. The radiopharmaceutical conjugate of claim 1, 2 or 83, which is a compound described in Table 1, 2A, 2B, 2B-Lu, 2B-Lu-177, 2B-Ac-225, or 2C.

132. (a) a peptide having avidity for ephrin type A receptor 2 (EphA2), comprising SEQ ID NO: 1: da-MeF-NL-Hgl-MeF-W1Me-V-W1Me-T-E-C (SEQ ID NO: 1) a peptide having an amino acid sequence containing one or more amino acid deletions, substitutions, and / or additions in the amino acid sequence of (b) a metal chelator configured to bind a radionuclide, the metal chelator being conjugated to a peptide.

10. A radiopharmaceutical conjugate comprising:

133. 133. The radiopharmaceutical conjugate of claim 2 or 132, wherein the eighth V is substituted.

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

135. (a) A peptide having avidity for ephrin type-A receptor 2 (EphA2), comprising the formula (I): X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) (In the formula, X1 is an 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 variants thereof), glycine (G), alanine (A) or variants 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 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, an N-methylated amino acid, or a variant thereof; X9 is an amino acid containing an aromatic ring (e.g., W or a variant thereof); X10 is absent or a hydrophilic amino acid (e.g., threonine (T) or a variant thereof); X11 is absent or a hydrophilic amino acid; X12 is cysteine ​​(C) or a variant thereof or a pharmaceutically acceptable salt thereof; and (b) a metal chelator configured to bind a radionuclide, the metal chelator being conjugated to a peptide.

10. A radiopharmaceutical conjugate comprising:

136. (a) A cyclic peptide having avidity for ephrin type-A receptor 2 (EphA2), comprising the formula (I): X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) (In the formula, X1, X2, X3, X4, X5, X6, and X8 are each independently an amino acid; X7 is W1Me or a variant thereof; X9 is W1Me or a variant thereof; X10 and X11 are each independently absent or an amino acid; X12 is cysteine ​​(C) or a variant thereof or a pharmaceutically acceptable salt thereof; (b) a metal chelator configured to bind to a radionuclide; and (c) a linker connecting the peptide to the metal chelator 10. A radiopharmaceutical conjugate comprising:

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

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

139. 139. The radiopharmaceutical conjugate of 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 Asp53, Met55, Asn57, Met59, Met66, Thr101, Arg103, Phe156, Glu157, Arg159, Val161, Val189, and Ala190.

140. 140. The radiopharmaceutical conjugate of claim 139, wherein the peptide competes for binding to human EphA2 at one or more amino acid residues selected from Asp53, Phel56, and Glul57.

141. 141. The radiopharmaceutical conjugate of 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. 142. A radiopharmaceutical conjugate which is a salt of the conjugate of any one of claims 1 to 141.

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

144. 143. A radiolabeled human EphA2 protein that binds to the radiopharmaceutical conjugate of any one of claims 1 to 142.

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

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

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

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

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

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

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

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

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

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

Images