Combination therapies for treatment of melanoma

Abstract

The present invention relates to treatment of melanoma with a combination therapy comprising a radioconjugate comprising alpha-melanocyte-stimulating hormone analogues which target melanocortin 1 receptor and (i) one or more checkpoint inhibitors; or (ii) one or more targeted therapies.

Description

COMBINATION THERAPIES FOR TREATMENT OF MELANOMACROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 776,748, filed March 24, 2025, and U.S. Provisional Patent Application No. 63 / 776,752, filed March 24, 2025, the contents of which are hereby incorporated by reference in their entireties for all purposes.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (A9TH_038_01 WO_SeqList_ST26.xml; Size: 165,101 bytes; and Date of Creation: March 23, 2026) are herein incorporated by reference in their entirety.FIELD

[0003] The present invention relates to use of alpha-melanocyte-stimulating hormone analogues which target melanocortin 1 receptor in the treatment of melanoma.BACKGROUND

[0004] Current imaging technologies for metastatic melanomas, e.g. including cutaneous, amelanotic and uveal melanomas, have limited sensitivity for detecting small metastatic lesions, early nodal metastases, and liver metastases. In addition, current treatments for metastatic melanomas have limited success at later stages.

[0005] Melanocortin 1 receptor (MC1R) is specifically expressed in cutaneous, amelanotic and uveal melanomas. The low level of MC1 R expression in normal tissues makes this protein an attractive target for radionuclide imaging and therapy for melanomas. The endogenous ligand of MC1 R is alpha-melanocyte-stimulating hormone (aMSH), which binds MC1 R with sub-nanomolar binding affinity. However, aMSH also binds to other melanocortin receptors, including MC3R, MC4R and MC5R. aMSH does not bind to MC2R, which is selectively activated by adrenocorticotropic hormone.

[0006] While peptide analogues of aMSH have been developed for imaging applications (e.g.68Ga-labeled CCZ01048 having sequence DOTA-Pip-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 1); see Zhang et al., 2017 Theranostics 7(4):805-813)), there remains a need for higher selectivity for MC1 R over the other melanocortin receptors to reduce off-target accumulation of MC1 R targeting radiolabeled peptides in vivo. The metabolic stability of the peptide analogues is also important to achieve high tumour accumulation and long-term retention of the radiolabeled peptide analogues tor in vivo for imaging of MC1 R-expressing tissues and / or therapy of MC1 R-related conditions or diseases, e.g. melanoma, non-melanoma skin cancers and others.

[0007] There remains a need for effective treatment of melanoma with acceptable safety profiles.

[0008] No admission is necessarily intended, nor should it be construed, that any of the preceding information constitutes prior art against the present disclosure.SUMMARY

[0009] Various embodiments in this disclosure relate to a combination therapy comprising a radioconjugate comprising a melanocortin 1 receptor (MC1R) targeting peptide (MC1RTP), a radiolabeling group (e.g., a CROWN chelator) for chelating a radionuclide, and a linker joining the MC1RTP to the radiolabeling group and (i) one or more checkpoint inhibitors; or (ii) one or more targeted therapies.

[0010] In one aspect, the present disclosure covers a method of treating melanoma, comprising administering to a subject (e.g., a patient) in need thereof a combination of:(a) one or more checkpoint inhibitors, and(b) a radioconjugate comprising a melanocortin 1 receptor (MC1R) targeting peptide (MC1 RTP) linked to a CROWN, a CROWNGA, or a CROWN Amide chelator by a linker, or a pharmaceutically acceptable salt thereof, wherein:the MCR1TP is cyclized and comprises a sequence of Formula A or B:Xaa1-Xaa2a-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7a(A) (SEQ ID NO: 2) Xaa1-Xaa2b-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7b(B) (SEQ ID NO: 3) Xaa1is selected from the group consisting of norleucine (Nle), D-Nle, Ala, D-Ala, Leu, D-Leu, He, D-lle, Cys, D-Cys, Met, D-Met, Phe, D-Phe, Trp, D-Trp, Vai, D-Val, 3-(1-naphthyl)alanine (Nal), D-Nal, 3-(2-naphthyl)alanine (2-Nal), D-2-Nal, Gly, a-aminobutyric acid, norvaline, D-norvaline, homonorleucine, and D-homonorleucine;Xaa2ais selected from the group consisting of Cys, D-Cys, Asp, D-Asp, Glu, D-Glu, 2-aminoadipic acid (2-Aad), D-2-Aad, 3-aminoadipic acid (3-Aad), D-3-Aad, propargylglycine (Pra), D-Pra, homopropargylglycine (Hpg), D-Hpg, beta-homopropargylglycine (Bpg), and D-Bpg;Xaa2bis selected from the group consisting of Cys, D-Cys, Lys, D-Lys, Ornithine (Orn), D-Orn, 2,4-diaminobutyric acid (Dab), D-Dab, 2,3-diaminopropionic acid (Dap), D-Dap, Lys(N3), D-Lys(N3), Orn(N3), D-Orn(N3), Dab(N3), D-Dab(N3), Dap(N3), D-Dap(N3), 2-(5'-azidopentyl)alanine, D-2-(5'-azidopentyl)alanine, 2-(6'-azidohexyl)alanine, and D-2-(6'-azidohexyl)alanine;Xaa3is His;Xaa4is D-Phe;Xaa5is Arg;Xaa6is Trp;Xaa7ais selected from the group consisting of Cys, D-Cys, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, Lys(N3), D-Lys(N3), Orn(N3), D-Orn(N3), Dab(N3), D-Dab(N3), Dap(N3), D-Dap(N3), 2-(5’-azidopentyl)alanine, D-2-(5’-azidopentyl)alanine, 2-(6’-azidohexyl)alanine, and D-2-(6’-azidohexyl)alanine;Xaa7bis selected from the group consisting of Cys, D-Cys, Asp, D-Asp, Glu, D-Glu, 2-Aad, D-2-Aad, 3-Aad, D-3-Aad, Pra, D-Pra, Hpg, D-Hpg, Bpg, and D-Bpg;wherein one or more of Xaa3, Xaa5, Xaa6, and Xaa7ais alpha N-methylated in Formula A, and one or more of Xaa3, Xaa5, Xaa6, and Xaa7bis alpha N-methylated in Formula B; andwherein the MCR1TP is optionally C-terminally amidated.A9TH-038 / 01WG 344158-2244

[0011] In another aspect, the present disclosure covers a method of treating melanoma, comprising administering to a subject (e.g., a patient) in need thereof a combination of:(a) one or more targeted therapies, and(b) a radioconjugate comprising a melanocortin 1 receptor (MC1R) targeting peptide (MC1 RTP) linked to a CROWN, a CROWNGA, or a CROWN Amide chelator by a linker, or a pharmaceutically acceptable salt thereof, wherein:the MCR1TP is cyclized and comprises a sequence of Formula A or B:Xaa1-Xaa2a-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7a(A) (SEQ ID NO: 2) Xaa1-Xaa2b-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7b(B) (SEQ ID NO: 3) Xaa1is selected from the group consisting of norleucine (Nle), D-Nle, Ala, D-Ala, Leu, D-Leu, He, D-lle, Cys, D-Cys, Met, D-Met, Phe, D-Phe, Trp, D-Trp, Vai, D-Val, 3-(1-naphthyl)alanine (Nal), D-Nal, 3-(2-naphthyl)alanine (2-Nal), D-2-Nal, Gly, a-aminobutyric acid, norvaline, D-norvaline, homonorleucine, and D-homonorleucine;Xaa2ais selected from the group consisting of Cys, D-Cys, Asp, D-Asp, Glu, D-Glu, 2-aminoadipic acid (2-Aad), D-2-Aad, 3-aminoadipic acid (3-Aad), D-3-Aad, propargylglycine (Pra), D-Pra, homopropargylglycine (Hpg), D-Hpg, beta-homopropargylglycine (Bpg), and D-Bpg;Xaa2bis selected from the group consisting of Cys, D-Cys, Lys, D-Lys, Ornithine (Orn), D-Orn, 2,4-diaminobutyric acid (Dab), D-Dab, 2,3-diaminopropionic acid (Dap), D-Dap, Lys(N3), D-Lys(N3), Orn(N3), D-Orn(N3), Dab(N3), D-Dab(N3), Dap(N3), D-Dap(N3), 2-(5'-azidopentyl)alanine, D-2-(5'-azidopentyl)alanine, 2-(6'-azidohexyl)alanine, and D-2-(6'-azidohexyl)alanine;Xaa3is His;Xaa4is D-Phe;Xaa5is Arg;Xaa6is Trp;Xaa7ais selected from the group consisting of Cys, D-Cys, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, Lys(N3), D-Lys(N3), Orn(N3), D-Orn(N3), Dab(N3), D-Dab(N3), Dap(N3), D-Dap(N3), 2-(5’-azidopentyl)alanine, D-2-(5’-azidopentyl)alanine, 2-(6’-azidohexyl)alanine, and D-2-(6’-azidohexyl)alanine;Xaa7bis selected from the group consisting of Cys, D-Cys, Asp, D-Asp, Glu, D-Glu, 2-Aad, D-2-Aad, 3-Aad, D-3-Aad, Pra, D-Pra, Hpg, D-Hpg, Bpg, and D-Bpg;wherein one or more of Xaa3, Xaa5, Xaa6, and Xaa7ais alpha N-methylated in Formula A, and one or more of Xaa3, Xaa5, Xaa6, and Xaa7bis alpha N-methylated in Formula B; andwherein the MCR1TP is optionally C-terminally amidated.

[0012] In some embodiments, the method uses a radioconjugate comprising a radionuclide chelated to a compound of Formula I or II, or a stereoisomer or a pharmaceutically acceptable salt or solvate thereof:Formula I (SEQ ID NO: 4),Formula II (SEQ ID NO: 5),wherein the linker comprises one or more O, S, NR, C=O, C1-6 alkyl, C3-6 cycloalkyl, C1-6 heterocycloalkyl, aryl, or heteroaryl, or a combination thereof, R being H or C1-3 alkyl; and wherein the linker optionally comprises an albumin binding moiety.

[0013] In some embodiments, the method uses one or more checkpoint inhibitors selected from a CTLA-4 inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a LAG-3 inhibitor, or a combination thereof.

[0014] In some embodiments, the method uses a single PD-1 inhibitor or more than one PD-1 inhibitors.

[0015] In some embodiments, the one or more targeted therapies are selected from a BRAF inhibitor, a MEK inhibitor, or a combination thereof.

[0016] In some embodiments, the melanoma is metastatic cutaneous melanoma or metastatic uveal melanoma.

[0017] In some embodiments, the melanoma is unresectable or metastatic cutaneous, uveal, or mucosal melanoma.

[0018] In some embodiments, the melanoma is unresectable or metastatic cutaneous melanoma with disease progression while receiving an anti-PD-1 / PD-L1 -containing regimen as the most recent line of therapy.

[0019] In some embodiments, the subject has failed treatment with a PD-1 inhibitor, a PD-L1-inhibitor, or a combination thereof.A9TH-038 / 01WG 344158-2244BRIEF DESCRIPTION OF THE DRAWINGS

[0020] These and other features of the invention will become more apparent from the following description in which reference is made to the appended drawings wherein:

[0021] FIG. 1 shows change in tumor volume in a dose escalation study between225Ac-labeled Compound C (at 15 kBq and 30 kBq) and177Lu-labeled CCZ01158 (at 20 MBq and 40 MBq) in SK-MEL-1 tumor-bearing NRG mice.

[0022] FIG. 2 shows probability of survival of SK-MEL-1 tumor-bearing NRG mice injected with ^Ac-labeled Compound C (at 15 kBq and 30 kBq) or177Lu-labeled CCZ01158 (at 20 MBq and 40 MBq).DETAILED DESCRIPTIONDefinitions

[0023] As used herein, the terms “comprising,” “having”, “including” and “containing,” and grammatical variations thereof, are inclusive or open-ended and do not exclude additional, non-recited elements and / or method steps. The term “consisting essentially of’ if used herein in connection with a compound, composition, use or method, denotes that additional elements and / or method steps may be present, but that these additions do not materially affect the manner in which the recited compound, composition, method or use functions. The term “consisting of’ when used herein in connection with a composition, use or method, excludes the presence of additional elements and / or method steps. A compound, composition, use or method described herein as comprising certain elements and / or steps may also, in certain embodiments, consist essentially of those elements and / or steps, and in other embodiments consist of those elements and / or steps, whether or not these embodiments are specifically referred to. A use or method described herein as comprising certain elements and / or steps may also, in certain embodiments, consist essentially of those elements and / or steps, and in other embodiments, consist of those elements and / or steps, whether or not these embodiments are specifically referred to.

[0024] Unless otherwise specified, “certain embodiments”, “various embodiments”, “an embodiment” and similar terms includes the particular feature(s) described for that embodiment either alone or in combination with any other embodiment or embodiments described herein, whether or not the other embodiments are directly or indirectly referenced and regardless of whether the feature or embodiment is described in the context of a compound, method, product, use, composition, etcetera.

[0025] A reference to an element by the indefinite article “a” does not exclude the possibility that more than one of the elements is present, unless the context clearly requires that there be one and only one of the elements. The singular forms “a”, “an”, and “the” include plural referents unless the content clearly dictates otherwise. The use of the word “a” or “an” when used herein in conjunction with the term “comprising” may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one” and “one or more than one.” The term “plurality” if used herein means more than one, for example, two or more, three or more, four or more, and the like.

[0026] As used herein, the term “about” has the meaning that the following value may vary by ± 20 %. For example, about 1000 mg means 1000 ± 200 mg.

[0027] The term “alkyl” refers to an optionally substituted straight-chain, or optionally substituted branched-chain saturated hydrocarbon monoradical. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, n-pentyl, t-amyl, and hexyl, and longer alkyl groups, such as heptyl, octyl, and the like. Whenever it appears herein, a numerical range such as “C1-10 alkyl” or “C1-C10 alkyl” means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.

[0028] The term “alkylene” refers to a straight or branched divalent hydrocarbon chain. Examples of alkylene include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, and -CH2CH(CH3)CH2-.

[0029] The term “alkenyl” refers to an optionally substituted straight-chain, or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds.Examples of alkenyl include, but are not limited to, ethenyl (-CH=CH2), 1 -propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1 ,3-butadienyl, and the like. The double bond in an alkenyl may be in either the cis or trans configuration and should be understood to include both isomers.Whenever it appears herein, a numerical range such as “C2-6 alkenyl” or“C2-Ce alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0030] The term “alkynyl” refers to an optionally substituted straight-chain or optionally substituted branched- chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds. Examples of alkynyl include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1 ,3-butadiynyl, and the like.

[0031] The term “alkylamino” refers to a radical of the formula -NHR or -NRR’, where R and R’ are, independently, an alkyl radical as defined. Examples of alkylamino include, but are not limited to, -NHMe, -NHEt, -NHPh, -N(Me)2, and -NMeEt.

[0032] The term “alkoxy” refers to a radical of the formula -OR where R is an alkyl radical as defined. Examples of alkoxy include, but are not limited to, -OMe, -OEt, and -OBu‘.

[0033] The term “aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Examples of aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, and aminopentyl.

[0034] The term “aryl” refers to monocyclic and bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. The term “aryl” may be used interchangeably with the term “aryl ring”. In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl”, as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. An aryl can be a monocyclic or polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) ring system, which may include fused, spiro or bridged ring systems.

[0035] The term “carbocycle” refers to a ring system that contains only carbon atoms within the ring. A carbocycle can comprise one or more rings, wherein each ring can be saturated, partially saturated, or unsaturated. A carbocycle can be an aryl (e.g., phenyl) or a cycloalkyl (e.g., cyclohexyl), as defined below, or a combination thereof. As used herein, a carbocycle can be fused with an aryl or a heteroaryl, as defined below, or another carbocycle, to form a fused bicyclic system.

[0036] The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. Cycloalkyls can be saturated or partially unsaturated. Cycloalkyls can also be spirocyclic or bridged compounds. In addition, cycloalkyls can be fused with an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0037] The term “halo” or “halogen” refers to bromo, chloro, fluoro, or iodo.

[0038] The term “haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halogens. Examples of haloalkyl include, but are not limited to, iodoalkyl, bromoalkyl, chloroalkyl, and fluoroalkyl. A haloalkyl can comprise one or more halo atoms. For example, “fluoroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like.

[0039] The term “heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof. Examples of heteroalkyl include, but are not limited to, -CH2-O-CH2-, -CH2-NH-CH2-, -CH2-N(alkyl)-CH2-, -OCH2CH2O-, and -OCH2CH2OCH2CH2O-.

[0040] The term “heterocycloalkyl” refers to a cycloalkyl group that includes at least one hetero ring atom, e.g., a heteroatom selected from nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, or bicyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. The nitrogen, carbon or sulfur atom in the heterocyclyl radical may be optionally oxidized. The nitrogen atom may be optionally quaternized. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, tetrahydroquinolyl, imidazolinyl, imidazolidinyl, morpholinyl, piperidinyl, and piperazinyl.

[0041] The term “heteroaryl” refers to a ring system radical comprising carbon atom(s) and one or more ring heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, heteroaryl is monocyclic, bicyclic or polycyclic. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, furazanyl, indolizine, indole, benzofuran, benzothiophene, and indazole. A heteroaryl radical can be a monocyclic or polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) ring system, which may include fused, spiro or bridged ring systems.

[0042] The terms “heterocycle”, “heterocyclyl”, “heterocyclic radical”, and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms (e.g., oxygen, sulfur, nitrogen, phosphorus, or silicon). When used in reference to a ring atom of a heterocycle, the term “nitrogen” includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2 / 7- _N ^NHpyrrolyl -), NH (as in pyrrolidinyl - ), NR (as in N-substituted 2- pyrrolidinyl -R? ,* ) or+NR (as in N-substituted 1 -pyrrolidinyl -). As used herein, a heterocycle can be fused with an aryl, cycloalkyl, heteroaryl, or another heterocycle, to form a fused bicyclic system.

[0043] Unless stated otherwise specifically in the specification, alkyl, alkylene, alkenyl, alkynyl, alkoxy, alkylamino, aminoalkyl, aryl, carbocycle, cycloalkyl, haloalkyl, heterocycloalkyl, heteroaryl, or heterocycle, as used throughout the present disclosure, is optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxy, oxo (=O), alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heterocycle, and the like.

[0044] The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[0045] As used herein, the term “cyclic” may be used as it is normally understood to a person of skill in the art and generally refers to a chemical group having a covalent bond between two moieties within the group to form a ring structure.

[0046] As used herein, the term “branched” may be used as it is normally understood to a person of skill in the art and generally refers to a chemical entity that comprises a skeleton or main chain that splits off into more than one contiguous chain. The portions of the skeleton or main chain that split off in more than one direction may be linear, cyclic or any combination thereof. Non-limiting examples of a branched alkyl group include tert-butyl and isopropyl.

[0047] As used herein, the term “saturated” when referring to a chemical entity may be used as it is normally understood to a person of skill in the art and generally refers to a chemical entity that comprises only single bonds. Non-limiting examples of a saturated C1-C15 alkyl group may include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, i-pentyl, secpentyl, t-pentyl, n-hexyl, i-hexyl, 1 ,2-dimethylpropyl, 2-ethylpropyl, 1-methyl-2-ethylpropyl, l-ethyl-2-methylpropyl, 1 ,1 ,2-trimethylpropyl, 1 ,1 ,2-triethylpropyl, 1 ,1 -dimethylbutyl, 2,2-dimethylbutyl, 2-ethylbutyl, 1 ,3-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, sec-hexyl, t-hexyl, n-heptyl, i-heptyl, secheptyl, t-heptyl, n-octyl, i-octyl, sec-octyl, t-octyl, n-nonyl, i-nonyl, sec-nonyl, t-nonyl, n-decyl, i-decyl, sec-decyl and t-decyl. Non-limiting examples of C2-C15 alkenyl group may include vinyl, allyl, isopropenyl, l-propene-2-yl, 1-butene-l-yl, l-butene-2-yl, l-butene-3-yl, 2-butene-l-yl, 2-butene-2-yl, octenyl and decenyl. Non-limiting examples of C2-C15 alkynyl group may include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl and decynyl. Without limitation, the above-defined saturated C1-C15 alkyls, C2-C15 alkenyls and C2-C15 alkynyls are all encompassed within the term “X1-X15 alkyl”, as used herein. Without limitation, the term “X1-X15 heteroalkyl” would encompass each of the above-defined saturated C1-C15 alkyls, C2-C15 alkenyls and C2-C15 alkynyls, where one or more of the carbon atoms is independently replaced with a heteroatom. The person of skill in the art would understand that various combinations of different heteroatoms may be used.

[0048] As used herein, the term “substituted” is used as it would normally be understood to a person of skill in the art and generally refers to a compound or chemical entity that has one chemical group replaced with a different chemical group. Unless otherwise specified, a substituted alkyl is an alkyl in which one or more hydrogen atom(s) are independently each replaced with an atom that is not hydrogen. For example, chloromethyl is a non-limiting example of a substituted alkyl, more particularly an example of a substituted methyl. Aminoethyl is another non-limiting example of a substituted alkyl, more particularly an example of a substituted ethyl. Unless otherwise specified, a substituted compound or group (e.g. alkyl, heteroalkyl, aryl, heteroaryl and the like) may be substituted with any chemical group reasonable to the person of skill in the art. For example, but without limitation, a hydrogen bonded to a carbon or heteroatom (e.g. N) may be substituted with halide (e.g. F, I, Br, Cl), amine, amide, oxo, hydroxyl, thiol, phosphate, phosphonate, sulfate, SO2H, SO3H, alkyls, heteroalkyls, aryl, heteroaryl, ketones, carboxaldehyde, carboxylates, carboxamides, nitriles, monohalomethyl, dihalomethyl ortrihalomethyl.

[0049] As used herein, the term “unsubstituted” is used as it would normally be understood to a person of skill in the art. Non-limiting examples of unsubstituted alkyls include methyl, ethyl, tert-butyl, pentyl and the like. The expression “optionally substituted” is used interchangeably with the expression “unsubstituted or substituted”.

[0050] In the structures provided herein, hydrogen may or may not be shown. In some embodiments, hydrogens (whether shown or implicit) may be protium (i.e.1H), deuterium (i.e.2H) or combinations of1H and2H. Methods for exchanging1H with2H are well known in the art. For solventexchangeable hydrogens, the exchange of1H with2H occurs readily in the presence of a suitable deuterium source, without any catalyst. The use of acid, base or metal catalysts, coupled with conditions of increased temperature and pressure, can facilitate the exchange of non-exchangeable hydrogen atoms, generally resulting in the exchange of all1H to2H in a molecule.

[0051] Unless otherwise specified a “peptide” as referred to herein may comprise proteinogenic and / or non-proteinogenic amino acid residues. Non-limiting examples of nonproteinogenic amino acids include: D-amino acids (including without limitation any D-form of the following amino acids), ornithine (Orn), 3-(1-naphtyl)alanine (Nal), 3-(2-naphtyl)alanine (2-Nal), a-aminobutyric acid, norvaline, norleucine (Nle), homonorleucine, beta-(1 ,2,3-triazol-4-yl)-L-alanine, 1 ,2,4-triazole-3-alanine, Phe(4-F), Phe(4-CI), Phe(4-Br), Phe(4-I), Phe(4-NH2), Phe(4-NC>2), homoarginine (hArg), 2-amino-4-guanidinobutyric acid (Agb), 2-amino-3-guanidinopropionic acid (Agp), Trp(5-Br), Trp(5-OCH3), Trp(6-F), Trp(5-OH) orTrp(CHO), 2-aminoadipic acid (2-Aad), 3-aminoadipic acid (3-Aad), propargylglycine (Pra), homopropargylglycine (Hpg), beta-homopropargylglycine (Bpg), 2,3-diaminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab), azidolysine (Lys(Ns)), azido-ornithine (Orn(Ns)), 2-amino-4-azidobutanoic acid Dab(Ns), Dap(Ns), 2-(5'-azidopentyl)alanine, 2-(6'-azidohexyl)alanine, 4-amino-1-carboxymethyl-piperidine (Pip), 4-(2-aminoethyl)-1 -carboxymethylpiperazine (Acp).

[0052] If not specified as an L- or D-amino acid, an amino acid shall be understood to be an L-amino acid.

[0053] Unless otherwise specified, amino acids may be modified by any modifications known in the art subject to the common general knowledge of the person of skill in the art. For example, but without limitation, a C-terminal amino acid residue may be amidated, which refers to replacement of the C-terminal carboxylate with an amide, i.e. -C(O)NH2 instead 0f -C(O)OH. Amidated residues are identified with -NH2 (e.g. Lys-NH2, Trp-NH2 and the like). As a further non-limiting example, amino acids may be methylated, e.g. N-methylated or alpha N-methylated.

[0054] The terms “treat,” “prevent,” “ameliorate,” and “inhibit,” as well as words stemming therefrom, as used herein, do not necessarily imply 100% or complete treatment, prevention, amelioration, or inhibition. Rather, there are varying degrees of treatment, prevention, amelioration, and inhibition of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect. Accordingly, the disclosed methods can provide any amount of any level of treatment, prevention, amelioration, or inhibition of the disorder in a subject. For example, a disorder, including symptoms or conditions thereof, may be reduced by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%. Furthermore, the treatment, prevention, amelioration, or inhibition provided by the methods disclosed herein can include treatment, prevention, amelioration, or inhibition of one or more conditions or symptoms of the disorder, e.g., cancer. As used herein, “treating” includes the concepts of “alleviating”, which refers to lessening the frequency of occurrence or recurrence, orthe severity, of any symptoms or other ill effects related to a disorder and / or the associated side effects. The term “treating” also encompasses the concept of “managing” which refers to reducing the severity of a particular disease or disorder in a patient or delaying its recurrence, e.g., lengthening the period of remission in a patient who had suffered from the disease.

[0055] In certain embodiments, the term “prevent” or “preventing” as related to a disease or disorder can referto a compound that in a statistical sample, reduces the occurrences of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.

[0056] The term “therapeutically effective amount” as used herein refers to an amount effective at the dosage and duration necessary to achieve the desired therapeutic result. A therapeutically effective amount of the composition may vary depending on factors such as the individual’s condition, age, sex, and weight, and the ability ofthe protein to elicit the desired response of the individual. A therapeutically effective amount can also be an amount that exceeds any toxic or deleterious effect of the composition that would have a beneficial effect on the treatment.

[0057] As used herein, the term “combination therapy” or “combination” as used in reference to the methods of the disclosure refers a therapy wherein a radioconjugate as disclosed herein and a combination partner, e.g., one or more checkpoint inhibitors or one or more targeted therapies, may be administered concurrently or separately, i.e., separately within time intervals or treatment cycles,especially where these time intervals allow that the combination partners exhibit a cooperative effect with the radioconjugate, e.g., a synergistic effect. The single components may be packaged in a kit or separately. One or both of the components (e.g., powders or liquids) may be reconstituted or diluted to a desired dose prior to administration.

[0058] As used herein, the term “targeted therapy” refers to precision cancer treatment that uses drugs to block specific biomolecules, genes, or proteins responsible for cancer growth and survival. Unlike chemotherapy, targeted therapies are target-specific and therefore have reduced side effects and toxicity towards healthy cells and tissues. Non-limiting examples of targeted therapies include small molecules (e.g., BRAF inhibitors and MEK inhibitors) and monoclonal antibodies.

[0059] The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means an alkyl, as defined above, that is either substituted or unsubstituted. Further, an optionally substituted group may be un- substituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and monosubstituted (e.g., -CH2CHF2, - CH2CF3, -CF2CH3, -CFHCHF2, etc.).

[0060] As used herein, the term “substituent” means positional variables on the atoms of a core molecule that are substituted at a designated atom position, replacing one or more hydrogens on the designated atom, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. A person of ordinary skill in the art should note that any carbon as well as heteroatom with valences that appear to be unsatisfied as described or shown herein is assumed to have a sufficient number of hydrogen atom(s) to satisfy the valences described or shown. In certain instances, one or more substituents having a double bond (e.g., “oxo” or “=O”) as the point of attachment may be described, shown or listed herein within a substituent group, wherein the structure may only show a single bond as the point of attachment to the core structure. A person of ordinary skill in the art would understand that, while only a single bond is shown, a double bond is intended forthose substituents.

[0061] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure, i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure. For example, referring to Formula I or II, each amino acid moiety as depicted includes both D- and L- forms, when applicable, of the corresponding amino acid.

[0062] The term “amino acid” is used in its broadest meaning, and it embraces not only natural amino acids but also derivatives thereof and artificial amino acids. For example, the term “amino acid” also encompasses unnatural amino acids.

[0063] The term “natural amino acid” refers to the 20 naturally occurring amino acids that are identified throughout by the conventional three- or one-letter abbreviations indicated in Table 1 below,which are as generally accepted in the art and recommended by the IUPAC-IUB commission in biochemical nomenclature.Table 1. Amino acid codesName 3-Letter 1 -Letter Name 3-Letter 1 -Letter Code Code Code Code Alanine Ala A Leucine Leu LArginine Arg R Lysine Lys K Asparagine Asn N Methionine Met MAspartic Acid Asp D Phenylalanine Phe FCysteine Cys C Proline Pro PGlutamic Acid Glu E Serine Ser SGlutamine Gin Q Threonine Thr TGlycine Gly G Tryptophan Trp WHistidine His H Tyrosine Tyr YIsoleucine He I Valine Vai V

[0064] The term “unnatural amino acid,” interchangeably used with “non-natural amino acid” or “synthetic amino acid”, as used herein, may be any molecule that falls under the general definition of an amino acid, i.e., that comprises an amino group and a carboxyl group, but that is other than the 20 natural amino acids set forth in Table 1 . Thus, non-natural amino acids are preferably obtained by chemical synthesis.

[0065] Ranges provided herein are understood to be shorthand for all the values within the range. For example, a range of 1 to 20 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0066] As used herein, Ci-X(or Ci-Cx) refers to the number of carbons in the range of 1 to x, which includes C1-2, C1-3... Ci-X. For example, a group designated as “C1-5” indicates that there are one to five carbon atoms in the moiety, i.e. groups comprising 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, or 5 carbon atoms. Thus, by way of example only, “C1-4 alkyl” indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group ca n b e m et h y l , ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl. Accordingly, as used herein, C1-50 alkyl includes, but is not limited to, Ci alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, Ce alkyl, C7 alkyl, Ca alkyl, C9 alkyl, C10 alkyl, C11 alkyl, C12 alkyl, C13 alkyl, C14 alkyl, C15 alkyl, C16 alkyl, C17 alkyl, Cis alkyl, C19 alkyl, C20 alkyl, C30 alkyl, C40 alkyl, C50 alkyl, C1-10 alkyl, C1-20 alkyl, C1-30 alkyl, C1-40 alkyl, and any combination therebetween.

[0067] The term “subject” or “patient” refers to both human and non-human primates, including, but not limited to, mammals, birds and fish, and encompasses domestic, farm, zoo, laboratory and wild animals, such as, for example, cows, pigs, horses, goats, sheep and other hoofed animals; dogs; cats; chickens; ducks; non-human primates; guinea pigs; rabbits; ferrets; rats; hamsters and mice.A9TH-038 / 01WG 344158-2244

[0068] The compounds disclosed herein may also include base-free forms, prodrugs, salts or pharmaceutically acceptable salts thereof. Unless otherwise specified, the compounds claimed and described herein are meant to include all racemic mixtures and all individual enantiomers or combinations thereof, whether or not they are explicitly represented herein.

[0069] The compounds disclosed herein may be shown as having one or more charged groups, may be shown with ionizable groups in an uncharged (e.g. protonated) state or may be shown without specifying formal charges. As will be appreciated by the person of skill in the art, the ionization state of certain groups within a compound (e.g. without limitation, CO2H, PO3H2, SO2H, SO3H, SO4H, OPO3H2 and the like) is dependent, inter alia, on the pKa of that group and the pH at that location. For example, but without limitation, a carboxylic acid group (i.e. COOH) would be understood to usually be deprotonated (and negatively charged) at neutral pH and at most physiological pH values, unless the protonated state is stabilized (e.g. due to intramolecular H-bonding). Likewise, OSO3H (i.e. SO4H) groups, SO2H groups, SO3H groups, OPO3H2 (i.e. PO4H2) groups and PO3H groups would generally be deprotonated (and negatively charged) at neutral and physiological pH values.

[0070] As used herein, the terms “salt” and “solvate” have their usual meaning in chemistry. As such, when the compound is a salt or solvate, it is associated with a suitable counter-ion. It is well known in the art how to prepare salts or to exchange counter-ions. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of a suitable base (e.g. without limitation, Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of a suitable acid. Such reactions are generally carried out in water or in an organic solvent, or in a mixture of the two. Counter-ions may be changed, for example, by ion-exchange techniques such as ion-exchange chromatography. All zwitterions, salts, solvates and counter-ions are intended, unless a particular form is specifically indicated.

[0071] The term “MC1 R-targeting contrast agent” as used herein refers to diagnostic radiopharmaceutical comprising a MC1R targeting moiety and radiometal chelator conjugated to a diagnostic radionuclide that can detect MC1R-positive tumors or lesions in a subject using SPECT, PET / MRI or PET / CT. Non-limiting examples of MClRtargeting contrast agents include Mb-Compound E, Mb-VMT01 , Mb-VMT02, Mb-DOTA-NAPamide, Mb-DOTA-ReCCMSH, Mb-a-MSH, Mb-ADVC002, Mb-MTI-201 , or a pharmaceutically acceptable salt thereof, that are conjugated to diagnostic radionuclide (e.g.,18F, AI18F,43Sc,44Sc,51Cr,52mMn,52Fe,61Cu,62Cu,64Cu,67Cu,67Ga,66Ga,68Ga,72As,82Rb,86Y,89Zr,94mTc,97Ru,99mTc,111In,117mSn,123l,124l,125l,133mln,152Tb,155Tb,157Gd,169Yb,172Tm,177Lu, or203Pb).

[0072] In certain embodiments, the salt or counter-ion may be pharmaceutically acceptable, e.g. for administration to a subject. More generally, with respect to any pharmaceutical composition disclosed herein, non-limiting examples of suitable excipients include any suitable buffers, stabilizing agents, salts, antioxidants, complexing agents, tonicity agents, cryoprotectants, lyoprotectants, suspending agents, emulsifying agents, antimicrobial agents, preservatives, chelating agents, binding agents, surfactants, wetting agents, non-aqueous vehicles such as fixed oils, or polymers for sustained or controlled release. See, for example, Berge et al. 1977. (J. Pharm Sci. 66:1-19), or Remington- TheScience and Practice of Pharmacy, 21st edition (Gennaro et al editors. Lippincott Williams & Wilkins Philadelphia).

[0073] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of the ordinary skills in the art to which this invention belongs.Compounds and Radioconjugates

[0074] The compounds or radioconjugates used in the present methods incorporate peptides, which may be synthesized by any of a variety of methods established in the art. This includes but is not limited to liquid-phase as well as solid-phase peptide synthesis using methods employing 9-fluorenylmethoxycarbonyl (Fmoc) and / or t-butyloxycarbonyl (Boc) chemistries, and other synthetic approaches.

[0075] Solid-phase peptide synthesis methods and technology are well-established in the art. For example, peptides may be synthesized by sequential incorporation of the amino acid residues of interest one at a time. In such methods, peptide synthesis is typically initiated by attaching the C-terminal amino acid of the peptide of interest to a suitable resin. Prior to this, reactive side chain and alpha amino groups of the amino acids are protected from reaction by suitable protecting groups, allowing only the alpha carboxyl group to react with a functional group such as an amine group, a hydroxyl group, or an alkyl halide group on the solid support. Following coupling of the C-terminal amino acid to the support, the protecting group on the side chain and / or the alpha amino group of the amino acid is selectively removed, allowing the coupling of the next amino acid of interest. This process is repeated until the desired peptide is fully synthesized, at which point the peptide can be cleaved from the support and purified. A non-limiting example of an instrument for solid-phase peptide synthesis is the Aapptec Endeavor 90 peptide synthesizer.

[0076] The choice of resin determines whether the peptide will have either a C-terminal carboxylate or a C-terminal amide (i.e. whether or not the C-terminus of the peptide is amidated). For example, but without limitation, 4-(2',4'- Dimethoxyphenyl-Fmoc-aminomethyl)phenoxy resin (Rink Amide Resin) or 9-Fmoc-aminoxanthen-3-yloxy-Merrifield resin (Sieber Amide resin) may be used for a C-terminal amide once the peptide is cleaved. Without limitation, p-benzyloxybenzyl alcohol resin (Wang resin) or 2— chlorotrityl chloride resin may be used for a C-terminal carboxylate once the peptide is cleaved. During use, the resin is swelled in solvents, such as N,N-dimethylformamide (DMF), dichloromethane (DCM) or 1-methyl-2-pyrrolidone (NMP), and the like.

[0077] To allow coupling of additional amino acids, Fmoc protecting groups may be removed from the amino acid on the solid support, e.g. under mild basic conditions, such as piperidine (20-50% v / v) in DMF. The amino acid to be added must also have been activated for coupling (e.g. at the alpha carboxylate). Non-limiting examples of activating reagents include without limitation 2-(1H-benzotriazol-1 -yl)-1 , 1 ,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium tetrafluoro borate (TBTU), 2-(7-Aza-1 H-benzotriazole-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate (HATU), benzotriazole-1-yl-oxy-tris(dimethylamino)phosphoniumhexafluorophosphate (BOP), benzotriazole-1-yl-oxy-tris(pyrrolidino)phosphoniumhexafluorophosphate (PyBOP). Racemization is minimized by using triazoles, such as 1-hydroxy-benzotriazole (HOBt) and 1-hydroxy-7-aza-benzotriazole (HOAt).Coupling may be performed in the presence of a suitable base, such as N,N-diisopropylethylamine (DIPEA / DIEA) and the like. For long peptides, peptide synthesis and ligation may be used.

[0078] Cyclization of the peptide may be performed by any known method. Cyclization may be performed on-resin or off-resin. Non-limiting examples of peptide cyclization include: forming a lactam bridge between an amino acid side chain containing a carboxyl group (e.g. Asp, D-Asp, Glu, D-Glu, and the like) and an amino acid side chain containing an amino group (e.g. Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, and the like); forming a 1 , 2, 3-triazole via click chemistry between an amino acid side chain containing an azide group (e.g. Lys(Na), D-Lys(N3), and the like) and an alkyne group (e.g. Pra, D-Pra, and the like); and forming a disulfide bridge between side chains of Cys residues. Since cyclization occurs between amino acid side chains, the protecting groups on these amino acids must be selectively removed before cyclization except the reaction between an alkyne and an azido groups via the click reaction to form an 1 ,2, 3-triazole. Non-limiting examples of selectively removable protecting groups include acetaminomethyl (Acm) (e.g. on Cys), 2-phenylisopropyl esters (O-2-PhiPr) (e.g. on Asp / Glu) as well as 4-methyltrityl (Mtt), allyloxycarbonyl (alloc), 1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene))ethyl (Dde), and 1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl (ivDde) (e.g. on Lys / Orn / Dab / Dap). The Acm group on Cys can be selectively removed by 2 eq. of thallium (III) trifluoroacetate in DMF, which simultaneously induces cyclization via the formation of the disulfide bridge. O-2-PhiPr and Mtt protecting groups can be selectively deprotected under mild acidic conditions, such as 2.5% trifluoroacetic acid (TFA) in DCM. Alloc protecting groups can be selectively deprotected using tetrakis(triphenylphosphine)palladium(0) and phenyl silane in DCM. Dde and ivDde protecting groups can be selectively deprotected using 2-5% of hydrazine in DMF. Deprotected side chains of Asp / Glu (L- or D-forms) and Lys / Orn / Dab / Dap (L- or D-forms) can then be cyclized, e.g. by using the coupling reaction conditions described above.

[0079] Peptide backbone amides may be N-methylated (i.e. alpha amino methylated). This may be achieved by directly using Fmoc-N-methylated amino acids during peptide synthesis. Alternatively, N-methylation under Mitsunobu conditions may be performed. First, a free primary amine group is protected using a solution of 4-nitrobenzenesulfonyl chloride (Ns-CI) and 2,4,6-trimethylpyridine (collidine) in NMP. N-methylation may then be achieved in the presence of triphenylphosphine, diisopropyl azodicarboxylate (DIAD) and methanol. Subsequently, N-deprotection may be performed using mercaptoethanol and 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in NMP. For coupling protected amino acids to N-methylated alpha amino groups, HATU, HOAt and DIEA may be used.

[0080] As described further below, chelators and linkers (peptide or non-peptide linkers) may be coupled to the peptide N-terminus while the peptide is attached to the solid support. This is facile when the chelator, linker and / or albumin-binding groups comprise an activated carboxylate (and protected groups if necessary) so that coupling can be performed on resin.

[0081] When the peptide has been fully synthesized on the solid support, the desired peptide may be cleaved from the solid support using suitable reagents, such as TFA, tri-isopropylsilane (TIS) and water. Side chain protecting groups, such as Boc, pentamethyldihydrobenzofuran-5-sulfonyl (Pbf), trityl (Trt) and tert-butyl (tBu) are simultaneously removed (i.e. deprotection). The crude peptide may be precipitated and collected from the solution by adding cold ether followed by centrifugation.Purification and characterization of the peptides may be performed by standard separation techniques, such as high-performance liquid chromatography (HPLC) based on the size, charge and polarity of the peptides. The identity of the purified peptides may be confirmed by mass spectrometry or other similar approaches.

[0082] As provided above, the present disclosure covers a method of treating melanoma, comprising administering to a subject (e.g., a patient) in need thereof a combination of:(a) one or more checkpoint inhibitors or one or more targeted therapies; and(b) a radioconjugate comprising a melanocortin 1 receptor (MC1R) targeting peptide (MC1 RTP) linked to a CROWN, a CROWNGA, or a CROWN Amide chelator by a linker, or a pharmaceutically acceptable salt thereof, wherein:the MCR1TP is cyclized and comprises a sequence of Formula A or B:Xaa1-Xaa2a-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7a(A) (SEQ ID NO: 2) Xaa1-Xaa2b-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7b(B) (SEQ ID NO: 3) Xaa1is selected from the group consisting of norleucine (Nle), D-Nle, Ala, D-Ala, Leu, D-Leu, He, D-lle, Cys, D-Cys, Met, D-Met, Phe, D-Phe, Trp, D-Trp, Vai, D-Val, 3-(1-naphthyl)alanine (Nal), D-Nal, 3-(2-naphthyl)alanine (2-Nal), D-2-Nal, Gly, a-aminobutyric acid, norvaline, D-norvaline, homonorleucine, and D-homonorleucine;Xaa2ais selected from the group consisting of Cys, D-Cys, Asp, D-Asp, Glu, D-Glu, 2-aminoadipic acid (2-Aad), D-2-Aad, 3-aminoadipic acid (3-Aad), D-3-Aad, propargylglycine (Pra), D-Pra, homopropargylglycine (Hpg), D-Hpg, beta-homopropargylglycine (Bpg), and D-Bpg;Xaa2bis selected from the group consisting of Cys, D-Cys, Lys, D-Lys, Ornithine (Orn), D-Orn, 2,4-diaminobutyric acid (Dab), D-Dab, 2,3-diaminopropionic acid (Dap), D-Dap, Lys(N3), D-Lys(N3), Orn(N3), D-Orn(N3), Dab(N3), D-Dab(N3), Dap(N3), D-Dap(N3), 2-(5'-azidopentyl)alanine, D-2-(5'-azidopentyl)alanine, 2-(6'-azidohexyl)alanine, and D-2-(6'-azidohexyl)alanine;Xaa3is His;Xaa4is D-Phe;Xaa5is Arg;Xaa6is Trp;Xaa7ais selected from the group consisting of Cys, D-Cys, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, Lys(N3), D-Lys(N3), Orn(N3), D-Orn(N3), Dab(N3), D-Dab(N3), Dap(N3), D-Dap(N3), 2-(5’-azidopentyl)alanine, D-2-(5’-azidopentyl)alanine, 2-(6’-azidohexyl)alanine, and D-2-(6’-azidohexyl)alanine;Xaa7bis selected from the group consisting of Cys, D-Cys, Asp, D-Asp, Glu, D-Glu, 2-Aad, D-2-Aad, 3-Aad, D-3-Aad, Pra, D-Pra, Hpg, D-Hpg, Bpg, and D-Bpg; andone or more amino acid residues of the MC1RTP is alpha N-methylated,A9TH-038 / 01WG 344158-2244wherein one or more of Xaa3, Xaa5, Xaa6, and Xaa7ais alpha N-methylated, and one or more of Xaa3, Xaa5, Xaa6, and Xaa7bis alpha N-methylated; and the MCR1TP is optionally C-terminally amidated.

[0083] In some embodiments, one or more of Xaa3, Xaa5, Xaa6, and Xaa7ais alpha N-methylated in Formula A and one or more of Xaa3, Xaa5, Xaa6, and Xaa7bis alpha N-methylated in Formula B.

[0084] In another aspect, the present disclosure covers a method of treating melanoma, comprising administering to a subject (e.g., a patient) in need thereof a combination of:(a) one or more checkpoint inhibitors or one or more targeted therapies; and(b) a radioconjugate comprising a melanocortin 1 receptor (MC1R) targeting peptide (MC1 RTP) linked to a CROWN chelator by a linker, or a pharmaceutically acceptable salt thereof, wherein:the MCR1TP is cyclized and comprises a sequence of Formula A or B:Xaa1-Xaa2a-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7a(A) (SEQ ID NO: 2) Xaa1-Xaa2b-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7b(B) (SEQ ID NO: 3) Xaa1is selected from the group consisting of norleucine (Nle), D-Nle, Ala, D-Ala, Leu, D-Leu, He, D-lle, Cys, D-Cys, Met, D-Met, Phe, D-Phe, Trp, D-Trp, Vai, D-Val, 3-(1-naphthyl)alanine (Nal), D-Nal, 3-(2-naphthyl)alanine (2-Nal), D-2-Nal, Gly, a-aminobutyric acid, norvaline, D-norvaline, homonorleucine, and D-homonorleucine;Xaa2ais selected from the group consisting of Cys, D-Cys, Asp, D-Asp, Glu, D-Glu, 2-aminoadipic acid (2-Aad), D-2-Aad, 3-aminoadipic acid (3-Aad), D-3-Aad, propargylglycine (Pra), D-Pra, homopropargylglycine (Hpg), D-Hpg, beta-homopropargylglycine (Bpg), and D-Bpg;Xaa2bis selected from the group consisting of Cys, D-Cys, Lys, D-Lys, Ornithine (Orn), D-Orn, 2,4-diaminobutyric acid (Dab), D-Dab, 2,3-diaminopropionic acid (Dap), D-Dap, Lys(N3), D-Lys(N3), Orn(N3), D-Orn(N3), Dab(N3), D-Dab(N3), Dap(N3), D-Dap(N3), 2-(5'-azidopentyl)alanine, D-2-(5'-azidopentyl)alanine, 2-(6'-azidohexyl)alanine, and D-2-(6'-azidohexyl)alanine;Xaa3is His;Xaa4is D-Phe;Xaa5is Arg;Xaa6is Trp;Xaa7ais selected from the group consisting of Cys, D-Cys, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, Lys(N3), D-Lys(N3), Orn(N3), D-Orn(N3), Dab(N3), D-Dab(N3), Dap(N3), D-Dap(N3), 2-(5’-azidopentyl)alanine, D-2-(5’-azidopentyl)alanine, 2-(6’-azidohexyl)alanine, and D-2-(6’-azidohexyl)alanine;Xaa7bis selected from the group consisting of Cys, D-Cys, Asp, D-Asp, Glu, D-Glu, 2-Aad, D-2-Aad, 3-Aad, D-3-Aad, Pra, D-Pra, Hpg, D-Hpg, Bpg, and D-Bpg; andone or more amino acid residues of the MC1RTP is alpha N-methylated,wherein one or more of Xaa3, Xaa5, Xaa6, and Xaa7ais alpha N-methylated, and one or more of Xaa3, Xaa5, Xaa6, and Xaa7bis alpha N-methylated; and the MCR1TP is optionally C-terminally amidated.

[0085] In some embodiments, the present disclosure provides a method of treating melanoma, comprising administering to a subject (e.g., a patient) in need thereof a combination of:(a) one or more checkpoint inhibitors, and(b) a radioconjugate comprising a melanocortin 1 receptor (MC1R) targeting peptide (MC1 RTP) linked to a CROWN, a CROWNGA, or a CROWN Amide chelator by a linker, or a pharmaceutically acceptable salt thereof, wherein:the MCR1TP is cyclized and comprises a sequence of Formula A:Xaa1-Xaa2a-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7a(A) (SEQ ID NO: 2) Xaa1is selected from the group consisting of norleucine (Nle), D-Nle, Ala, D-Ala, Leu, D-Leu, He, D-lle, Cys, D-Cys, Met, D-Met, Phe, D-Phe, Trp, D-Trp, Vai, D-Val, 3-(1-naphthyl)alanine (Nal), D-Nal, 3-(2-naphthyl)alanine (2-Nal), D-2-Nal, Gly, a-aminobutyric acid, norvaline, D-norvaline, homonorleucine, and D-homonorleucine;Xaa2ais selected from the group consisting of Cys, D-Cys, Asp, D-Asp, Glu, D-Glu, 2-aminoadipic acid (2-Aad), D-2-Aad, 3-aminoadipic acid (3-Aad), D-3-Aad, propargylglycine (Pra), D-Pra, homopropargylglycine (Hpg), D-Hpg, beta-homopropargylglycine (Bpg), and D-Bpg;Xaa3is His;Xaa4is D-Phe;Xaa5is Arg;Xaa6is Trp;Xaa7ais selected from the group consisting of Cys, D-Cys, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, Lys(N3), D-Lys(N3), Orn(N3), D-Orn(N3), Dab(N3), D-Dab(N3), Dap(N3), D-Dap(N3), 2-(5’-azidopentyl)alanine, D-2-(5’-azidopentyl)alanine, 2-(6’-azidohexyl)alanine, and D-2-(6’-azidohexyl)alanine; andone or more amino acid residues of the MC1RTP is alpha N-methylated,wherein one or more of Xaa3, Xaa5, Xaa6, and Xaa7ais alpha N-methylated; and the MCR1TP is optionally C-terminally amidated.

[0086] In some embodiments, the present disclosure provides a method of treating melanoma, comprising administering to a subject (e.g., a patient) in need thereof a combination of:(a) one or more checkpoint inhibitors, and(b) a radioconjugate comprising a melanocortin 1 receptor (MC1R) targeting peptide (MC1 RTP) linked to a CROWN, a CROWNGA, or a CROWN Amide chelator by a linker, or a pharmaceutically acceptable salt thereof, wherein:the MCR1TP is cyclized and comprises a sequence of Formula B:Xaa1-Xaa2b-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7b(B) (SEQ ID NO: 3) Xaa1is selected from the group consisting of norleucine (Nle), D-Nle, Ala, D-Ala, Leu, D-Leu, He, D-lle, Cys, D-Cys, Met, D-Met, Phe, D-Phe, Trp, D-Trp, Vai, D-Val, 3-(1-naphthyl)alanine (Nal), D-Nal, 3-(2-naphthyl)alanine (2-Nal), D-2-Nal, Gly, a-aminobutyric acid, norvaline, D-norvaline, homonorleucine, and D-homonorleucine;Xaa2bis selected from the group consisting of Cys, D-Cys, Lys, D-Lys, Ornithine (Orn), D-Orn, 2,4-diaminobutyric acid (Dab), D-Dab, 2,3-diaminopropionic acid (Dap), D-Dap, Lys(N3), D-Lys(N3), Orn(N3), D-Orn(N3), Dab(N3), D-Dab(N3), Dap(N3), D-Dap(N3), 2-(5'-azidopentyl)alanine, D-2-(5'-azidopentyl)alanine, 2-(6'-azidohexyl)alanine, and D-2-(6'-azidohexyl)alanine;Xaa3is His;Xaa4is D-Phe;Xaa5is Arg;Xaa6is Trp;Xaa7bis selected from the group consisting of Cys, D-Cys, Asp, D-Asp, Glu, D-Glu, 2-Aad, D-2-Aad, 3-Aad, D-3-Aad, Pra, D-Pra, Hpg, D-Hpg, Bpg, and D-Bpg; andone or more amino acid residues of the MC1RTP is alpha N-methylated,wherein one or more of Xaa3, Xaa5, Xaa6, and Xaa7bis alpha N-methylated; and the MCR1TP is optionally C-terminally amidated.

[0087] In some embodiments, the present disclosure provides a method of treating melanoma, comprising administering to a subject (e.g., a patient) in need thereof a combination of:(a) one or more targeted therapies, and(b) a radioconjugate comprising a melanocortin 1 receptor (MC1R) targeting peptide (MC1 RTP) linked to a CROWN, a CROWNGA, or a CROWN Amide chelator by a linker, or a pharmaceutically acceptable salt thereof, wherein:the MCR1TP is cyclized and comprises a sequence of Formula A:Xaa1-Xaa2a-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7a(A) (SEQ ID NO: 2) Xaa1is selected from the group consisting of norleucine (Nle), D-Nle, Ala, D-Ala, Leu, D-Leu, He, D-lle, Cys, D-Cys, Met, D-Met, Phe, D-Phe, Trp, D-Trp, Vai, D-Val, 3-(1-naphthyl)alanine (Nal), D-Nal, 3-(2-naphthyl)alanine (2-Nal), D-2-Nal, Gly, a-aminobutyric acid, norvaline, D-norvaline, homonorleucine, and D-homonorleucine;Xaa2ais selected from the group consisting of Cys, D-Cys, Asp, D-Asp, Glu, D-Glu, 2-aminoadipic acid (2-Aad), D-2-Aad, 3-aminoadipic acid (3-Aad), D-3-Aad, propargylglycine (Pra), D-Pra, homopropargylglycine (Hpg), D-Hpg, beta-homopropargylglycine (Bpg), and D-Bpg;Xaa3is His;Xaa4is D-Phe;Xaa5is Arg;Xaa6is Trp;Xaa7ais selected from the group consisting of Cys, D-Cys, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, Lys(N3), D-Lys(N3), Orn(N3), D-Orn(N3), Dab(N3), D-Dab(N3), Dap(N3), D-Dap(N3), 2-(5’-azidopentyl)alanine, D-2-(5’-azidopentyl)alanine, 2-(6’-azidohexyl)alanine, and D-2-(6’-azidohexyl)alanine; andone or more amino acid residues of the MC1RTP is alpha N-methylated,wherein one or more of Xaa3, Xaa5, Xaa6, and Xaa7ais alpha N-methylated; and the MCR1TP is optionally C-terminally amidated.

[0088] In some embodiments, the present disclosure provides a method of treating melanoma, comprising administering to a subject (e.g., a patient) in need thereof a combination of:(a) one or more targeted therapies, and(b) a radioconjugate comprising a melanocortin 1 receptor (MC1R) targeting peptide (MC1 RTP) linked to a CROWN, a CROWNGA, or a CROWN Amide chelator by a linker, or a pharmaceutically acceptable salt thereof, wherein:the MCR1TP is cyclized and comprises a sequence of Formula B:Xaa1-Xaa2b-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7b(B) (SEQ ID NO: 3) Xaa1is selected from the group consisting of norleucine (Nle), D-Nle, Ala, D-Ala, Leu, D-Leu, He, D-lle, Cys, D-Cys, Met, D-Met, Phe, D-Phe, Trp, D-Trp, Vai, D-Val, 3-(1-naphthyl)alanine (Nal), D-Nal, 3-(2-naphthyl)alanine (2-Nal), D-2-Nal, Gly, a-aminobutyric acid, norvaline, D-norvaline, homonorleucine, and D-homonorleucine;Xaa2bis selected from the group consisting of Cys, D-Cys, Lys, D-Lys, Ornithine (Orn), D-Orn, 2,4-diaminobutyric acid (Dab), D-Dab, 2,3-diaminopropionic acid (Dap), D-Dap, Lys(N3), D-Lys(N3), Orn(N3), D-Orn(N3), Dab(N3), D-Dab(N3), Dap(N3), D-Dap(N3), 2-(5'-azidopentyl)alanine, D-2-(5'-azidopentyl)alanine, 2-(6'-azidohexyl)alanine, and D-2-(6'-azidohexyl)alanine;Xaa3is His;Xaa4is D-Phe;Xaa5is Arg;Xaa6is Trp;Xaa7bis selected from the group consisting of Cys, D-Cys, Asp, D-Asp, Glu, D-Glu, 2-Aad, D-2-Aad, 3-Aad, D-3-Aad, Pra, D-Pra, Hpg, D-Hpg, Bpg, and D-Bpg; andone or more amino acid residues of the MC1RTP is alpha N-methylated,wherein one or more of Xaa3, Xaa5, Xaa6, and Xaa7bis alpha N-methylated; and the MCR1TP is optionally C-terminally amidated.

[0089] In some embodiments, Xaa1is norleucine (Nle), D-Nle, Ala, D-Ala, Leu, D-Leu, He, D-lle, Cys, D-Cys, Met, D-Met, Phe, D-Phe, Trp, D-Trp, Vai, D-Val, 3-(1-naphtyl)alanine (Nal), D-Nal, 3-(2-naphtyl)alanine (2-Nal), D-2-Nal, Gly, a-aminobutyric acid, D-a-aminobutyric acid, norvaline, D-norvaline, homonorleucine, or D-homonorleucine. In some embodiments, Xaa1is Nle, Ala, Leu, lie, Cys, Met, Phe, Trp, Vai, Nal, 2-Nal, Gly, a-aminobutyric acid, norvaline or homonorleucine. In some embodiments, Xaa1is Nle, Ala, Leu, lie, Cys, Met, Phe, Trp, Vai, Nal, 2-Nal, a-aminobutyric acid, norvaline or homonorleucine. In some embodiments, Xaa1is Nle.

[0090] In some embodiments, Xaa2ais Cys, D-Cys, Asp, D-Asp, Glu, D-Glu, 2-aminoadipic acid (2-Aad), D-2-Aad, 3-aminoadipic acid (3-Aad), D-3-Aad, propargylglycine (Pra), D-Pra, homopropargylglycine (Hpg), D-Hpg, beta-homopropargylglycine (Bpg) or D-Bpg. In some embodiments, Xaa2ais Cys, Asp, Glu, 2-Aad, 3-Aad, Pra, Hpg, or Bpg. In some embodiments, Xaa2ais Asp, Glu, Pra or D-Pra. In some embodiments, Xaa2ais Asp, Glu, or Pra. In some embodiments, Xaa2ais Asp.

[0091] In some embodiments, Xaa2bis Cys, D-Cys, Lys, D-Lys, Ornithine (Orn), D-Orn, 2,4-diaminobutyric acid (Dab), D-Dab, 2,3-diaminopropionic acid (Dap), D-Dap, Lys(Ns), D-Lys(Ns), Om(Ns), D-Orn(N3), Dab(Ns), D-Dab(Ns), Dap(Ns), D-Dap(Ns), 2-(5'-azidopentyl)alanine, D-2-(5'-azidopentyl)alanine, 2-(6'-azidohexyl)alanine or D-2-(6'-azidohexyl)alanine. In some embodiments, Xaa2bis Cys, Lys, Orn, Dab, Dap, Lys(Ns), Om(Ns), Dab(Ns), Dap(Ns), or 2-(5'-azidopentyl)alanine, 2-(6'-azidohexyl)alanine. In some embodiments, Xaa2bis Lys Orn, Dab, Dap, Lys(Ns), Om(Ns), Dab(Ns), Dap(Ns), 2-(5'-azidopentyl)alanine, or 2-(6'-azidohexyl)alanine. In some embodiments, Xaa2bis Lys.A9TH-038 / 01WG 344158-2244

[0092] In some embodiments, Xaa3is His, D-His, Pro, beta-(1 ,2,3-triazol-4-yl)-DL-alanine, beta-(1 ,2,3-triazol-4-yl)-L-alanine, beta-(1 ,2,3-triazol-4-yl)-D-alanine, 1 ,2,4-triazole-3-alanine, or 1 ,2,4-triazole-3-D-alanine. In some embodiments, Xaa3is His, Pro, beta-(1 ,2,3-triazol-4-yl)-L-alanine, or 1 ,2,4-triazole-3-alanine. In some embodiments, Xaa3is His, beta-(1 ,2,3-triazol-4-yl)-DL-alanine, or 1 ,2,4-triazole-3-alanine. In some embodiments, Xaa3is His.

[0093] In some embodiments, Xaa4is Phe, D-Phe, 2-Nal, D-2-Nal, Phe(4-F), D-Phe(4-F), Phe(4-CI), D-Phe(4-CI), Phe(4-Br), D-Phe(4-Br), Phe(4-I), D-Phe(4-I), Phe(4-NH2), D-Phe(4-NH2), Phe(4-NO2), or D-Phe(4-NO2). In some embodiments, Xaa4is D-Phe, D-2-Nal, D-Phe(4-F), D-Phe(4-CI), D-Phe(4-Br), D-Phe(4-I), D-Phe(4-NH2), or D-Phe(4-NO2). In some embodiments, Xaa4is Phe, D-Phe, 2-Nal or D-2-Nal. In some embodiments, Xaa4is D-Phe or D-2-Nal. In some embodiments, Xaa4is D-Phe.

[0094] In some embodiments, Xaa5is Arg, D-Arg, homoarginine (hArg), D-hArg, Leu, D-Leu, 2-amino-4-guanidinobutyric acid (Agb), D-Agb, 2-amino-3-guanidinopropionic acid (Agp), or D-Agp. In some embodiments, Xaa5is Arg, D-Arg, hArg, Leu, D-hArg, Agb, D-Agb, Agp or D-Agp. In some embodiments, Xaa5is Arg, hArg, Leu, Agb, or Agp. In some embodiments, Xaa5is Arg.

[0095] In some embodiments, Xaa6is Phe, D-Phe, Trp, D-Trp, Trp(5-Br), D-Trp(5-Br), Trp(5-OCH3), D-Trp(5-OCH3), Trp(6-F), D-Trp(6-F), Trp(5-OH), D-Trp(5-OH), Trp(CHO), or D-Trp(CHO). In some embodiments, Xaa6is Phe, Trp, Trp(5-Br), Trp(5-OCH3), Trp(6-F), Trp(5-OH), orTrp(CHO). In some embodiments, Xaa6is Trp or D-Trp. In some embodiments, Xaa6is Trp.

[0096] In some embodiments, Xaa7ais Cys, D-Cys, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, Lys(N3), D-Lys(N3), Orn(N3), D-Orn(N3), Dab(N3), D-Dab(N3), Dap(N3), D-Dap(N3), 2-(5'-azidopentyl)alanine, D-2-(5'-azidopentyl)alanine, 2-(6'-azidohexyl)alanine or D-2-(6'-azidohexyl)alanine. In some embodiments, Xaa7ais Cys, Lys, Orn, Dab, Dap, Lys(N3), Orn(N3), Dab(N3), Dap(N3), 2-(5'-azidopentyl)alanine, or 2-(6'-azidohexyl)alanine. In some embodiments, Xaa7ais Lys Orn, Dab, Dap, Lys(N3), Orn(N3), Dab(N3), Dap(N3), 2-(5'-azidopentyl)alanine, or 2-(6'-azidohexyl)alanine. In some embodiments, Xaa7ais Lys.

[0097] In some embodiments, Xaa7bis Cys, D-Cys, Asp, D-Asp, Glu, D-Glu, 2-Aad, D-2-Aad, 3-Aad, D-3-Aad, Pra, D-Pra, Hpg, D-Hpg, Bpg or D-Bpg. In some embodiments, Xaa7bis Cys, Asp, Glu, 2-Aad, 3-Aad, Pra, Hpg, or Bpg. In some embodiments, Xaa7bis Asp, Glu, Pra or D-Pra. In some embodiments, Xaa7bis Asp.

[0098] In some embodiments, each of Xaa1, Xaa2a, Xaa2b, Xaa3, Xaa5, Xaa6, Xaa7a, and Xaa7bare L-amino acids and Xaa4is a D-amino acid.

[0099] In some embodiments, the sequence of the MC1RTP consists essentially of the sequence defined by Formula A or B, wherein Xaa1, Xaa2a, Xaa2b, Xaa3, Xaa4, Xaa5, Xaa6, Xaa7a, and Xaa7bare as defined for any combination of embodiments defined in this disclosure. In some embodiments, the sequence of the MC1RTP consists of the sequence defined by Formula A or B, wherein Xaa1, Xaa2a, Xaa2b, Xaa3, Xaa4, Xaa5, Xaa6, Xaa7a, and Xaa7bare as defined for any combination of embodiments defined in this disclosure. In some embodiments, the sequence of the MC1RTP comprises, consists or consists essentially of the sequence defined by Formula A, wherein Xaa1, Xaa2a, Xaa3, Xaa4, Xaa5, Xaa6, and Xaa7aare as defined for any combination of embodiments defined in this disclosure. In some embodiments, the sequence of the MC1RTP comprises, consists or consists essentially of thesequence defined by Formula B, wherein Xaa1, Xaa2b, Xaa3, Xaa4, Xaa5, Xaa6, and Xaa7bare as defined for any combination of embodiments defined in this disclosure.

[0100] In some embodiments, the sequence of MC1RTP comprises, consists or consists essentially of the sequence defined by Formula A, wherein: Xaa1is Nle, Ala, Leu, He, Cys, Met, Phe, Trp, Vai, Nal, 2-Nal, a-aminobutyric acid, norvaline or homonorleucine; Xaa2ais Asp, Glu, Pra or D-Pra; Xaa3is His, beta-(1 ,2,3-triazol-4-yl)-DL-alanine, or 1 ,2,4-triazole-3-alanine; Xaa4is Phe, D-Phe, 2-Nal or D-2-Nal; Xaa5is Arg, D-Arg, hArg, Leu, D-hArg, Agb, D-Agb, Agp or D-Agp; Xaa6is Trp or D-Trp; and Xaa7ais Lys Orn, Dab, Dap, Lys(Na), Orn(Ns), Dab(Ns), Dap(Ns), 2-(5'-azidopentyl)alanine, or 2-(6'-azidohexyl)alanine.

[0101] In some embodiments, Xaa1is Nle, Xaa2ais Asp, Xaa3is His, Xaa4is D-Phe, Xaa5is Arg, Xaa6is Trp and Xaa7is Lys. The sequence of MC1 RTP may consist essentially of Nle-Asp-His-(D-Phe)-Arg-Trp-Lys, linear or cyclic, optionally C-terminally amidated, and alpha N-methylated as elsewhere defined in this disclosure. The sequence of MC1 RTP may consist of Nle-Asp-His-(D-Phe)-Arg-Trp-Lys, linear or cyclic, optionally C-terminally amidated, and alpha N-methylated as elsewhere defined in this disclosure.

[0102] The MC1RTP may or may not be C-terminally amidated (e.g. at Xaa7aorXaa7b). In some embodiments, the MC1RTP is C-terminally amidated. In some embodiments, the MC1RTP has a C-terminal carboxylate.

[0103] One or more amino acid residues of the MC1RTP is alpha N-methylated, including N-methylation of 1 , 2, 3 or 4 of Xaa3, Xaa5, Xaa6and Xaa7ain the sequence defined by Formula A and / or 1 , 2, 3 or 4 of Xaa3, Xaa5, Xaa6and Xaa7bin the sequence defined by Formula B. In some embodiments, the MC1 RTP has only 1 , only 2, only 3 or only 4 alpha N-methylations. In some embodiments, Xaa5and Xaa7ain the sequence defined by Formula A are alpha N-methylated. In some embodiments, Xaa5and Xaa7bin the sequence defined by Formula B are alpha N-methylated. In some embodiments, the N-methylations are (N-Me-Xaa3), (N-Me-Xaa5), (N-Me-Xaa6) and (N-Me-Xaa7a). In some embodiments, the N-methylations are (N-Me-Xaa3), (N-Me-Xaa5), (N-Me-Xaa6) and (N-Me-Xaa7b). In some embodiments, the N-methylations are (N-Me-Xaa5), (N-Me-Xaa6) and (N-Me-Xaa73). In some embodiments, the N-methylations are (N-Me-Xaa5), (N-Me-Xaa6) and (N-Me-Xaa7b). In some embodiments, the N-methylations are (N-Me-Xaa5) and (N-Me-Xaa6). In some embodiments, the N-methylations are (N-Me-Xaa6) and (N-Me-Xaa7a). In some embodiments, the N-methylations are (N-Me-Xaa6) and (N-Me-Xaa7b). In some embodiments, the N-methylations are (N-Me-Xaa5) and (N-Me-Xaa7a). In some embodiments, the N-methylations are (N-Me-Xaa5) and (N-Me-Xaa7b). In some embodiments, the only N-methylation is (N-Me-Xaa6).

[0104] In some embodiments, the MC1RTP is linear. In some embodiments, the MC1RTP is cyclized. In some embodiments, the MC1RTP comprises, consists or consists essentially of Xaa1-cyclo[Xaa2a-Xaa3-Xaa4-Xaab-Xaa6-Xaa73]. In some embodiments, the MC1RTP comprises, consists or consists essentially of cyclo[Xaa1-Xaa2a-Xaa3-Xaa4-Xaa5-Xaa6-Xaa73]. In some embodiments, the MC1RTP comprises, consists or consists essentially of Xaa1-cyclo[Xaa2b-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7b], In some embodiments, the MC1RTP comprises, consists or consists essentially of cyclo[Xaa1-Xaa23-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7b], In the foregoing sequences, Xaa1, Xaa2a, Xaa2b, Xaa3, Xaa4,Xaa5, Xaa6, Xaa7a, Xaa7bmay have any of the alternative definitions presented in the paragraphs above or elsewhere in this disclosure.

[0105] The MC1RTP may be cyclized by a lactam bridge connecting Xaa2ato Xaa7ain the sequence defined by Formula A, formed by connecting the side chain of Asp, D-Asp, Glu, D-Glu, 2-Aad, or D-2-Aad with the side chain of Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, or D-Dap. The MC1 RTP may be cyclized by a lactam bridge connecting Xaa2bto Xaa7bin the sequence defined by Formula B, formed by connecting the side chain of Asp, D-Asp, Glu, D-Glu, 2-Aad, or D-2-Aad with the side chain of Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, or D-Dap.

[0106] The MC1RTP may be cyclized by a 1 ,2,3-triazole connecting Xaa2ato Xaa7ain the sequence defined by Formula A, formed by connecting the side chains of Pra, D-Pra, Hpg, D-Hpg, Bpg or D-Bpg with Lys(N3), D-Lys(N3), Orn(N3), D-Orn(N3), Dab(N3), D-Dab(N3), Dap(N3), D-Dap(N3), 2-(5'-azidopentyl)alanine, D-2-(5'-azidopentyl)alanine, 2-(6'-azidohexyl)alanine or D-2-(6'-azidohexyl)alanine. The MC1 RTP may be cyclized by a 1 ,2,3-triazole connecting Xaa2bto Xaa7bin the sequence defined by Formula B, formed by connecting the side chains of Pra, D-Pra, Hpg, D-Hpg, Bpg or D-Bpg with Lys(N3), D-Lys(N3), Orn(N3), D-Orn(N3), Dab(N3), D-Dab(N3), Dap(N3), D-Dap(N3), 2-(5'-azidopentyl)alanine, D-2-(5'-azidopentyl)alanine, 2-(6'-azidohexyl)alanine or D-2-(6'-azidohexyl)alanine.

[0107] The MC1RTP may be cyclized by a disulfide bridge connecting Xaa1to Xaa7ain the sequence defined by Formula A when both Xaa1and Xaa7aare Cys (D- and / or L-form). The MC1 RTP may be cyclized by a disulfide bridge connecting Xaa2ato Xaa7ain the sequence defined by Formula A when both Xaa2aand Xaa7aare Cys (D- and / or L-form). The MC1RTP may be cyclized by a disulfide bridge connecting Xaa1to Xaa7bin the sequence defined by Formula B when both Xaa1and Xaa7band are Cys (D- or L- form). The MC1 RTP may be cyclized by a disulfide bridge connecting Xaa2bto Xaa7bin the sequence defined by Formula B when both Xaa2band Xaa7band are Cys (D- or L-form).

[0108] In some embodiments, the MC1RTP may comprise, consist or consist essentially of:Xaa1-cyclo[Xaa2a-Xaa3-Xaa4-( / V-Me-Xaa5)-( / V-Me-Xaa6)-( / V-Me-Xaa7a)]-NH2(SEQ ID NO: 6);Xaa1-cyclo[Xaa2a-Xaa3-Xaa4-( / V-Me-Xaa5)-( / V-Me-Xaa6)-Xaa7a]-NH2(SEQ ID NO: 7);Xaa1-cyclo[Xaa2a-Xaa3-Xaa4-Xaa5-( / V-Me-Xaa6)-( / V-Me-Xaa7a)]-NH2(SEQ ID NO: 8);Xaa1-cyclo[Xaa2a-Xaa3-Xaa4-( / V-Me-Xaa5)-Xaa6-( / V-Me-Xaa7a)]-NH2(SEQ ID NO: 9);Xaa1-cyclo[Xaa2a-Xaa3-Xaa4-( / V-Me-Xaa5)-Xaa6-Xaa7a]-NH2(SEQ ID NO: 10);Xaa1-cyclo[Xaa2b-Xaa3-Xaa4-( / V-Me-Xaa5)-( / V-Me-Xaa6)-( / V-Me-Xaa7b)]-NH2(SEQ ID NO: 11);Xaa1-cyclo[Xaa2b-Xaa3-Xaa4-( / V-Me-Xaa5)-( / V-Me-Xaa6)-Xaa7b]-NH2(SEQ ID NO: 12);Xaa1-cyclo[Xaa2b-Xaa3-Xaa4-Xaa5-( / V-Me-Xaa6)-( / V-Me-Xaa7b)]-NH2(SEQ ID NO: 13);Xaa1-cyclo[Xaa2b-Xaa3-Xaa4-( / V-Me-Xaa5)-Xaa6-( / V-Me-Xaa7b)]-NH2(SEQ ID NO: 14); orXaa1-cyclo[Xaa2b-Xaa3-Xaa4-( / V-Me-Xaa5)-Xaa6-Xaa7b]-NH2(SEQ ID NO: 15);wherein Xaa1, Xaa2a, Xaa2b, Xaa3, Xaa4, Xaa5, Xaa6, Xaa7aand Xaa7bmay be any of the alternative definitions provided above. The MC1RTP may be cyclized by the formation of a lactam bridge, a 1 ,2,3-triazole, or a disulfide bridge. In some such embodiments, Xaa2ais Asp and Xaa7ais Lys, and a lactam bridge is formed between Xaa2aand Xaa7a. In some such embodiments, Xaa2bis Lys and Xaa7bis Asp, and a lactam bridge is formed between Xaa2band Xaa7b. In some such embodiments,Xaa2ais Glu and Xaa7ais Orn, and a lactam bridge is formed between Xaa2aand Xaa7a. In some such embodiments, Xaa2bis Orn and Xaa7bis Glu, and a lactam bridge is formed between Xaa2band Xaa7b.

[0109] In some embodiments, the MC1RTP comprises Nle-cyclo[Asp-His-(D-Phe)-Arg-Trp-Lys] (SEQ ID NO: 16), wherein the MC1RTP is optionally C-terminally amidated, and wherein 1 , 2, 3 or 4 of Xaa3, Xaa5, Xaa6and Xaa7ain the sequence defined by Formula A is alpha N-methylated. In some embodiments, the MC1RTP comprises, consists or consists essentially of:Nle-cyclo[Asp-(N-Me-His)-(D-Phe)-( / V-Me-Arg)-( / V-Me-Trp)-( / V-Me-Lys)] (SEQ ID NO: 17);Nle-cyclo[Asp-His-(D-Phe)-( / V-Me-Arg)-( / V-Me-Trp)-( / V-Me-Lys)] (SEQ ID NO: 18);Nle-cyclo[Asp-His-(D-Phe)-( / V-Me-Arg)-( / V-Me-Trp)-Lys] (SEQ ID NO: 19);Nle-cyclo[Asp-His-(D-Phe)-Arg-( / V-Me-Trp)-( / V-Me-Lys)] (SEQ ID NO: 20);Nle-cyclo[Asp-His-(D-Phe)-( / V-Me-Arg)-Trp-( / V-Me-Lys)] (SEQ ID NO: 21);Nle-cyclo[Asp-His-(D-Phe)-( / V-Me-Arg)-Trp-Lys] (SEQ ID NO: 22);Nle-cyclo[Asp-(N-Me-His)-(D-Phe)-( / V-Me-Arg)-( / V-Me-Trp)-( / V-Me-Lys)]-NH2(SEQ ID NO: 23);Nle-cyclo[Asp-His-(D-Phe)-( / V-Me-Arg)-( / V-Me-Trp)-( / V-Me-Lys)]-NH2(SEQ ID NO: 24);Nle-cyclo[Asp-His-(D-Phe)-( / V-Me-Arg)-( / V-Me-Trp)-Lys]-NH2(SEQ ID NO: 25);Nle-cyclo[Asp-His-(D-Phe)-Arg-( / V-Me-Trp)-( / V-Me-Lys)]-NH2(SEQ ID NO: 26);Nle-cyclo[Asp-His-(D-Phe)-( / V-Me-Arg)-Trp-( / V-Me-Lys)]-NH2(SEQ ID NO: 27); orNle-cyclo[Asp-His-(D-Phe)-( / V-Me-Arg)-Trp-Lys]-NH2(SEQ ID NO: 28).In some such embodiments, the MC1RTP is cyclized by a lactam bridge.

[0110] In some embodiments, the radioconjugate used in the method disclosed herein comprises a radionuclide chelated to a compound of Formula I or II, or a stereoisomer or a pharmaceutically acceptable salt or solvate thereof:Formula I (SEQ ID NO: 4),Formula II (SEQ ID NO: 5),wherein the linker comprises one or more O, S, NR, C=O, C1-6 alkyl, C3-6 cycloalkyl, C1-6 heterocycloalkyl, aryl, or heteroaryl, or a combination thereof, R being H or C1-3 alkyl; and wherein the linker optionally comprises an albumin binding moiety.

[0111] The linker may be attached to the N-terminus of the MC1RTP shown in Formula I or II. The linker may be any linker, e.g. but without limitation, ether, ester, thioether, disulfide, thioester, amide, carbamate, ureido, phosphodiester, polyethylene glycol (PEG), peptide, polypeptide, alkyl (e.g. C1-C10, C1-C15, C1-C20, C1-C30, C1-C50, C1-C75, C1-C100, C1-C120 and the like), heteroalkyl (e.g. C1-C10, C1-C15, C1-C20, C1-C30, C1-C50, C1-C75, and C1-C100 alkyl wherein one or more carbon atoms are replaced with a heteroatom, and the like), aryl (e.g. C6-C10, C6-C15, C6-C20, C6-C30, and the like) or heteroaryl (e.g. 5-10 membered, 5-15 membered, 5-20 membered heteroaryls and the like). The alkyl or heteroalkyl may be one or more of: branched or linear; acyclic, cyclic or multi-cyclic; saturated or unsaturated; and unsubstituted or substituted. The aryl or heteroaryl may be one or more of: cyclic or multi-cyclic; aromatic or nonaromatic; and unsubstituted or substituted. Without limitation, in substituted embodiments, the alkyl, heteroalkyl, aryl or heteroaryl may be substituted with one or more of halide, amide, oxo, hydroxyl, thiol, phosphate and sulfate. In certain embodiments, each X is independently C, N, O, P, Se or S. The halide may be -F, -Br, -I or -Cl. In certain embodiments, the halide is -Br, -I or -Cl. In some embodiments, the linker is cationic. In some embodiments, the linker has net neutral charge.

[0112] In some embodiments, the linker consists or consists essentially of a C1-C120 alkylenyl which is: linear or branched; saturated or unsaturated; and acyclic or cyclic (including multi-cyclic). In some embodiments, the linker consists or consists essentially of a X1-X120 heteroalkylenyl, which is: linear or branched; saturated or unsaturated; and acyclic or cyclic (including multi-cyclic). In some such embodiments, the linker comprises a peptide. In some such embodiments, the linker consists or consists essentially of a peptide attached to the N-terminus of the MC1RTP.

[0113] In some embodiments, the linker comprises one or more (e.g., 2-20) O, NR, C=O, C1-6 alkyl, C1-6 heterocycloalkyl, or a combination thereof, R being H or C1-3 alkyl.

[0114] In some embodiments, the linker comprises O, NH, C=O, C1-6 alkyl, or C1-6 heterocycloalkyl.

[0115] In some embodiments, the linker comprises one or more\ , in which each of X and Y is independently carbon or nitrogen, e.g., X is carbon and Y is nitrogen, orX is carbon and Y iscarbon, orX is nitrogen and Y is nitrogen. In some embodiments, each of X and Y is independently CH or N, e.g., X is CH and Y is N, orX is CH and Y is CH, orX is N and Y is N. In some embodiments, the linker comprises one or more structures shown below:

[0116] In some embodiments, the linker comprises 4-amino-1-carboxymethyl-piperidine (Pip), withthe structure:

[0117] In some embodiments, the linkeris

[0118] In some embodiments, the linker comprises one or morein which n is an integer of 1-5 and each of V and Wis independently oxygen or NH, with exemplary structures shown below:

[0119] In some embodiments, the linker is C1-10 alkyl wherein one or more carbons are each, independently, replaced with O, NR, or C=O, wherein R is H or CH3. Examples of the linker include, but are not limited to, the following:Hoo

[0120] In some embodiments, the linker further comprises one or more (e.g., one to two, one to three, or one to four) charge-modifying groups at either end of the linker. As used herein, the term “charge-modifying group” refers to a chemical group comprising a moiety that can attract a proton to form a positive charge (e.g., a tertiary amine) or lose a proton to form a negative charge (e.g., a carboxylic acid).

[0121] In some embodiments, the charge-modifying group is an amino acid unit formed from a natural or unnatural amino acid. Examples of such charge-modifying group include, but are not limited to, 4-amino-1-carboxymethyl-piperidine (Pip), 2-aminohexanedioic acid (Aad), glutamic acid (Glu), and aspartic acid (Asp):HO

[0122] In some embodiments, the linker comprises one or more charge-modifying groups selected from the group consisting of 4-amino-1-carboxymethyl-piperidine (Pip), 2-aminohexanedioic acid (Aad), aspartic acid (Asp), and glutamic acid (Glu). Examples of the linker comprising a chargemodifying group include, but are not limited to, the following:

[0123] According to certain embodiments, suitable linkers include peptides (i.e., amino acids linked together) alone, a non-peptide group (e.g., hydrocarbon chain) or a combination thereof containing amino acids and non-peptide groups. In certain embodiments, a linker may be a single amino acid or a peptide with 2-10 amino acids, which can be represented by (Xaa)i-io, wherein Xaa can be a proteinogenic amino acid or non-proteinogenic amino acid.

[0124] The term “proteinogenic amino acid” as used herein refers to the 22 amino acids that can be incorporated biosynthetically into proteins during translation, and which includes the 20 amino acids that are in the standard genetic code, specifically alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine (Cys), glutamic acid (Glu), glutamine (Gin), glycine (Gly), histidine (His), isoleucine (He), leucine (Leu), lysine (Lys), methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr) and valine (Vai), as well as the 2 additional amino acids (selenocysteine and pyrrolysine) that can be incorporated by special translation mechanisms. The term “non-proteinogenic amino acid” as used herein refers to all other amino acids that are distinct from the proteinogenic amino acids, and includes non-canonical amino acids as well as non-natural or synthetic amino acids.

[0125] Table 2 lists exemplary non-proteinogenic amino acids. In certain embodiments, Xaa is an L-amino acid. In certain embodiments, Xaa is a D-amino acid. In certain embodiments, Xaa is a derivative of L- or D-amino acid. Examples of such linkers may include, but are not limited to, Glu, aminoadipic acid (Aad), Asp, Gly-Glu, Gly-Glu-Gly, Gly-Gly-Glu-Gly-Gly (SEQ ID NO: 51), Glu-Glu-Asp, Glu-Gly-Glu, Nle-Glu-Glu, Glu-Nle-Glu, and Glu-aminoadipic acid-Glu, Glu-Glu-Glu, Glu-Glu, and any derivatives or modifications thereof.TABLE 2. List of non-limiting examples of non-proteinogenic amino acidsp-aminomethylaniline-diglycolic acid (pABzA-DIG) 2-amino-(anthracen-2-yl)propanoic acid ornithine (Orn) 2-amino-(anthracen-9-yl)propanoic acid 3-(1-naphtyl)alanine (Nal) 2-amino-3-(pyren-1 -yl)propanoic acid3-(2-naphtyl)alanine (2-Nal) Trp(5-Br),a-aminobutyric acid Trp(5-OCH3),norvaline Trp(6-F)norleucine (Nle) Trp(5-OH)homonorleucine Trp(CHO)beta-(1 ,2,3-triazol-4-yl)-L-alanine / V£, / V£, / VMrimethyl-lysine1 ,2,4-triazole-3-alanine cysteic acidPhe(4-F), Phe(2-F), Phe(3-F), 2-aminoadipic acid (2-Aad)Phe(4-CI), Phe(2-CI), Phe(3-CI), 3-aminoadipic acid (3-Aad)Phe(4-Br), Phe(2-Br), Phe(3-Br), propargylglycine (Pra)Phe(4-I), Phe(2-I), Phe(2-I), homopropargylglycine (Hpg)Phe(4-NH2), Phe(2-NH2), Phe(3-NH2), beta-homopropargylglycine (Bpg) Phe(4-NO2), Phe(2-NO2), Phe(2-NO2), 2,3-diaminopropionic acid (Dap) homoarginine (hArg) 2,4-diaminobutyric acid (Dab)4-(2-aminoethyl)-1 -carboxymethyl-piperazine (Acp) azidolysine (Ly’(Ns))2-(5'-azidopentyl)alanine, 2-(6'-azidohexyl)alanine azido-ornithine (Orn(Ns))2-amino-4-guanidinobutyric acid (Agb) amino-4-azidobutanoic acid Dab(Ns) 2-amino-3-guanidinopropionic acid (Agp) tranexamic acidp-alanine 4-amino-1 -carboxymethyl-piperidine (Pip) 4-aminobutyric acid NH2(CH2)2O(CH2)2C(O)OH5-aminovaleric acid NH2(CH2)2[O(CH2)2]2C(O)OH (dPEG2) 6-aminohexanoic acid NH2(CH2)2[O(CH2)2]3C(O)OH7-aminoheptanoic acid NH2(CH2)2[O(CH2)2]4C(O)OH8-aminooctanoic acid NH2(CH2)2[O(CH2)2]5C(O)OH9-aminononanoic acid NH2(CH2)2[O(CH2)2]6C(O)OH10-aminodecanoic acid citrulline (Cit)2-aminooctanoic acid p-(3-benzothienyl)alanine (Bta)tert-leucine (Tie) oxazolidine-4-carboxylic acid (4-oxa-L-Pro) 4-chlorophenylalanine (Cpa) cyclopentylglycine (Cpg)thiazoline-4-carboxylic acid (Thz) any N-methylated version of a proteinogenic amino acid or non-proteinogenic amino acid in this TableaMe-Trp any D-amino acid of a proteinogenic amino acid or any D-amino acid of a non- proteinogenic amino acid in this Table T rp(Me) Trp(7-Me)Trp(6-Me) Trp(5-Me)Trp(4-Me) Trp(2-Me)Trp(7-F) Trp(5-F)Tpi(2,3,4,9-tetrahydro-1 H-pyrido[3,4-b]indol-3- 5,5-dimethyl-1 ,3-thiazolidine-4-carboxylic acid carboxylic acid) (Me2Thz)Trp(4-F) cyclobutylglycine7 -Aza (7-azatryptophan) 2,3-dehyrdo-Val4,4-difluoroproline (difluoroPro) cyclopropylglycinestatin e (Sta)

[0126] In certain embodiments, the linker comprises carboxylic acid and amine reactive groups. Examples of such linkers include, but are not limited to, 4-amino-(1 -carboxymethyl) piperidine (Pip), 2-aminobutyric acid (Abu), 4-aminobutyric acid (y-Abu or GABA), a-aminoisobutyric acid (Aib), 5-aminovaleric acid (5-Ava), 6-aminohexanoic acid (s-Ahx or Ahx), 7-aminoheptanoic acid, 8-aminooctanoic acid (8-Aoc), 9-aminononanoic acid, 10-aminodecanoic acid, 11-aminoundecanoic acid (11-Aun), [2-(2-amino-ethoxy)-ethoxy]-acetic acid (also known as 9-amino-4,7-dioxanonanoic acid (mini-PEG)), {2-[2-(2-amino-ethoxy)-ethoxy]-ethoxy}-acetic acid (mini-PEG3), 3-[2-(2-aminoethoxy)ethoxy]propanoic acid (PEG2), PEG4, and the like. Other examples include peptide linkers such as glycine linkers (for example, GG, GGG, GGGG (SEQ ID NO: 29), GGGGG (SEQ ID NO: 30)); AAA; SAT; PYP; ASA; SGG; GGSGGS (SEQ ID NO: 31); ASASA(SEQ ID NO: 32); PSGSP (SEQ ID NO: 33); PSPSP (SEQ ID NO: 34); ASASA (SEQ ID NO: 35); PSPSP (SEQ ID NO: 36); KKKK (SEQ ID NO: 37); RRRR (SEQ ID NO: 38); Gly4Ser (SEQ ID NO: 39); (Gly4Ser)2(SEQ ID NO: 40); (Gly4Ser)3(SEQ ID NO: 41); (Gly4Ser)4(SEQ ID NO: 42); (Gly4Ser)5(SEQ ID NO: 43) and (Gly4Ser)6(SEQ ID NO: 44).

[0127] In one embodiment, examples of linkers include, but are not limited to, 4-amino-(1-carboxymethyl) piperidine, glycine, cysteic acid, glutamate, aspartic acid, aminoadipic acid, hexyl, polyethylene glycol (PEG), or derivative thereof. In certain embodiments, a linker may contain two to 20 PEGs (PEG2-20) connected together. In certain embodiments, a linker may be:oor a derivative thereof wherein R1can be a chelator or another linker, and R2can be another linker, or a spacer, or a cellular antigen binding moiety.

[0128] In certain embodiments, the linker can be a single atom, such as a heteroatom (e.g., O, N, or S), a group of atoms, such as a functional group (e.g., amine, — C(=O) — , — CH2 — ), or multiple groups of atoms, such as an alkylene chain. Suitable linkers include but are not limited to oxygen, sulfur, carbon, nitrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkoxyl, aryl, heteroaryl, ether, amine, diamine, amide, alkylamine, thioether, carboxylates, polymer, derivatives or combinations thereof.

[0129] In certain embodiments, the linker can be any of R1, -C(O)ORiOC(O)-, -C(O)RiN-, C(O)ORiNH-, -C(O)RiC(O)-, -NHR1NH-, -C(O)NHRiNHC(O)-, or -C(S)ORiOC(S)-; wherein R1 is O, S, C1-C20 alkyl; C1-C20 heteroalkyl; C1-C20 alkylamine; C1-C20 alkoxyl; C1-C20 alkanoyloxyl; or C1-C20 alkylamido, any of which can optionally be substituted with one or more substituents including halogen, alkoxyl, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, amine, cyano, nitro, hydroxyl, carbonyl, acyl, carboxylic acid ( — COOH), — C(O)R2, — C(O)OR2, carboxylate ( — COO — ), primary amide (e.g., — CONH2), secondary amide (e.g., — CONHR2), — C(O)NR2R3, — NR2R3, — NR2S(O)2R3, — NR2C(O)R3, — S(O)2R2, — SR2, and -S(O)2NR2R3, sulfinyl group (e.g., — SOR2), and sulfonyl group (e.g., — SOOR2); wherein R2 and R3 can each independently be hydrogen, halogen, hydroxyl, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,carbonyl, cyano, amino, alkylamino, dialkylamino, alkoxyl, aryloxyl, cycloalkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl.

[0130] In certain embodiments, the linker can be: a hydrocarbon linker containing between 1 and 10 carbon atoms (C1-C10), including 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms that is optionally saturated or unsaturated, optionally substituted with one or more heteroatoms or having one or more substituents; the hydrocarbon linker can be linear, cyclic and / or branched, e.g 8-aminooctanoic acid, 6- aminohexanoic acid; an aromatic linker containing an aromatic moiety such as a benzyl group, e.g. aminophenylacetic acid; an amino acid linker having between 1 and 10 amino acid residues, including 2, 3, 4, 5, 6, 7, 8, or 9 amino acid residues, any one or more of which may be naturally occurring amino acid residues, D-amino acid residues or other non-naturally occurring residues, examples of which include GlyGly, GluGluGlu, GlySerGlySer (SEQ ID NO: 45); a cyclized linker, or cyclized ring structure, optionally a cyclized amino acid linker, e.g. aminocyclohexanecarboxylic acid; a PEG-linker of any suitable length; cationic linkers, whether formed from amino acid residues or other residues, e.g., Pip, 4-(2-aminoethyl)-1-carboxymethyl-piperazine (Acp); anionic linkers, whether formed from amino acid residues or other residues, e.g. AspAsp, GluGlu; a carbohydrate containing linker; click chemistry linkers (triazoles), and any other suitable linker or combinations or modifications thereof.

[0131] In one embodiment, the linker includes L-glutamine and a hydrocarbon chain, or a combination thereof.

[0132] In another embodiment, the linker includes a pure peptide linker consisting of a series of amino acids (e.g., diglycine, triglycine, gly-gly-glu, gly-ser-gly, etc.), in which the total number of atoms between the N-terminal residue of the targeting molecule and the metal chelator in the polymeric chain is 1-12 atoms.

[0133] In yet a further embodiment, the linker includes a hydrocarbon chain [i.e., Ri-(CH2)n-R2] wherein n is 0-10, preferably n=3 to 9, Ri is a group (e.g., H2N-, -SH, -COOH) that can be used as a site for covalently linking to the radiolabeled chelator (RC) (or unlabeled chelator (C) used to form the radiolabeled chelator (RC)); and R2 is a group that is used for covalent coupling to the SSTR-binding moiety (TM). Several chemical methods for conjugating ligands or preferred metal chelators to biomolecules have been well described in the literature [Wilbur, 1992; Parker, 1990; Hermanson, 1996; Frizberg et al., 1995], One or more of these methods could be used to link the radiolabeled chelator (RC) (or unlabeled chelator (C) used to form the radiolabeled chelator (RC)) to the SSTR-binding moiety (TM). These methods include the formation of acid anhydrides, aldehydes, arylisothiocyanates, activated esters, or N-hydroxysuccinimides [Wilbur, 1992; Parker, 1990;Hermanson, 1996; Frizberg et al., 1995],

[0134] In certain embodiments, any of the linkers described herein can be connected together to form a group of linkers.

[0135] The compounds disclosed in the present disclosure can optionally comprise an albumin binder (i.e., albumin-binding group) within their linkers. Introducing an albumin binder into radiopharmaceutical compounds can modify the pharmacokinetic properties and the tissue distribution profile thereof. Exemplary albumin binders include, but are not limited to, the following:-(CH2)ni-CH3 wherein n1 is 8-20;-(CH2)n2-C(O)OH wherein n2 is 8-20;(Rb)n3wherein n3 is 1-5, n4 is 1-4, Rais H or methyl, and Rbis I, Br, F, Cl, H, OH, OCH3, NH2, NO2or C1-C6 alkyl;Cl, H, OH, OCH3, NH2, NO2or Ci-C6alkyl; and

[0136] (albumin-binding group) , wherein R is H, C1-5 alkyl, or (CH2)nCO2H, n being an integer of1-3. In some embodiment, the linker is (albumin-binding group) In some embodiment,the linker is (albumin-binding group)anc|t ealbumin-binding group is / V-[4-(p-tolyl)butanoyl],

[0137] The albumin-binding group may have the following structure, wherein each R4is independently H, halogen, C1-5 alkyl, C1-5 alkoxyl or nitro group:

[0138] In some embodiments, three R4groups are H and two R4group are independently I, F, Br, Cl or methyl in meta / meta, ortho / ortho, para / meta, meta / para, para / ortho, ortho / para, meta / ortho or ortho / meta. In some embodiments, four R4groups are H and one R4group is I, F, Br, Cl or methyl in para, meta or ortho position. In some embodiments, the albumin-binding group is N-[4-(iodophenyl)butanoyl], / V-[4-(fluorophenyl)butanoyl], / V-[4-(bromophenyl)butanoyl], N-[4-(chlorophenyl)butanoyl], or / V-[4-(tolyl)butanoyl], In some embodiments, the albumin-binding group is / V-[4-(tolyl)butanoyl], In some embodiments, the albumin-binding group is / V-[4-(p-iodophenyl)butanoyl], / V-[4-(p-fluorophenyl)butanoyl], / V-[4-(p-bromophenyl)butanoyl], N-[4-(p-chlorophenyl)butanoyl], or / V-[4-(p-tolyl)butanoyl], In some embodiments, the albumin-binding group is / V-[4-(p-tolyl)butanoyl],

[0139] In embodiments where the linker comprises the linear peptide, the albumin-binding group may be coupled to the a-amino group of Xaa8and the radiolabeling group may be coupled to the side chain of Xaa9. In other such embodiments, the radiolabeling group may be coupled to the a-amino group of Xaa8and the albumin-binding group may be coupled to the side chain of Xaa9.

[0140] In embodiments where the linker comprises the branched peptide, the albumin-binding group may be coupled to the a-amino group of Xaa8and the radiolabeling group may be coupled to the a-amino group of Xaa9. In other such embodiments, the radiolabeling group may be coupled to the a-amino group of Xaa8and the albumin-binding group may be coupled to the a-amino group of Xaa9.

[0141] In some embodiments, the compound used in the method of this disclosure is selected from the following:(SEQ ID NO: 46), or(SEQ ID NO: 47),(SEQ ID NO: 48), or(SEQ ID NO: 49),or a stereoisomer or a pharmaceutically acceptable salt or solvate thereof.

[0142] In some embodiments, the CROWN chelator or the like, as shown in Formula I or II, is conjugated with a radionuclide. The conjugated radionuclide may be selected from, without limitation,44Sc,47Sc,61Cu,64Cu,67Cu,67Ga,68Ga,72As,77As,86Y,90Y,89Zr, "Nb,94mTc,99mTc,105Rh,109Pd,111ln, 114m|n, 117mStl i137Cs, 141Cs>141Ce>142pr, 149pm, 149Tb152Tb155Tb161Tb153Sm159Gd165Ef- 166|_|O175Yb,177Lu,186Re,188Re,198Au,199Au,211At,203Pb,212Pb,212Bi,213Bi,223Ra,224Ra,225Ac, and227Th, and the like. In some embodiments, the conjugated radionuclide is a therapeutic radionuclide (e.g. a beta emitter or an alpha emitter). Non-limiting examples of therapeutic radionuclides include,47Sc,64Cu,67Cu,77As, "Y,105Rh,109Pd,111ln,117mSn,142Pr,149Pm,149Tb,161Tb,153Sm,159Gd,165Er,166Ho,175Yb,177Lu,198Au,199Au,203Pb,212Pb,211At,212Bi,213Bi,223Ra,224Ra,225Ac, and227Th. In some embodiments, the radionuclide is149Tb,161Tb,177Lu,225Ac, or227Th. In some embodiments, the radionuclide is225Ac.

[0143] As used herein, “CROWN chelator” refers to 2,2’,2”,2”’-(1 ,10-dioxa-4,7,13,16-tetraazacyclooctadecane-4,7,13,16-tetrayl)tetraacetic acid and when connected to a linker, it can do so by replacing one or more atoms to form a covalent bond with the linker (e.g., forming an amide bond through one of the carboxylic acids, see Compound A). In some embodiments, when CROWN chelator is part of a larger compound, such as a compound of formula I, the CROWN chelator can be expressed as:

[0144] As used herein, the like of a CROWN chelator can include a CROWN chelator functionalized at the alpha carbon next to one of the carboxylic acid as shown in Formula II.

[0145] As used herein, the like of a CROWN chelator can include CROWNGA chelator (2-(7,13,16-tris(carboxymethyl)-1 ,10-dioxa-4,7,13,16-tetraazacyclooctadecan-4-yl)pentanedioic acid) and when it is connected to a linker, it can do so by replacing one or more atoms to form a covalent bond with the linker (e.g., forming an amide bond through one of the carboxylic acids, see Compound B). In some embodiments, when CROWNGA chelator is part of a larger compound, such as a compound of formula II, the CROWNGA chelator can be expressed as:

[0146] As used herein, the like of a CROWN chelator can include CROWN Amide chelator (2,2',2",2"'-(1 ,10-dioxa-4,7,13,16-tetraazacyclooctadecane-4,7,13,16-tetrayl)tetraacetamide) and when it is connected to a linker, it can do so by replacing one or more atoms to form a covalent bond with the linker (e.g., forming an amide bond through one of the carboxylic acids, see Compound F). In some embodiments, when CROWN Amide chelator is part of a larger compound, such as a compound of formula II, the CROWN Amide chelator can be expressed as:

[0147] In some embodiments, the method uses a radioconjugate comprising a radionuclide chelated to Compound A having the following structure or a stereoisomer or a pharmaceutically acceptable salt or solvate thereof:Compound A (SEQ ID NO: 46)In some embodiments, the compound is conjugated with225Ac. In some embodiment, the compound is225Ac-Compound A.A9TH-038 / 01WQ 344158-2244

[0148] In some embodiments, the method uses a radioconjugate comprising a radionuclide chelated to Compound B having the following structure or a stereoisomer or a pharmaceutically acceptable salt or solvate thereof:Compound B (SEQ ID NO: 47)In some embodiments, the compound is conjugated with225Ac. In some embodiment, the compound is225Ac-Compound B.

[0149] In some embodiments, the method uses a radioconjugate comprising a radionuclide chelated to Compound C having the following structure or a stereoisomer or a pharmaceutically acceptable salt or solvate thereof:Compound C (SEQ ID NO: 48)In some embodiments, the compound is conjugated with225Ac. In some embodiment, the compound is225Ac-Compound C.

[0150] In some embodiments, the method uses a radioconjugate comprising a radionuclide chelated to Compound D having the following structure or a stereoisomer or a pharmaceutically acceptable salt or solvate thereof:A9TH-038 / 01WQ 344158-2244Compound D (SEQ ID NO: 49)In some embodiments, the compound is conjugated with225Ac. In some embodiment, the compound is225Ac-Compound D.

[0151] In some embodiments, the method uses a radioconjugate comprising a radionuclide chelated to Compound F having the following structure or a stereoisomer or a pharmaceutically acceptable salt or solvate thereof:CH3Compound F (SEQ ID NO: 52)In some embodiments, the compound is conjugated with135La,155Tb,177Lu,203Pb,213Bi,225Ac, or227Th. In some embodiment, the compound is203Pb- Compound F or225Ac-Compound F.

[0152] In certain embodiments, the compounds of Formula I or II used in the methods disclosed herein may possess a sufficiently acidic group, a sufficiently basic group, or both functional groups, and accordingly react with a number of organic and inorganic bases, or organic and inorganic acids, to form pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” as usedherein, refers to a salt of a sequence or compound of Formula I or II, which is substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compound of the present invention with a pharmaceutically acceptable mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition and base addition salts.

[0153] Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulphonic acid, methanesulphonic acid, oxalic acid, p-bromophenylsulphonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts are the sulphate, pyrosulphate, bisulphate, sulphite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1 ,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulphonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulphonate, propanesulphonate, naphthalene-1 -sulfonate, napththalene-2-sulfonate, mandelate and the like. Pharmaceutically acceptable acid addition salts of particular interest are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid and methanesulphonic acid.

[0154] Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen carries a suitable organic group such as an alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, or aralkyl moiety.

[0155] Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Bases useful in preparing pharmaceutically acceptable salts thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.

[0156] One skilled in the art will understand that the particular counterion forming a part of a pharmaceutically acceptable salt is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole.

[0157] In some embodiments, the present disclosure further encompasses pharmaceutically acceptable solvates of a compound of Formula I or II. The compounds of Formula I or II can combine with solvents such as water, methanol, ethanol and acetonitrile to form pharmaceutically acceptable solvates such as the corresponding hydrate, methanolate, ethanolate or acetonitrilate.

[0158] In some embodiments, the method comprises administering the radioconjugate is administered 1 to 20 times, 3 to 12 times, 4 to 10 times, or 4 to 8 times in a course of a treatment cycle.

[0159] In some embodiments, the method comprises administering the radioconjugate 1 time, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, or 10 times. In some embodiments, the radioconjugate is administered 4 times. In some embodiments, the radioconjugate is administered 6 times.

[0160] In some embodiments, the method comprises an administration interval of 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, or 15 weeks. In some embodiments, the administration interval is 4 weeks.

[0161] In some embodiments, the radioconjugate is administered at a dose ranging from about 0.1 MBq to about 30 MBq, from about 1.5 MBq to about 18 MBq, from about 2 MBq to about 15 MBq, from about 3 MBq to about 20 MBq, from about 6 MBq to about 12 MBq, from about 4 MBq to about 12 MBq, from about 9 MBq to about 11 MBq, from about 8 MBq to about 13 MBq, about 1 MBq, about 2 MBq, about 3 MBq, about 3.5 MBq, about 4 MBq, about 4.5 MBq, about 5 MBq, about 5.5 MBq, about 6 MBq, about 6.5 MBq, about 7 MBq, about 7.5 MBq, about 8 MBq, about 8.5 MBq, about 9 MBq, about 9.5 MBq, about 10 MBq, about 10.5 MBq, about 11 MBq, about 11.5 MBq, about 12 MBq, about 12.5 MBq, about 13 MBq, about 14 MBq, about 15 MBq, about 16 MBq, about 17 MBq, about 18 MBq, about 19 MBq, or about 20 MBq. In some embodiments, the radioconjugate is administered at a dose of about 0.1 MBq. In some embodiments, the radioconjugate is administered at a dose of about 0.2 MBq. In some embodiments, the radioconjugate is administered at a dose of about 0.3 MBq. In some embodiments, the radioconjugate is administered at a dose of about 0.4 MBq. In some embodiments, the radioconjugate is administered at a dose of about 0.5 MBq. In some embodiments, the radioconjugate is administered at a dose of about 0.6 MBq. In some embodiments, the radioconjugate is administered at a dose of about 0.7 MBq. In some embodiments, the radioconjugate is administered at a dose of about 0.75 MBq. In some embodiments, the radioconjugate is administered at a dose of about 0.8 MBq. In some embodiments, the radioconjugate is administered at a dose of about 0.9 MBq. In some embodiments, the radioconjugate is administered at a dose of about 1 MBq. In some embodiments, the radioconjugate is administered at a dose of about 1.5 MBq. In some embodiments, the radioconjugate is administered at a dose of about 1.75 MBq. In some embodiments, the radioconjugate is administered at a dose of about 2 MBq. In some embodiments, the radioconjugate is administered at a dose of about 2.5 MBq. In some embodiments, the radioconjugate is administered at a dose of about 2.75 MBq. In some embodiments, the radioconjugate is administered at a dose of about 3 MBq. In some embodiments, the radioconjugate is administered at a dose of about 3.5 MBq. In some embodiments, the radioconjugate is administered at a dose of about 3.75 MBq. In some embodiments, the radioconjugate is administered at a dose of about 4 MBq. In some embodiments, the radioconjugate is administered at a dose of about 4.5 MBq. In some embodiments, the radioconjugate is administered at a dose of about 4.75 MBq. In some embodiments, the radioconjugate is administered at a dose of about 5 MBq. In some embodiments, the radioconjugate is administered at a dose of about 5.5 MBq. In some embodiments, the radioconjugate is administered at a dose of about 5.75 MBq. In some embodiments, the radioconjugate is administered at a dose of about 6 MBq. In some embodiments, the radioconjugate is administered at a dose of about 6.5 MBq. In some embodiments, the radioconjugate isadministered at a dose of about 6.75 MBq. In some embodiments, the radioconjugate is administered at a dose of about 7 MBq. In some embodiments, the radioconjugate is administered at a dose of about 7.5 MBq. In some embodiments, the radioconjugate is administered at a dose of about 7.75 MBq. In some embodiments, the radioconjugate is administered at a dose of about 8 MBq. In some embodiments, the radioconjugate is administered at a dose of about 8.25 MBq. In some embodiments, the radioconjugate is administered at a dose of about 8.5 MBq. In some embodiments, the radioconjugate is administered at a dose of about 8.75 MBq. In some embodiments, the radioconjugate is administered at a dose of about 9 MBq. In some embodiments, the radioconjugate is administered at a dose of about 9.25 MBq. In some embodiments, the radioconjugate is administered at a dose of about 9.5 MBq. In some embodiments, the radioconjugate is administered at a dose of about 9.75 MBq. In some embodiments, the radioconjugate is administered at a dose of about 10 MBq. In some embodiments, the radioconjugate is administered at a dose of about 10.25 MBq. In some embodiments, the radioconjugate is administered at a dose of about 10.5 MBq. In some embodiments, the radioconjugate is administered at a dose of about 10.75 MBq. In some embodiments, the radioconjugate is administered at a dose of about 11 MBq. In some embodiments, the radioconjugate is administered at a dose of about 11.25 MBq. In some embodiments, the radioconjugate is administered at a dose of about 11.5 MBq. In some embodiments, the radioconjugate is administered at a dose of about 11.75 MBq. In some embodiments, the radioconjugate is administered at a dose of about 12 MBq. In some embodiments, the radioconjugate is administered at a dose of about 12.25 MBq. In some embodiments, the radioconjugate is administered at a dose of about 12.5 MBq. In some embodiments, the radioconjugate is administered at a dose of about 12.75 MBq.

[0162] In some embodiments, the radiometal is225Ac and the radioconjugate is administered at a dose ranging from about 0.1 MBq to about 30 MBq, from about 1.5 MBq to about 18 MBq, from about 2 MBq to about 15 MBq, from about 3 MBq to about 20 MBq, from about 6 MBq to about 12 MBq, from about 4 MBq to about 12 MBq, about 1 MBq, about 2 MBq, about 3 MBq, about 3.5 MBq, about 4 MBq, about 4.5 MBq, about 5 MBq, about 5.5 MBq, about 6 MBq, about 6.5 MBq, about 7 MBq, about 7.5 MBq, about 8 MBq, about 8.5 MBq, about 9 MBq, about 9.5 MBq, about 10 MBq, about 10.5 MBq, about 11 MBq, about 11.5 MBq, about 12 MBq, about 12.5 MBq, about 13 MBq, about 14 MBq, about 15 MBq, about 16 MBq, about 17 MBq, about 18 MBq, about 19 MBq, or about 20 MBq. In some embodiments, the radioconjugate is administered at a dose of about 0.1 MBq. In some embodiments, the radioconjugate is administered at a dose of about 0.2 MBq. In some embodiments, the radioconjugate is administered at a dose of about 0.3 MBq. In some embodiments, the radioconjugate is administered at a dose of about 0.4 MBq. In some embodiments, the radioconjugate is administered at a dose of about 0.5 MBq. In some embodiments, the radioconjugate is administered at a dose of about 0.6 MBq. In some embodiments, the radioconjugate is administered at a dose of about 0.7 MBq. In some embodiments, the radioconjugate is administered at a dose of about 0.75 MBq. In some embodiments, the radioconjugate is administered at a dose of about 0.8 MBq. In some embodiments, the radioconjugate is administered at a dose of about 0.9 MBq. In some embodiments, the radioconjugate is administered at a dose of about 1 MBq. In some embodiments,the radioconjugate is administered at a dose of about 1.5 MBq. In some embodiments, the radioconjugate is administered at a dose of about 1.75 MBq. In some embodiments, the radioconjugate is administered at a dose of about 2 MBq. In some embodiments, the radioconjugate is administered at a dose of about 2.5 MBq. In some embodiments, the radioconjugate is administered at a dose of about 2.75 MBq. In some embodiments, the radioconjugate is administered at a dose of about 3 MBq. In some embodiments, the radioconjugate is administered at a dose of about 3.5 MBq. In some embodiments, the radioconjugate is administered at a dose of about 3.75 MBq. In some embodiments, the radioconjugate is administered at a dose of about 4 MBq. In some embodiments, the radioconjugate is administered at a dose of about 4.5 MBq. In some embodiments, the radioconjugate is administered at a dose of about 4.75 MBq. In some embodiments, the radioconjugate is administered at a dose of about 5 MBq. In some embodiments, the radioconjugate is administered at a dose of about 5.5 MBq. In some embodiments, the radioconjugate is administered at a dose of about 5.75 MBq. In some embodiments, the radioconjugate is administered at a dose of about 6 MBq. In some embodiments, the radioconjugate is administered at a dose of about 6.5 MBq. In some embodiments, the radioconjugate is administered at a dose of about 6.75 MBq. In some embodiments, the radioconjugate is administered at a dose of about 7 MBq. In some embodiments, the radioconjugate is administered at a dose of about 7.5 MBq. In some embodiments, the radioconjugate is administered at a dose of about 7.75 MBq. In some embodiments, the radioconjugate is administered at a dose of about 8 MBq. In some embodiments, the radioconjugate is administered at a dose of about 8.25 MBq. In some embodiments, the radioconjugate is administered at a dose of about 8.5 MBq. In some embodiments, the radioconjugate is administered at a dose of about 8.75 MBq. In some embodiments, the radioconjugate is administered at a dose of about 9 MBq. In some embodiments, the radioconjugate is administered at a dose of about 9.25 MBq. In some embodiments, the radioconjugate is administered at a dose of about 9.5 MBq. In some embodiments, the radioconjugate is administered at a dose of about 9.75 MBq. In some embodiments, the radioconjugate is administered at a dose of about 10 MBq. In some embodiments, the radioconjugate is administered at a dose of about 10.25 MBq. In some embodiments, the radioconjugate is administered at a dose of about 10.5 MBq. In some embodiments, the radioconjugate is administered at a dose of about 10.75 MBq. In some embodiments, the radioconjugate is administered at a dose of about 11 MBq. In some embodiments, the radioconjugate is administered at a dose of about 11.25 MBq. In some embodiments, the radioconjugate is administered at a dose of about 11.5 MBq. In some embodiments, the radioconjugate is administered at a dose of about 11.75 MBq. In some embodiments, the radioconjugate is administered at a dose of about 12 MBq. In some embodiments, the radioconjugate is administered at a dose of about 12.25 MBq. In some embodiments, the radioconjugate is administered at a dose of about 12.5 MBq. In some embodiments, the radioconjugate is administered at a dose of about 12.75 MBq.

[0163] In some embodiments, the radioconjugate is administered at a dose of about 1 MBq every 8 weeks, about 1.5 MBq every 8 weeks, about 2 MBq every 8 weeks, about 3 MBq every 8 weeks, about 4 MBq every 8 weeks, or about 5 MBq every 8 weeks.A9TH-038 / 01WG 344158-2244

[0164] In some embodiments, the radioconjugate is administered at a dose of about 1 MBq every 7 weeks, about 1.5 MBq every 7 weeks, about 2 MBq every 7 weeks, about 3 MBq every 7 weeks, about 4 MBq every 7 weeks, or about 5 MBq every 7 weeks.

[0165] In some embodiments, the radioconjugate is administered at a dose of about 1 MBq every 6 weeks, about 1.5 MBq every 6 weeks, about 2 MBq every 6 weeks, about 3 MBq every 6 weeks, about 4 MBq every 6 weeks, or about 5 MBq every 6 weeks.

[0166] In some embodiments, the radioconjugate is administered at a dose of about 1 MBq every 5 weeks, about 1.5 MBq every 5 weeks, about 2 MBq every 5 weeks, about 3 MBq every 5 weeks, about 4 MBq every 5 weeks, or about 5 MBq every 5 weeks.

[0167] In some embodiments, the radioconjugate is administered at a dose of about 1 MBq every 4 weeks, about 1.5 MBq every 4 weeks, about 2 MBq every 4 weeks, about 3 MBq every 4 weeks, about 4 MBq every 4 weeks, or about 5 MBq every 4 weeks.

[0168] In some embodiments, the radioconjugate is administered at a dose of about 1 MBq every 3 weeks, about 1.5 MBq every 3 weeks, about 2 MBq every 3 weeks, about 3 MBq every 3 weeks, about 4 MBq every 3 weeks, or about 5 MBq every 3 weeks.

[0169] In some embodiments, the radioconjugate is administered at a dose of about 0.5 MBq every 6 weeks. In some embodiments, the radioconjugate is administered at a dose of about 1 MBq every 6 weeks. In some embodiments, the radioconjugate is administered at a dose of about 1.5 MBq every 6 weeks. In some embodiments, the radioconjugate is administered at a dose of about 2 MBq every 6 weeks. In some embodiments, the radioconjugate is administered at a dose of about 2.5 MBq every 6 weeks. In some embodiments, the radioconjugate is administered at a dose of about 3 MBq every 6 weeks. In some embodiments, the radioconjugate is administered at a dose of about 3.5 MBq every 6 weeks. In some embodiments, the radioconjugate is administered at a dose of about 4 MBq every 6 weeks. In some embodiments, the radioconjugate is administered at a dose of about 4.5 MBq every 6 weeks. In some embodiments, the radioconjugate is administered at a dose of about 5 MBq every 6 weeks.

[0170] In some embodiments, the radioconjugate is administered at a dose ranging from about 0.1 GBq to about 30 GBq, from about 1.5 GBq to about 18 GBq, from about 2 GBq to about 15 GBq, from about 3 GBq to about 20 GBq, from about 6 GBq to about 12 GBq, from about 4 GBq to about 12 GBq, about 1 GBq, about 2 GBq, about 3 GBq, about 3.5 GBq, about 4 GBq, about 4.5 GBq, about 5 GBq, about 5.5 GBq, about 6 GBq, about 6.5 GBq, about 7 GBq, about 7.5 GBq, about 8 GBq, about 8.5 GBq, about 9 GBq, about 9.5 GBq, about 10 GBq, about 10.5 GBq, about 11 GBq, about 11.5 GBq, about 12 GBq, about 12.5 GBq, about 13 GBq, about 14 GBq, about 15 GBq, about 16 GBq, about 17 GBq, about 18 GBq, about 19 GBq, or about 20 GBq. In some embodiments, the radioconjugate is administered at a dose of about 0.1 GBq. In some embodiments, the radioconjugate is administered at a dose of about 0.2 GBq. In some embodiments, the radioconjugate is administered at a dose of about 0.3 GBq. In some embodiments, the radioconjugate is administered at a dose of about 0.4 GBq. In some embodiments, the radioconjugate is administered at a dose of about 0.5 GBq. In some embodiments, the radioconjugate is administered at a dose of about 0.6 GBq. In some embodiments, the radioconjugate is administered at a dose of about 0.7 GBq. In some embodiments,A9TH-038 / 01WG 344158-2244the radioconjugate is administered at a dose of about 0.75 GBq. In some embodiments, the radioconjugate is administered at a dose of about 0.8 GBq. In some embodiments, the radioconjugate is administered at a dose of about 0.9 GBq. In some embodiments, the radioconjugate is administered at a dose of about 1 GBq. In some embodiments, the radioconjugate is administered at a dose of about 1.5 GBq. In some embodiments, the radioconjugate is administered at a dose of about 1.75 GBq. In some embodiments, the radioconjugate is administered at a dose of about 2 GBq. In some embodiments, the radioconjugate is administered at a dose of about 2.5 GBq. In some embodiments, the radioconjugate is administered at a dose of about 2.75 GBq. In some embodiments, the radioconjugate is administered at a dose of about 3 GBq. In some embodiments, the radioconjugate is administered at a dose of about 3.5 GBq. In some embodiments, the radioconjugate is administered at a dose of about 3.75 GBq. In some embodiments, the radioconjugate is administered at a dose of about 4 GBq. In some embodiments, the radioconjugate is administered at a dose of about 4.5 GBq. In some embodiments, the radioconjugate is administered at a dose of about 4.75 GBq. In some embodiments, the radioconjugate is administered at a dose of about 5 GBq. In some embodiments, the radioconjugate is administered at a dose of about 5.5 GBq. In some embodiments, the radioconjugate is administered at a dose of about 5.75 GBq. In some embodiments, the radioconjugate is administered at a dose of about 6 GBq. In some embodiments, the radioconjugate is administered at a dose of about 6.5 GBq. In some embodiments, the radioconjugate is administered at a dose of about 6.75 GBq. In some embodiments, the radioconjugate is administered at a dose of about 7 GBq. In some embodiments, the radioconjugate is administered at a dose of about 7.5 GBq. In some embodiments, the radioconjugate is administered at a dose of about 7.75 GBq. In some embodiments, the radioconjugate is administered at a dose of about 8 GBq. In some embodiments, the radioconjugate is administered at a dose of about 8.25 GBq. In some embodiments, the radioconjugate is administered at a dose of about 8.5 GBq. In some embodiments, the radioconjugate is administered at a dose of about 8.75 GBq. In some embodiments, the radioconjugate is administered at a dose of about 9 GBq. In some embodiments, the radioconjugate is administered at a dose of about 9.25 GBq. In some embodiments, the radioconjugate is administered at a dose of about 9.5 GBq. In some embodiments, the radioconjugate is administered at a dose of about 9.75 GBq. In some embodiments, the radioconjugate is administered at a dose of about 10 GBq. In some embodiments, the radioconjugate is administered at a dose of about 10.25 GBq. In some embodiments, the radioconjugate is administered at a dose of about 10.5 GBq. In some embodiments, the radioconjugate is administered at a dose of about 10.75 GBq. In some embodiments, the radioconjugate is administered at a dose of about 11 GBq. In some embodiments, the radioconjugate is administered at a dose of about 11.25 GBq. In some embodiments, the radioconjugate is administered at a dose of about 11.5 GBq. In some embodiments, the radioconjugate is administered at a dose of about 11.75 GBq. In some embodiments, the radioconjugate is administered at a dose of about 12 GBq. In some embodiments, the radioconjugate is administered at a dose of about 12.25 GBq. In some embodiments, the radioconjugate is administered at a dose of about 12.5 GBq. In some embodiments, the radioconjugate is administered at a dose of about 12.75 GBq.A9TH-038 / 01WG 344158-2244

[0171] In some embodiments, the radiometal is177Lu and the radioconjugate is administered at a dose ranging from about 0.1 GBq to about 30 GBq, from about 1.5 GBq to about 18 GBq, from about 2 GBq to about 15 GBq, from about 3 GBq to about 20 GBq, from about 6 GBq to about 12 GBq, from about 9 GBq to about 11 GBq, from about 8 GBq to about 13 GBq, from about 4 GBq to about 12 GBq, about 1 GBq, about 2 GBq, about 3 GBq, about 3.5 GBq, about 4 GBq, about 4.5 GBq, about 5 GBq, about 5.5 GBq, about 6 GBq, about 6.5 GBq, about 7 GBq, about 7.5 GBq, about 8 GBq, about 8.5 GBq, about 9 GBq, about 9.5 GBq, about 10 GBq, about 10.5 GBq, about 11 GBq, about 11.5 GBq, about 12 GBq, about 12.5 GBq, about 13 GBq, about 14 GBq, about 15 GBq, about 16 GBq, about 17 GBq, about 18 GBq, about 19 GBq, or about 20 GBq. In some embodiments, the radioconjugate is administered at a dose of about 0.1 GBq. In some embodiments, the radioconjugate is administered at a dose of about 0.2 GBq. In some embodiments, the radioconjugate is administered at a dose of about 0.3 GBq. In some embodiments, the radioconjugate is administered at a dose of about 0.4 GBq. In some embodiments, the radioconjugate is administered at a dose of about 0.5 GBq. In some embodiments, the radioconjugate is administered at a dose of about 0.6 GBq. In some embodiments, the radioconjugate is administered at a dose of about 0.7 GBq. In some embodiments, the radioconjugate is administered at a dose of about 0.75 GBq. In some embodiments, the radioconjugate is administered at a dose of about 0.8 GBq. In some embodiments, the radioconjugate is administered at a dose of about 0.9 GBq. In some embodiments, the radioconjugate is administered at a dose of about 1 GBq. In some embodiments, the radioconjugate is administered at a dose of about 1.5 GBq. In some embodiments, the radioconjugate is administered at a dose of about 1.75 GBq. In some embodiments, the radioconjugate is administered at a dose of about 2 GBq. In some embodiments, the radioconjugate is administered at a dose of about 2.5 GBq. In some embodiments, the radioconjugate is administered at a dose of about 2.75 GBq. In some embodiments, the radioconjugate is administered at a dose of about 3 GBq. In some embodiments, the radioconjugate is administered at a dose of about 3.5 GBq. In some embodiments, the radioconjugate is administered at a dose of about 3.75 GBq. In some embodiments, the radioconjugate is administered at a dose of about 4 GBq. In some embodiments, the radioconjugate is administered at a dose of about 4.5 GBq. In some embodiments, the radioconjugate is administered at a dose of about 4.75 GBq. In some embodiments, the radioconjugate is administered at a dose of about 5 GBq. In some embodiments, the radioconjugate is administered at a dose of about 5.5 GBq. In some embodiments, the radioconjugate is administered at a dose of about 5.75 GBq. In some embodiments, the radioconjugate is administered at a dose of about 6 GBq. In some embodiments, the radioconjugate is administered at a dose of about 6.5 GBq. In some embodiments, the radioconjugate is administered at a dose of about 6.75 GBq. In some embodiments, the radioconjugate is administered at a dose of about 7 GBq. In some embodiments, the radioconjugate is administered at a dose of about 7.5 GBq. In some embodiments, the radioconjugate is administered at a dose of about 7.75 GBq. In some embodiments, the radioconjugate is administered at a dose of about 8 GBq. In some embodiments, the radioconjugate is administered at a dose of about 8.25 GBq. In some embodiments, the radioconjugate is administered at a dose of about 8.5 GBq. In some embodiments, the radioconjugate is administered at a dose of about 8.75 GBq. In some embodiments, theradioconjugate is administered at a dose of about 9 GBq. In some embodiments, the radioconjugate is administered at a dose of about 9.25 GBq. In some embodiments, the radioconjugate is administered at a dose of about 9.5 GBq. In some embodiments, the radioconjugate is administered at a dose of about 9.75 GBq. In some embodiments, the radioconjugate is administered at a dose of about 10 GBq. In some embodiments, the radioconjugate is administered at a dose of about 10.25 GBq. In some embodiments, the radioconjugate is administered at a dose of about 10.5 GBq. In some embodiments, the radioconjugate is administered at a dose of about 10.75 GBq. In some embodiments, the radioconjugate is administered at a dose of about 11 GBq. In some embodiments, the radioconjugate is administered at a dose of about 11.25 GBq. In some embodiments, the radioconjugate is administered at a dose of about 11.5 GBq. In some embodiments, the radioconjugate is administered at a dose of about 11.75 GBq. In some embodiments, the radioconjugate is administered at a dose of about 12 GBq. In some embodiments, the radioconjugate is administered at a dose of about 12.25 GBq. In some embodiments, the radioconjugate is administered at a dose of about 12.5 GBq. In some embodiments, the radioconjugate is administered at a dose of about 12.75 GBq.Pharmaceutical Compositions

[0172] The radioconjugates comprising a compound of Formula A, B, I, or II disclosed herein can be formulated as pharmaceutical compositions for administration to a patient. The pharmaceutical compositions typically comprise a compound of Formula A, B, I, or II and a pharmaceutically acceptable carrier, diluent, or excipient. The pharmaceutical compositions are prepared by known procedures using well-known and readily available ingredients.

[0173] The pharmaceutical compositions comprising the compound described above are typically formulated for parenteral administration. The term parenteral as used herein includes subcutaneous, intradermal, intra-articular, intravenous, intraperitoneal, intramuscular, intravascular, intrasternal, intrathecal injection or infusion techniques.

[0174] In certain embodiments, the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or a suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1 ,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Adjuvants such as local anesthetics, preservatives and buffering agents can also be included in the injectable solution or suspension.

[0175] Other pharmaceutical compositions and methods of preparing pharmaceutical compositions are known in the art and are described, for example, in “Remington: The Science and Practice ofA9TH-038 / 01WG 344158-2244Pharmacy" (formerly “Remingtons Pharmaceutical Sciences”)’, Gennaro, A., Lippincott, Williams & Wilkins, Philadelphia, PA (2000).

[0176] The invention features pharmaceutical compositions in a unit dosage form, wherein the pharmaceutical composition comprises a radioconjugate of Formula A, B, I, or II disclosed herein.

[0177] In some embodiments, the pharmaceutical composition comprises about 0.1 pg / mL, about 0.5 pg / mL, about 0.6 pg / mL, about 0.7 pg / mL, about 0.8 pg / mL, about 0.9 pg / mL, about 1 pg / mL, about 1.1 pg / mL, about 1.2 pg / mL, about 1.3 pg / mL, about 1.4 pg / mL, about 1.5 pg / mL, about 1.6 pg / mL, about 1.7 pg / mL, about 1.8 pg / mL, about 1.9 pg / mL, about 2 pg / mL, about 3 pg / mL, about 4 pg / mL, about 5 pg / mL, about 6 pg / mL, about 7 pg / mL, about 8 pg / mL, about 9 pg / mL, or about 10 pg / mL of the radioconjugate of Formula (I).

[0178] In some embodiments, the pharmaceutical composition comprises a molar activity from about 1 - nmol of in —jected peptide to about 5 - nmol of in —jected peptide of the radioconjugate of Formula A, B, I, or II disclosed herein. In some embodiments, the molar activity is about 1 - nmol of in —jecte -d peptide , about 2MBq . . MBq . . . MBq . .rMBq - nmol of inject -e -d peptide , about 3 - nmol of inject -ed peptide , about 3.4 - nmol of inject -ed peptide , about 3.5 - nmol of inject -ed peptide , about 4 - nmol of in —jected peptide , or about 5 - nmol of in —jecte -d peptide .Checkpoint inhibitors

[0179] This section incorporates all embodiments and combinations of features of the compounds or radioconjugates described in the previous section.

[0180] Immune checkpoint inhibitors (e.g., CTLA-4, PD-1 , PD-L1 , or LAG-3 inhibitors) constitute a breakthrough in terms of a new type of immunotherapy in the treatment of cancer (e.g., melanoma). Despite their promise, however, it is reasonable to expect that both patients and clinicians will have to contend with a wide spectrum of immune-related adverse reactions associated with the treatment. How to best use these therapies as effective and safe treatment of cancer remains to be explored.

[0181] The present disclosure provides a method of treating an MC1R-related disease or condition by administering to a subject (e.g., a patient) a combination of one or more checkpoint inhibitors and any one of the radioconjugates described above.

[0182] In some embodiments, the method uses a radioconjugate described above in combination with one or more checkpoint inhibitors selected from a CTLA-4 inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a LAG-3 inhibitor, ora combination thereof.

[0183] In some embodiments, the one or more checkpoint inhibitors are at least one CTLA-4 inhibitor and at least one PD-1 or PD-L1 inhibitor.

[0184] In some embodiments, the one or more checkpoint inhibitors includes one CTLA-4 inhibitor and one PD-1 inhibitor. In some embodiments, the one or more checkpoint inhibitors includes ipilimumab and nivolumab.

[0185] In some embodiments, the one or more checkpoint inhibitors includes one LAG-3 inhibitor and one PD-1 inhibitor. In some embodiments, the one or more checkpoint inhibitors includes relatlimab and nivolumab.A9TH-038 / 01WG 344158-2244

[0186] In some embodiments, the one or more checkpoint inhibitors is ipilimumab, tremelimumab, pembrolizumab, nivolumab, atezolizumab, cemiplimab, dostarlimab, retifanlimab, toripalimab, tislelizumab, camrelizumab, avelumab, spartalizumab, sintilimab, acrixolimab, sasanlimab, cosibelimab, ordurvalumab.

[0187] In some embodiments, the one or more checkpoint inhibitors is ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, toripalimab, retifanlimab, cemiplimab, or dostarlimab.

[0188] In some embodiments, the CTLA-4 inhibitor is tremelimumab and the PD-L1 inhibitor is durvalumab.

[0189] In some embodiments, the LAG-3 inhibitor is relatlimab.

[0190] In some embodiments, the one or more checkpoint inhibitors is a PD-1 inhibitor and a LAG-3 inhibitor. In some embodiments, the one or more checkpoint inhibitors is relatlimab and nivolumab.

[0191] In some embodiments, the one or more checkpoint inhibitors is a single PD-1 inhibitor or more than one PD-1 inhibitors.

[0192] In some embodiments, the single PD-1 inhibitor is pembrolizumab, nivolumab, cemiplimab, dostarlimab, retifanlimab, toripalimab, spartalizumab, sintilimab, acrixolimab, sasanlimab, camrelizumab, or tislelizumab.

[0193] In some embodiments, the single PD-1 inhibitor is pembrolizumab, nivolumab, tislelizumab, toripalimab, dostarlimab, retifanlimab, or cemiplimab.

[0194] In some embodiments, the single PD-1 inhibitor is pembrolizumab.

[0195] In some embodiments, the single PD-1 inhibitor is nivolumab.

[0196] In some embodiments, the more than one PD-1 inhibitors is a combination of nivolumab and ipilimumab, a combination of pembrolizumab and ipilimumab, or a combination of durvalumab and tremelimumab.

[0197] In some embodiments, the one or more checkpoint inhibitors is a single PD-L1 inhibitor.

[0198] In some embodiments, the single PD-L1 inhibitor is atezolizumab, avelumab, durvalumab, or cosibelimab.

[0199] In some embodiments, the one or more checkpoint inhibitors is a single CTLA-4 inhibitor.

[0200] In some embodiments, the single CTLA-4 inhibitor is ipilimumab or tremelimumab.

[0201] In some embodiments, the method comprises administering the one or more checkpoint inhibitors 1 to 20 times, 3 to 12 times, 4 to 10 times, or 4 to 8 times in a course of a treatment cycle.

[0202] In some embodiments, the method comprises administering the one or more checkpoint inhibitors comprises at an interval of 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, or 15 weeks.

[0203] In some embodiments, the dose of the one or more checkpoint inhibitors ranges from about 1 mg to about 2000 mg, from about 100 mg to about 1000 mg, from about 200 mg to about 800 mg, or from about 600 mg to about 1200 mg.

[0204] In some embodiments, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, 115 mg, about 120 mg, about 150 mg, about 200 mg,about 240 mg, about 300 mg, about 350 mg, about 360 mg, about 400 mg, about 480 mg, about 500 mg, about 550 mg, about 600 mg, about 700 mg, about 800 mg, about 840 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1120 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1680 mg, about 1700 mg, about 1800 mg, about 1900 mg, or about 2000 mg of the one or more checkpoint inhibitors is administered to the subject.

[0205] In some embodiments, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, or about 20 mg / kg of the one or more checkpoint inhibitors is administered to the subject.

[0206] In some embodiments, the method includes administering to the subject about 3 mg / kg of ipilimumab every three weeks for a total of 4 doses.

[0207] In some embodiments, the method includes administering to the subject about 10 mg / kg of ipilimumab every three weeks for a total of 4 doses, followed by about 10 mg / kg of ipilimumab every 12 weeks.

[0208] In some embodiments, the method includes administering to the subject about 3 mg / kg of nivolumab and about 1 mg / kg ipilimumab every 3 weeks for 4 doses, followed by about 240 mg of nivolumab every 2 weeks or about 480 mg of nivolumab every 4 weeks.

[0209] In some embodiments, the method includes administering to the subject about 1 mg / kg of nivolumab and about 3 mg / kg ipilimumab every 3 weeks for 4 doses, followed by about 240 mg of nivolumab every 2 weeks or about 480 mg of nivolumab every 4 weeks.

[0210] In some embodiments, the method includes administering to the subject about 3 mg / kg of nivolumab every 2 weeks and about 1 mg / kg ipilimumab every 6 weeks.

[0211] In some embodiments, the method includes administering to the subject about 240 mg of nivolumab every 2 weeks.

[0212] In some embodiments, the method includes administering to the subject about 480 mg of nivolumab every 4 weeks.

[0213] In some embodiments, the method includes administering to the subject about 3 mg / kg of nivolumab every 2 weeks.

[0214] In some embodiments, the method includes administering to the subject about 200 mg of pembrolizumab every 3 weeks.

[0215] In some embodiments, the method includes administering to the subject about 400 mg of pembrolizumab every 6 weeks.

[0216] In some embodiments, the method includes administering to the subject about 2 mg / kg of pembrolizumab every 3 weeks.

[0217] In some embodiments, the method includes administering to the subject about 840 mg of atezolizumab every 2 weeks.

[0218] In some embodiments, the method includes administering to the subject about 1200 mg of atezolizumab every 3 weeks.

[0219] In some embodiments, the method includes administering to the subject about 1680 mg of atezolizumab every 4 weeks.

[0220] In some embodiments, the method includes administering to the subject about 800 mg of avelumab every 2 weeks.

[0221] In some embodiments, the method includes administering to the subject about 1500 mg of durvalumab every 3 weeks.

[0222] In some embodiments, the method includes administering to the subject about 1500 mg of durvalumab every 4 weeks.

[0223] In some embodiments, the method includes administering to the subject about 20 mg / kg of durvalumab every 3 weeks.

[0224] In some embodiments, the method includes administering to the subject about 20 mg / kg of durvalumab every 4 weeks.

[0225] In some embodiments, the method includes administering to the subject about 10 mg / kg of durvalumab every 2 weeks.

[0226] In some embodiments, the method includes administering to the subject about 1120 mg of durvalumab every 3 weeks.

[0227] In some embodiments, the method includes administering to the subject about 15 mg / kg of durvalumab every 3 weeks.

[0228] In some embodiments, the method includes administering to the subject about 240 mg toripalimab every 3 weeks.

[0229] In some embodiments, the method includes administering to the subject about 3 mg / kg toripalimab every 2 weeks.

[0230] In some embodiments, the method includes administering to the subject about 500 mg of retifanlimab every 4 weeks.

[0231] In some embodiments, the method includes administering to the subject 350 mg of cemiplimab every 3 weeks.

[0232] In some embodiments, the method includes administering to the subject about 500 mg of dostarlimab every 3 weeks.

[0233] In some embodiments, the method includes administering to the subject about 1000 mg of dostarlimab every 6 weeks.

[0234] In some embodiments, the method includes administering to the subject about 1 mg / kg of nivolumab and about 3 mg / kg ipilimumab every 3 weeks. In some embodiments, the method includes administering to the subject about 1 mg / kg of nivolumab and about 3 mg / kg ipilimumab every 3 weeks for a total of 4 treatment cycles.

[0235] In some embodiments, the method includes administering to the subject about 1 mg / kg of nivolumab and about 1 mg / kg ipilimumab every 3 weeks. In some embodiments, the method includes administering to the subject about 1 mg / kg of nivolumab and about 1 mg / kg ipilimumab every 3 weeks for a total of 4 treatment cycles.

[0236] In some embodiments, the method includes administering to the subject about 480 mg of nivolumab and about 160 mg of relatlimab every 4 weeks. In some embodiments, the methodincludes administering to the subject about 480 mg of nivolumab and about 160 mg of relatlimab-rmbw every 4 weeks.

[0237] In some embodiments, the method includes administering to the subject225Ac-Compound C and pembrolizumab. In some embodiments, the method includes administering to the subject from about 1 MBq to about 5 MBq of225Ac-Compound C and pembrolizumab. In some embodiments, the method includes administering to the subject from about 1 MBq to about 5 MBq of225Ac-Compound C and from about 0.5 mg / kg to about 2 mg / kg of pembrolizumab. In some embodiments, the method includes administering to the subject from about 1 MBq to about 5 MBq of225Ac-Compound C every 6 weeks and from about 0.5 mg / kg to about 2 mg / kg of pembrolizumab every 3 weeks. In some embodiments, the method includes administering to the subject from about 1 MBq to about 5 MBq of225Ac-Compound C and about 2 mg / kg of pembrolizumab. In some embodiments, the method includes administering to the subject from about 1 MBq to about 5 MBq of225Ac-Compound C and from about 100 mg to about 500 mg of pembrolizumab. In some embodiments, the method includes administering to the subject from about 1 MBq to about 5 MBq of225Ac-Compound C every 6 weeks and from about 100 mg to about 500 mg of pembrolizumab every 3 weeks.

[0238] In some embodiments, the method includes administering to the subject225Ac-Compound C, ipilimumab, and nivolumab. In some embodiments, the method includes administering to the subject from about 1 MBq to about 5 MBq of225Ac-Compound C, ipilimumab, and nivolumab. In some embodiments, the method includes administering to the subject from about 1 MBq to about 5 MBq of225Ac-Compound C, about 3 mg / kg of ipilimumab, and about 1 mg / kg nivolumab. In some embodiments, the method includes administering to the subject from about 1 MBq to about 5 MBq of225Ac-Compound C every 6 weeks, about 3 mg / kg of ipilimumab every 3 weeks, and about 1 mg / kg nivolumab every 3 weeks. In some embodiments, the method includes administering to the subject from about 1 MBq to about 5 MBq of225Ac-Compound C, about 1 mg / kg of ipilimumab, and about 1 mg / kg nivolumab. In some embodiments, the method includes administering to the subject from about 1 MBq to about 5 MBq of225Ac-Compound C every 6 weeks, about 1 mg / kg of ipilimumab every 3 weeks, and about 1 mg / kg nivolumab every 3 weeks.

[0239] In some embodiments, the method includes administering to the subject225Ac-Compound C, relatlimab, and nivolumab. In some embodiments, the method includes administering to the subject from about 1 MBq to about 5 MBq of225Ac-Compound C, relatlimab, and nivolumab. In some embodiments, the method includes administering to the subject from about 1 MBq to about 5 MBq of225Ac-Compound C, about 160 mg of relatlimab, and about 480 mg nivolumab. In some embodiments, the method includes administering to the subject from about 1 MBq to about 5 MBq of225Ac-Compound C every 6 weeks, about 160 mg of relatlimab every 4 weeks, and about 480 mg nivolumab every 4 weeks.

[0240] In some embodiments, administering a combination of one or more checkpoint inhibitors and an225Ac-labeled radioconjugate comprising the CROWN, CROWNGA, or CROWN Amide chelator (e.g.,225Ac-Compound A,225Ac-Compound B,225Ac-Compound C, or225Ac-Compound D), extends the survival of the subject when compared to administering a compound with a177Lu-labeled or ^Ac-labeled DOTA chelator (instead of the CROWN chelator or the like) where the rest of the compound isA9TH-038 / 01WG 344158-2244the same (i.e., same linker and same MC1 RTP). In some embodiments, the survival is extended by at least 3 months, at least 6 months, at least 9 months, or at least 12 months. In some embodiment, the survival is extended by at least 1 year, at least 2 years, at least 3 years, at least 4 years, or at least 5 years.

[0241] In some embodiment of the methods of treating cancer, when combining with one or more checkpoint inhibitors, administering a radioconjugate comprising a CROWN, a CROWNGA, or a CROWN Amide chelator is more effective at reducing the size of a tumor or slowing the progression of cancer when compared to administering a compound with a DOTA chelator (instead of the CROWN, CROWNGA, or CROWN Amide chelator) where the rest of the compound is the same (i.e., same linker and same MC1 RTP).

[0242] In some embodiment of the methods of treating cancer, when combining with one or more checkpoint inhibitors, administering a radioconjugate comprising225Ac labeled CROWN, CROWNGA, or CROWN Amide chelator is more effective at reducing the size of a tumor or slowing the progression of cancer when compared to administering a compound with a177Lu-labeled or ^Ac-labeled DOTA chelator (instead of the CROWN, CROWNGA, or CROWN Amide chelator) where the rest of the compound is the same (i.e., same linker and same MC1 RTP).

[0243] In some embodiment of the methods of treating cancer, when combining with one or more checkpoint inhibitors, administering a radioconjugate comprising225Ac labeled CROWN chelator is more effective at reducing the size of a tumor or slowing the progression of cancer when compared to administering a compound with a177Lu-labeled or225Ac-labeled DOTA chelator (instead of the CROWN chelator) where the rest of the compound is the same (i.e., same linker and same MC1RTP).

[0244] In some embodiments, the MC1 R-related disease or condition is an MC1 R-expressing cancer. In some embodiment, cancer is melanoma or non-melanoma skin cancer. For example, but without limitation, MC1 R is specifically expressed in cutaneous, amelanotic and uveal melanomas. In some embodiments, the MC1 R-expressing cancer is melanoma or non-melanoma skin cancer. In some embodiments, the MC1 R-expressing cancer is primary melanoma or metastatic melanoma. In some embodiments, the MC1 R-expressing cancer is uveal melanoma. In some embodiments, the MC1 R-expressing cancer is metastatic cutaneous melanoma or metastatic uveal melanoma. In some embodiments, the MC1 R-expressing cancer is unresectable or metastatic cutaneous, uveal, or mucosal melanoma. In some embodiments, the MC1 R-expressing cancer is unresectable or metastatic cutaneous melanoma with disease progression while receiving an anti-PD-1 / PD-L1-containing regimen as the most recent line of therapy. In some embodiments, the subject has failed treatment with an anti-PD-1 / PD-L1 -containing regimen.

[0245] Without limitation, the compound of the disclosure or a pharmaceutical composition comprising the compound may be administered to the subject intravenously, or as a subcutaneous or intradermal injection surrounding the site of the initial tumour (e.g. to detect lymphatic spread).Targeted therapies

[0246] This section incorporates all embodiments and combinations of features of the compounds or radioconjugates described in the previous section.

[0247] Pharmacologic inhibition of the mitogen-activated protein kinase (MAPK) pathway has proved to be a major advance in the treatment of metastatic melanoma. The use of BRAF inhibitors, e.g., vemurafenib or dabrafenib, that block MAPK signaling in patients with melanoma and the BRAF V600E mutation, has been associated with prolonged survival and progression-free survival. In combination therapy trials, dose-limiting toxic effects were observed in patients receiving combination therapy with BRAF inhibitors (e.g., dabrafenib) and MEK inhibitors (e.g., trametinib). How to best use these therapies as effective and safe treatment of melanoma remains to be explored.

[0248] The present disclosure provides a method of treating an MC1R-related disease or condition (e.g., melanoma with a BRAF V600 mutation) by administering to a subject (e.g., a patient) a combination of one or more targeted chemo therapies (e.g., one or more targeted therapies) and any one of the radioconjugates described above.

[0249] In some embodiments, this disclosure relates to a combination therapy comprising one or more targeted chemo therapies and a radioconjugate comprising a melanocortin 1 receptor (MC1R) targeting peptide (MC1RTP), a radiolabeling group (e.g., a CROWN chelator) for chelating a radionuclide, and a linker joining the MC1 RTP to the radiolabeling group.

[0250] More specifically, the present disclosure covers a method of treating melanoma with a BRAF V600 mutation, comprising administering to a subject in need thereof a combination of:(a) one or more targeted chemo therapies, and(b) a radioconjugate comprising a melanocortin 1 receptor (MC1R) targeting peptide (MC1 RTP) linked to a CROWN, a CROWNGA, or a CROWN Amide chelator by a linker, or a pharmaceutically acceptable salt thereof, wherein:the MCR1TP is cyclized and comprises a sequence of Formula A or B:Xaa1-Xaa2a-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7a(A) (SEQ ID NO: 2) Xaa1-Xaa2b-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7b(B) (SEQ ID NO: 3) Xaa1is selected from the group consisting of norleucine (Nle), D-Nle, Ala, D-Ala, Leu, D-Leu, He, D-lle, Cys, D-Cys, Met, D-Met, Phe, D-Phe, Trp, D-Trp, Vai, D-Val, 3-(1-naphthyl)alanine (Nal), D-Nal, 3-(2-naphthyl)alanine (2-Nal), D-2-Nal, Gly, a-aminobutyric acid, norvaline, D-norvaline, homonorleucine, and D-homonorleucine;Xaa2ais selected from the group consisting of Cys, D-Cys, Asp, D-Asp, Glu, D-Glu, 2-aminoadipic acid (2-Aad), D-2-Aad, 3-aminoadipic acid (3-Aad), D-3-Aad, propargylglycine (Pra), D-Pra, homopropargylglycine (Hpg), D-Hpg, beta-homopropargylglycine (Bpg), and D-Bpg;Xaa2bis selected from the group consisting of Cys, D-Cys, Lys, D-Lys, Ornithine (Orn), D-Orn, 2,4-diaminobutyric acid (Dab), D-Dab, 2,3-diaminopropionic acid (Dap), D-Dap, Lys(N3), D-Lys(N3), Orn(N3), D-Orn(N3), Dab(N3), D-Dab(N3), Dap(N3), D-Dap(N3), 2-(5'-azidopentyl)alanine, D-2-(5'-azidopentyl)alanine, 2-(6'-azidohexyl)alanine, and D-2-(6'-azidohexyl)alanine;Xaa3is His;Xaa4is D-Phe;Xaa5is Arg;Xaa6is Trp;Xaa7ais selected from the group consisting of Cys, D-Cys, Lys, D-Lys, Orn, D-Orn, Dab, D-A9TH-038 / 01WG 344158-2244Dab, Dap, D-Dap, Lys(N3), D-Lys(N3), Orn(N3), D-Orn(N3), Dab(N3), D-Dab(N3), Dap(N3), D-Dap(N3), 2-(5’-azidopentyl)alanine, D-2-(5’-azidopentyl)alanine, 2-(6’-azidohexyl)alanine, and D-2-(6’-azidohexyl)alanine;Xaa7bis selected from the group consisting of Cys, D-Cys, Asp, D-Asp, Glu, D-Glu, 2-Aad, D-2-Aad, 3-Aad, D-3-Aad, Pra, D-Pra, Hpg, D-Hpg, Bpg, and D-Bpg; andone or more amino acid residues of the MC1RTP is alpha N-methylated,wherein one or more of Xaa3, Xaa5, Xaa6, and Xaa7ais alpha N-methylated, and one or more of Xaa3, Xaa5, Xaa6, and Xaa7bis alpha N-methylated; and the MCR1TP is optionally C-terminally amidated.

[0251] In some embodiments, the one or more targeted chemo therapies is one or more targeted therapies.

[0252] In some embodiments, the method uses a radioconjugate described above in combination with one or more targeted therapies selected from a BRAF inhibitor, a MEK inhibitor, or a combination thereof.

[0253] In some embodiments, the MEK inhibitor is trametinib, cobimetinib, binimetinib, selumetinib, mirdametinib, or a combination thereof.

[0254] In some embodiments, the BRAF inhibitor is vemurafenib, dabrafenib, encorafenib, or a combination thereof.

[0255] In some embodiments, the one or more targeted therapies are selected from dabrafenib, trametinib, vemurafenib, cobimetinib, encorafenib, binimetinib, or a combination thereof.

[0256] In some embodiments, the one or more targeted therapies are a combination of dabrafenib and trametinib, a combination of vemurafenib and cobimetinib, or a combination of encorafenib and binimetinib.

[0257] In some embodiments, the method comprises administering the targeted therapies 1 to 20 times, 3 to 12 times, 4 to 10 times, or 4 to 8 times in a course of a treatment cycle.

[0258] In some embodiments, the method comprises administering the targeted therapies comprises at an interval of 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, or 15 weeks.

[0259] In some embodiments, the dose of the targeted therapies ranges from about 1 mg to about 2000 mg, from about 100 mg to about 1000 mg, from about 200 mg to about 800 mg, or from about 600 mg to about 1200 mg.

[0260] In some embodiments, about 1 mg, about 2 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, 115 mg, about 120 mg, about 150 mg, about 200 mg, about 240 mg, about 300 mg, about 350 mg, about 360 mg, about 400 mg, about 450 mg, about 480 mg, about 500 mg, about 550 mg, about 600 mg, about 700 mg, about 800 mg, about 840 mg, about 900 mg, about 950 mg, about 960 mg, about 1000 mg, about 1100 mg, about 1120 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1680 mg, about 1700 mg, about 1800 mg, about 1900 mg, or about 2000 mg of targeted therapies is administered to the subject.

[0261] In some embodiments, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, or about 20 mg / kg of targeted therapies is administered to the subject.

[0262] In some embodiments, about 150 mg of dabrafenib is administered to the subject. In some embodiments, about 2 mg of trametinib is administered to the subject.

[0263] In some embodiments, about 450 mg of encorafenib is administered to the subject. In some embodiments, about 45 mg of binimetinib is administered to the subject.

[0264] In some embodiments, about 960 mg of vemurafenib is administered to the subject. In some embodiments, about 60 mg of cobimetinib is administered to the subject.

[0265] In some embodiments, the method includes administering to the subject225Ac-Compound C, dabrafenib, and trametinib.

[0266] In some embodiments, the method includes administering to the subject225Ac-Compound C, encorafenib, and binimetinib.

[0267] In some embodiments, the method includes administering to the subject225Ac-Compound C, vemurafenib, and cobimetinib.

[0268] In some embodiment, the method of the present disclosure, administering a combination of one or more targeted therapies and an225Ac-labeled radioconjugate comprising the CROWN or CROWNGA chelator (e.g.,225Ac-Compound A,225Ac-Compound B,225Ac-Compound C, or ^Ac-Compound D), extends the survival of the subject when compared to administering a compound with a177Lu-labeled or225Ac-labeled DOTA chelator (instead of the CROWN chelator or the like) where the rest of the compound is the same (i.e., same linker and same MC1RTP). In some embodiment, the survival is extended by at least 3 months, at least 6 months, at least 9 months, or at least 12 months. In some embodiment, the survival is extended by at least 1 year, at least 2 years, at least 3 years, at least 4 years, or at least 5 years.

[0269] In some embodiment of the methods of treating cancer using a combination therapy with one or more targeted therapies, administering a radioconjugate comprising a CROWN, a CROWNGA, or a CROWN Amide chelator is more effective at reducing the size of a tumor or slowing the progression of cancer when compared to administering a compound with a DOTA chelator (instead of the CROWN, CROWNGA, or CROWN Amide chelator) where the rest of the compound is the same (i.e., same linker and same MC1 RTP).

[0270] In some embodiment of the methods of treating cancer using a combination therapy with one or more targeted therapies, administering a radioconjugate comprising225Ac labeled CROWN, CROWNGA, or CROWN Amide chelator is more effective at reducing the size of a tumor or slowing the progression of cancer when compared to administering a compound with a177Lu-labeled or ^Ac-labeled DOTA chelator (instead of the CROWN, CROWNGA, or CROWN Amide chelator) where the rest of the compound is the same (i.e., same linker and same MC1 RTP).

[0271] In some embodiment of the methods of treating cancer using a combination therapy with one or more targeted therapies, administering a radioconjugate comprising225Ac labeled CROWN chelatoris more effective at reducing the size of a tumor or slowing the progression of cancer when compared to administering a compound with a177Lu-labeled or225Ac-labeled DOTA chelator (instead of the CROWN chelator) where the rest of the compound is the same (i.e., same linker and same MC1RTP).

[0272] In some embodiments, the MC1 R-related disease or condition is melanoma with a BRAF V600 mutation. In some embodiments, the BRAF V600 melanoma comprise both V600E and V600K mutations.

[0273] Without limitation, MC1R can be specifically expressed in cutaneous, amelanotic and uveal melanomas. In some embodiments, the MC1R-expressing cancer is primary melanoma or metastatic melanoma. In some embodiments, the MC1R-expressing cancer is uveal melanoma. In some embodiments, the MC1R-expressing cancer is metastatic cutaneous melanoma or metastatic uveal melanoma. In some embodiments, the MC1R-expressing cancer is unresectable or metastatic cutaneous, uveal, or mucosal melanoma. In some embodiments, the MC1R-expressing cancer is unresectable or metastatic cutaneous melanoma with disease progression while receiving an anti-PD-1 / PD-L1-containing regimen as the most recent line of therapy. In some embodiments, the subject has failed treatment with an anti-PD-1 / PD-L1-containing regimen. In some embodiments, the subject has failed treatment with a MEK inhibitor, a BRAF inhibitor, or a combination thereof.

[0274] Without limitation, the compound of the disclosure or a pharmaceutical composition comprising the compound may be administered to the subject intravenously, or as a subcutaneous or intradermal injection surrounding the site of the initial tumour (e.g. to detect lymphatic spread).Methods for Selecting a Subject for Treatment

[0275] In some embodiments, the subject is selected for the treatment by SPECT, PET / CT, or PET / MRI imaging with a MC1R-targ eting contrast agent chelated to a radiometal Mb suitable for imaging based on detection of the radiometal in the imaging scan at the tumor or lesion region.

[0276] In some embodiments, the MC1R-targeting contrast agent is Mb-Compound E:Mb-Compound E (SEQ ID NO: 1)or a pharmaceutically acceptable salt thereof.

[0277] In some embodiments, the MC1 R-targeting contrast agent is Mb-ADVC002.

[0278] In some embodiments, the MC1R-targeting contrast agent is Mb-Compound E, Mb-VMT01 , Mb-VMT02, Mb-DOTA-NAPamide, Mb-DOTA-ReCCMSH, or Mb-MTI-201 :Mb-Compound E (SEQ ID NO: 1)VMT-01 (SEQ ID NO: 53),DOTA-NAPamide (SEQ ID NO: 55),DOTA-FteCCMSH (SEQ ID NO: 56), orMTI-201 (SEQ ID NO: 57),or a pharmaceutically acceptable salt thereof.

[0279] In some embodiments, Mb is18F, AI18F,43Sc,44Sc,51Cr,52mMn,52Fe,61Cu,62Cu,64Cu,67Cu,67Ga,66Ga,68Ga,72As,82Rb,86Y,89Zr,94mTc,97Ru,99mTc,111ln,117mSn,123l,124l,125l,133mln,152Tb,155Tb,157Gd,169Yb,172Tm,177Lu, or203Pb.

[0280] In some embodiments, Mb is64Cu,67Cu,67Ga,68Ga,99mTc, or203Pb. In some embodiments, Mb is68Ga.A9TH-038 / 01WG 344158-2244

[0281] In some embodiments,68Ga-Compound E (SEQ ID NO: 1) is used to select subjects for any of the treatment methods disclosed herein (i.e.,68Ga is chelated to DOTA):

[0282] In other embodiments, the subject is selected by evaluating the uptake of the MC1 R-targeting contrast agent by SPECT, PET / CT, or PET / MRI scan at the tumor or lesion region.

[0283] In some embodiments, a SPECT or PET scan with the MC1R-targeting contrast agent may be performed from 42 days to 1 day prior to the first administration of the radioconjugate for any of the treatment methods disclosed herein. Uptake of a MC1 R-targeting contrast agent (e.g.,68Ga-Compound E) by PET scan with at least one measurable lesion (per RECIST v1.1) having a maximum standardized uptake value (SUVmax) higher than the mean standardized uptake value (SUVmean) of the liver indicates a positive-MC1R lesion. Thus, the disclosure also relates to methods for determining whether a human subject having melanoma can be selected for the treatment methods as disclosed herein, the method comprising:(a) administering a sufficient amount of a MC1 R-targeting contrast agent to the subject and imaging the subject by SPECT, PET / MRI, or PET / CT; and(b) detecting MC1 R-positive tumors or lesions in the subject by calculating the liver SUVmax / SUVmean ratio of the MC1 R-targeting contrast agent in the image obtained from (a).

[0284] The objective of the above selection method is to select the subject with MC1 R-positive tumors or lesions, i.e., which subjects are better responders to the treatment methods as disclosed. MC1 R-positive tumors or lesions may be advantageously detected by evaluating the uptake of the MC1 R-targeting contrast agent by SPECT, PET / MRI, or PET / CT imaging after administration of the contrast agent.

[0285] In some embodiments, the SUVmax / SUVmean ratio in the liver is >1.

[0286] As used herein, a good responder is a subject selected from a patient population which shows statistically better response to a treatment disclosed herein as compared to a randomized patient population (i.e., which has not been selected by the selection step of the present method), and / or which shows fewer side effects to a treatment disclosed herein as compared to a randomized patient population (i.e., which has not been selected by the selection step of the present method).

[0287] In some embodiments, the selection of subject is performed from 1 to 30 days, e.g., about 5 days or about 14 days prior to the first administration of the radioconjugate disclosed herein.

[0288] In some embodiments, the MC1 R-targeting contrast agent (e.g.,68Ga-Compound 4) is administered at a single intravenous dose comprising about 1 MBq / kg to 3 MBq / kg (e.g., 2 MBq / kg).

[0289] In some embodiments, Mb is68Ga and from about 10 MBq to about 300 MBq of the MC1R-targeting contrast agent is administered to the subject. In some embodiments, from about 150 MBq to about 250 MBq of the68Ga-labelled MC1R-targeting contrast agent is administered to the subject. In some embodiments, from about 40 MBq to about 200 MBq of the68Ga-labelled MC1R-targeting contrast agent is administered to the subject.

[0290] In some embodiments, images of the subject’s body are acquired by SPECT, PET / MRI, or PET / CT imaging and the images are compared with a control image to identify whether the lesions identified by conventional imaging, for example by MRI or CT, are also identified by the uptake of the MC1R-targeting contrast agent. In some embodiments, SPECT, PET / MRI, or PET / CT imaging is performed from about 1 hour to about 48 hours (e.g., about 24 hours) or from 30 to 120 minutes (e.g., from 60 to 90 minutes) after the intravenous administration of the MC1 R-targeting contrast agent to the subject.

[0291] In some embodiments of the method, a subject that is selected for a treatment method of the disclosure fulfils the following condition: at least 10%, e.g., more than 20%, e.g., more than 30%, e.g., more than 40%, e.g., more than 50%, e.g., more than 60%, e.g., more than 70%, e.g., more than 80% of the lesion or lesions as detected by conventional imaging in said subject, for example by MRI or CT, are also identified by the uptake of the MC1 R-targeting contrast agent as determined by SPECT, PET / MRI, or PET / CT imaging in the subject.

[0292] In some embodiments of the method, a subject that is selected for a treatment method of the disclosure fulfils the following condition: at least one lesion or tumor exhibits greater uptake compared to background (e.g., liver uptake) by SPECT, PET / MRI, or PET / CT imaging in the subject.

[0293] In some embodiments, the term “lesion” refers to measurable lesions according to RECIST 1.1 criteria.EXAMPLES

[0294] To gain a better understanding of the invention described herein, the following examples are set forth. It will be understood that these examples are intended to describe illustrative embodiments of the invention and are not intended to limit the scope of the invention in anyway.Example 1: Synthesis of Compound C: ([4-(p-tolylphenyl)butanoyl]-Gly-Lys(CROWN)-Pip-Nle-cyclo[Asp-His-D-Phe- / V-Me-Arg-Trp- / V-Me-Lys]-NH2) (SEQ ID NO: 48), which is also known as CCZ01178.A9TH-038 / 01WG 344158-2244Compound C (“CCZ01178”) (SEQ ID NO: 48)

[0295] Compound C was synthesized according to a modified procedure disclosed inWO2019 / 222851.

[0296] Compound C was radiolabeled with225Ac to provide225Ac-labeled Compound C (CCZ01178).Example 2: Biodistribution

[0297] NRG mice bearing SK-MEL-1 human melanoma were injected with 1-2 MBq of225Ac-labeled Compound C via tail vein under anesthesia with or without co-injection of 0.5 mg of MC1 R-specific inhibitor BMS 470539. At various time points p.i., the mice were anesthetized again, and euthanized by CO2 inhalation. Blood was promptly withdrawn, and the organs of interest were harvested, rinsed with 1 x PBS (pH 7.4), and blotted dry. Each organ was then weighed and the radioactivity of the collected tissue was measured using a Wallac WIZARD2 gamma counter (Perkin Elmer), normalized to the injected dose using a standard curve and expressed as the percentage of the injected dose per gram of tissue (%ID / g). Table 3 summarizes the biodistribution data of225Ac-labeled Compound C (CCZ01178) at 24 h p.i. and Table 4 summarizes the biodistribution data of225Ac-labeled Compound C (CCZ01178) at additional time points.Table 3. Biodistribution of225Ac-labeled Compound C in NRG mice bearing SK-MEL-1 human melanoma at 24 h p.i. Values are in % ID / g (mean ± standard deviation).SK-MEL-1 24 hOrgan / Tissue Mean SD nBlood 0.27 0.02 3Fat 0.08 0.03 3Testes 0.38 0.01 3SK-MEL-1 24 hOrgan / Tissue Mean SD nIntestines 0.34 0.11 3Spleen 1.42 0.2 3Pancreas 0.14 0.03 3Stomach 0.97 0.4 3Liver 4.52 0.23 3Adrenals 0.49 0.43 3Kidneys 4.66 0.34 3Heart 0.39 0.03 3Lungs 0.77 0.19 3Thyroid 1.52 0.08 3Bone 0.43 0.08 3Muscle 0.06 0.05 3Brain 0.03 0.01 3SK-MEL-1 Tumor 10.58 0.76 3Tumor-to-Blood 39.68 2.62 3Tumor-to-Muscle 124.93 19.74 3Tumor-to-Bone 25.67 7.02 3Tumor-to-Kidneys 2.28 0.23 3Table 4. Biodistribution of225Ac-labeled Compound C in NRG mice bearing SK-MEL-1 human melanoma at various time points p.i. Values are in % ID / g (mean ± standard deviation).Time (h:m) 1:02 4:05 22:57 47:09 125:03 Organs AVG SD AVG SD AVG SD AVG SD AVG SD Blood 13.61 0.94 8.21 0.99 0.31 0.07 0.06 0.01 - - Tumor 6.97 0.95 11.67 0.64 19.21 2.39 14.99 2.61 10.51 3.97 Muscle 1.03 0.18 0.76 0.11 0.16 0.03 0.19 0.02 - - Bone 1.50 0.20 1.50 0.14 0.62 0.20 0.49 0.09 1.00 0.38 Spleen 2.69 0.65 1.63 0.65 2.01 0.56 2.20 0.53 1.83 1.30 Pancreas 1.56 0.09 1.22 0.26 0.29 0.16 0.27 0.10 - - Kidneys 10.14 1.21 9.93 1.18 9.24 0.90 6.27 1.70 2.82 1.23 Adrenals - - - - 6.53 2.09 - - - - Liver 5.60 0.51 5.79 1.60 3.71 0.36 4.79 0.55 4.75 0.91 Lungs 9.78 2.08 5.93 0.49 1.07 0.22 0.80 0.11 0.55 0.20 Stomach 2.37 0.44 2.09 0.16 0.66 0.19 0.58 0.06 0.38 0.12 Small intestine 1.49 0.22 1.28 0.01 0.29 0.03 0.20 0.05 0.13 0.06Large intestine 1.48 0.19 0.94 0.18 0.61 0.29 0.37 0.10 0.23 0.10Time (h:m) 1:02 4:05 22:57 47:09 125:03 Organs AVG SD AVG SD AVG SD AVG SD AVG SDTumor / Bone 4.70 0.79 7.80 0.58 34.12 12.95 30.92 2.28 10.66 1.88 Tumor / Muscle 7.05 2.17 15.51 1.38 117.65 3.02 - - - - Tumor / Blood 0.52 0.10 1.43 0.14 62.99 7.34 230.14 27.41 - - Tumor / Kidneys 0.69 0.13 1.19 0.16 2.07 0.08 2.46 0.45 3.84 0.05 Tumor / liver 1.26 0.25 2.11 0.44 5.18 0.35 3.11 0.27 2.19 0.53Tumor / pancreas 4.50 0.83 9.80 1.43 83.35 43.62 66.11 39.93 - -Example 3. Dose Escalation Study

[0298] Dose escalation study was conducted with225Ac-labeled Compound C (at 15 kBq and 30 kBq) and177Lu-labeled CCZ01158 (at 20 MBq and 40 MBq) in SL-MEL-1 bearing mice.177Lu-labeled CCZ01158 was obtained according to WO2019 / 222851. CCZ01158 ([4-(p-tolylphenyl)butanoyl]-Gly-Lys(DOTA)-Pip-Nle-cyclo[Asp-His-D-Phe- / V-Me-Arg-Trp- / V-Me-Lys]-NH2) (SEQ ID NO: 50) is shown below:CCZ01158 (SEQ ID NO: 50)

[0299] SK-MEL-1 human melanoma-bearing mice were injected with saline (control), [225Ac]Ac-Compound C (about 15 or 30 kBq / mouse), or [177Lu]Lu-CCZ01158 (about 20 or 40 MBq / mouse). Tumour size and body weight were measured every 2-4 days from the date of injection. Endpoint was defined as > 15% weight loss, ulceration of tumours, or tumour volume > 1000 mm3(Volume = width x width x length Z2, measured with calliper).

[0300] Fig. 1. Shows the change in tumor volume over time and Fig. 2 shows survival curve of different treatment groups.Example 4. Combination Study with Checkpoint Inhibitors

[0301] In this study, radioconjugates comprising compounds disclosed herein such Compound A, B, C, or D will be evaluated in combination with one or more checkpoint inhibitors such as ipilimumab, pembrolizumab, nivolumab, or atezolizumab.

[0302] For this assessment, a radioconjugate is administered using certain dosing regimen injected in mice via tail vein, with a predetermined interval between each administration.Checkpoint inhibitors including anti-CLTA4 and anti-PD-1 are administered via intraperitoneal injection. The combination of checkpoint inhibitors and a radioconjugate are administered concurrently, followed by routine doses of checkpoint inhibitors given via intraperitoneal injection. Upon conclusion of the study, tumor re-challenge may be conducted in animals that demonstrated complete tumor regression as results from the combination therapy.Example 5. Combination Study with BRAF / MEK Inhibitors

[0303] In this study, radioconjugates comprising compounds disclosed herein such Compound A, B, C, or D will be evaluated in combination with one or more BRAF inhibitors and MEK inhibitors such as dabrafenib, trametinib, vemurafenib, cobimetinib, encorafenib, and binimetinib.

[0304] For this assessment, a radioconjugate is administered using certain dosing regimen injected in mice via tail vein, with a predetermined interval between each administration.A BRAF inhibitor and a MEK inhibitor, e.g., dabrafenib and trametinib, can be orally administered. The combination of BRAF / MEK inhibitors and a radioconjugate are administered concurrently, followed by routine doses of BRAF / MEK inhibitors given orally. Upon conclusion of the study, tumor re-challenge may be conducted in animals that demonstrated complete tumor regression as results from the combination therapy.Example 6. Phase 1 / 1 b Clinical Study for Treating Melanoma

[0305] Provided herein is a protocol example describing multicenter, open-label Phase 1 -1 b study of Compound C in subjects with MC1R-positive unresectable or metastatic melanoma. The primary aim of the Phase 1 portion of the study is to evaluate the safety and tolerability of Compound C and to select a recommended phase 2 dose (RP2D). The aim of Phase 1 b will be to evaluate the safety, efficacy, and normal organ and tumor dosimetry of Compound C administered at the RP2D in subjects with unresectable or metastatic cutaneous melanoma who had confirmed disease progression while receiving an anti-PD-1 / PD-L1-containing regimen. Eligible subjects will undergo PET / CT using the investigational imaging agent, Compound E. Subject images will be examined by a local reader to determine if the subject has MC1R-positive disease defined as tumor uptake of Compound E by PET scan with at least one measurable lesion (per RECIST v1.1) having a maximum standardized uptake value (SUVmax) higher than the mean standardized uptake value (SUVmean) of the liver. Compound C will be administered on Day 1 of each 6-week cycle, repeated for a total of up to 6 cycles. The study objectives are summarized in Table 5.Table 5. Summary of Phase 1 / 1 b clinical trial objectives.ObjectivesPrimary:Phase 1:• Determine the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) of Compound CPhase 1b:• Characterize the safety and tolerability of Compound CSecondary:• Evaluate the preliminary efficacy of Compound C by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) in Phase 1b• Evaluate biodistribution and normal organ dosimetry of Compound CExploratory:• Evaluate tumor dosimetry of Compound C• Estimate the correlation between Compound E and [18F]Fluorodeoxyglucose (FDG) positron emission tomography (PET) scans• Conduct population pharmacokinetics (PK) and exposure-response analyses for Compound CStudy Design

[0306] This is a Phase 1-1 b first-in-human study intended to determine dose-limiting toxicities (DLTs), the MTD, and the RP2D, as well as to assess the biodistribution, normal organ dosimetry, and preliminary efficacy of Compound C. Adult subjects with unresectable or metastatic melanoma will be enrolled. The study will include 2 parts: Phase 1 (dose finding) and Phase 1b (cutaneous melanoma dose expansion). To be eligible for Phase 1 , subject must have histologically or cytolog ically confirmed unresectable or metastatic cutaneous, uveal, or mucosal melanoma that has progressed on or following at least one standard anticancer regimen. To be eligible for Phase 1b, subject must have histologically or cytologically confirmed unresectable or metastatic cutaneous melanoma with disease progression while receiving an anti-PD-1 / PD-L1 -containing regimen as the most recent line of therapy. Subjects with a BRAF activating mutation could have also received a BRAF inhibitor and / or MEK inhibitor regimen. The dosing schedule for Phase 1 and Phase 1b is summarized in Table 6.Table 6. Summary of Phase 1 and 1 b dosing schedulesStudy Phase Dose and Schedule of225Ac-Compound C AdministeredPhase 1 Dose Escalation Dose Level Activity Interval N DL -1 4 MBq 6 weeks (± 7 days) > 3 Starting Dose DL 1 6 MBq 6 weeks (± 7 days) > 3DL2 9 MBq 6 weeks (± 7 days) > 3 DL 3 12 MBq 6 weeks (± 7 days) > 3Subtotal - Dose ~12 Escalation:RP2D Expansion RP2D RP2D 6 weeks (± 7 days) ~12Subtotal - Phase ~24 1:Phase 1b AdministeredPopulation Specific Dose Expansion Activity Interval N Cutaneous melanoma with confirmed disease RP2D 6 weeks progression on anti-PD-1 / PD-L1 therapy 25Total Phase 1-1 b: ~50DL = Dose Level; MBq = megabecquerel; RP2D = recommended Phase 2 dose.Number of Participants

[0307] Approximately 24 subjects will be enrolled in the Phase 1 portion of the study, including approximately 12 DLT-evaluable subjects in dose escalation and approximately 12 subjects in the RP2D expansion cohort. Up to 25 subjects will be enrolled in the Phase 1b expansion cohort, inclusive of any Phase 1 b-eligible subjects who began treatment at the RP2D.Phase 1 Dose Escalation

[0308] Compound C will be evaluated at 3 dose levels (DL) ranging from 6 to 12 MBq administered approximately every 6 weeks for up to 6 doses, until confirmed radiographic disease progression, unacceptable toxicity, or any other reason for discontinuation. A lower dose level (DL-1 , 4 MBq) could be tested (Table 7).Table 7. Dose levels for Compound C.Dose Level Administered Activity (MBq)-1 41 62 93 12

[0309] Subjects will be enrolled into each DL cohort in a sequential, ascending-dose fashion. Phase 1 will follow a Bayesian optimal interval (BOIN) design. A minimum cohort size of 3 subjects will be treated prior to deciding to escalate, de-escalate, or remain at the same dose level. Subjects who are not dose-limiting toxicity (DLT)-evaluable will be replaced for the purpose of establishing MTD. The DLT observation period for each subject will be 4 weeks following the first dose of Compound C. When the DLT observation period concludes for the first 3 DLT-evaluable subjects in a cohort, the Dose Escalation Committee (DEC) will convene to review the totality of safety and available organ dosimetry data and to recommend escalation, expansion, or de-escalation of the starting dose level. Decisions regarding escalation or de-escalation will be guided by a BOIN design as shown in Table 8.Table 8. Dose escalation and de-escalation boundariesDose escalation and de-escalation boundaries for target toxicity rate = 30%The number of subjects treated at the current dose level Action 1 2 3 4 5 6 7 8 9 Escalate if # of DLTs < 0 0 0 0 1 1 1 1 2 De-escalate if # of DLTs > 1 1 2 2 2 3 3 3 4

[0310] After the dose escalation portion is completed with a maximum of 9 DLT-evaluable subjects at a given dose level, the maximum tolerated dose (MTD) is selected using a regression model based on the BOIN design, if appropriate.Phase 1 RP2D Expansion

[0311] The RP2D will be selected based on overall safety, tolerability (including chronic toxicities, discontinuations, or withdrawals during and beyond the DLT period), PK, dosimetry, and, if available, efficacy data. Once the RP2D has been provisionally determined, up to an additional 12 subjects may be enrolled and treated in a RP2D expansion cohort, to further characterize safety, tolerability, dosimetry, and PK of Compound C.Phase 1b Trial

[0312] After identification of the RP2D of Compound C, the study will continue to enroll subjects with cutaneous melanoma with confirmed tumor progression by RECIST v1.1 following an anti-PD-1 / PD-L1 containing regimen. The purpose of this expansion cohort is to allow collection of additional safety data and to preliminarily assess the single-agent efficacy of Compound C in this patient population.

[0313] This cohort will enroll up to 25 evaluable subjects. A subject who meets all the study eligibility criteria, receives at least 1 dose of Compound C, and has at least one on-treatment tumor assessment is considered evaluable. Subjects meeting the eligibility criteria for Phase 1 b who receive Compound C at the RP2D in the dose escalation portion of the study may be counted toward the total target sample size for Phase 1 b.Inclusion CriteriaSubjects must meet all of the following criteria to be eligible for the study.1. Able to provide written informed consent for receiving any investigational product.2. Male or female >18 years old at time of consent.3. Measurable disease by RECIST v1.1.4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.5. Resolution to baseline of prior treatment-related toxicities and laboratory abnormalities (parameters below apply). Exceptions include Grade 2 alopecia and Grade 2 fatigue, which are allowed.6. Adequate organ function within 14 days of first dose of investigational products:a. White blood cell count >2 x 1 o9 / L in absence of growth factor support b. Absolute neutrophil count >1.0 x 1 o9 / L in absence of growth factor support c. Platelet count >100 x 1 o9 / Ld. Hemoglobin >8 g / dLe. Serum creatinine <1.5 mg / dL or creatinine clearance >60 mL / min (calculated using the formula of local laboratory or measured)a. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <3 x upper limit of normal (ULN)b. Total bilirubin <1.5 x ULN, or direct bilirubin <ULN for subjects withtotal bilirubin levels >1.5 x ULNc. International normalized ratio (INR) or prothrombin time (PT) <1.5 x ULN unless subject is receiving anticoagulant therapy and PT is within therapeutic range of intended use of anticoagulantsd. Activated partial thromboplastin time (aPTT) <1.5 x ULN unless subject is receiving anticoagulant therapy and aPTT is within therapeutic range of intended use of anticoagulants7. Women of childbearing potential (WOCBP) must have a pregnancy test and a negative pregnancy test result prior to administration of any dose of investigational product.WOCBP must agree to follow instructions for method(s) of contraception for the duration of the Treatment Period and 6 months after the last dose of Compound C. Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of the Treatment Period and 3 months after the last dose of Compound C.Exclusion CriteriaSubjects will be excluded from the study if they meet any of the following criteria.1. Previous treatment with radioactive nuclides except radioactive imaging tracers.2. Treatment with another investigational product within the last 4 weeks or 5 halflives (whichever is longer) before the first dose of Compound C; investigational anti-PD-1 / PD-L1 agents are allowed.A9TH-038 / 01WG 344158-2244Concurrent treatment with any anticancer agent.Major surgery within 4 weeks of first dose of investigational product.Second malignancy (solid or hematologic) within the past 2 years except:a. Adequately treated basal cell or squamous cell skin cancer, orb. Carcinoma in situ of the cervix, orc. Prostate cancer Gleason score < 6 with undetectable prostate specific antigen (PSA) over 12 months, ord. Ductal breast carcinoma in situ with full surgical resection (i.e.,negative margins), ore. Treated medullary or papillary thyroid cancerActive, known, clinically serious infections (> Grade 2 according to NCI-CTCAE v 5.0) within 2 weeks prior to first dose of investigational product.7. History of infusion reaction to excipients in the formulation of the investigational products.8. Uncontrolled diabetes or hypertension.9. Poorly controlled human immunodeficiency virus (HIV) with detectable viral load, evidence of hepatitis B infection, chronic or untreated hepatitis C.10. Congestive heart failure (New York Heart Association Class III to IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction within 6 months prior to the first dose of investigational product. 11. QTcF prolongation (QTcF interval > 470 msec for females or > 450 msec for males) or congenital long QT syndrome.12. Known active central nervous system metastases and / or carcinomatous meningitis.Subjects with untreated brain metastases < 3 mm that are asymptomatic and do not have significant edema, cause shift, or require steroids or anti-seizure medications are eligible after discussion with the Medical Monitor. Lesions of any size in the posterior fossa are excluded. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using corticosteroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.13. Pregnant, breastfeeding, or unwilling to practice birth control during participationin the study.14. Any clinically significant psychiatric, social, or medical condition that, in the opinion of the investigator, could increase subject’s risk, interfere with protocol adherence, or affect a subject’s ability to give informed consent.Compound E Imaging

[0314] Compound E is a PET imaging agent intended to identify MC1R- positive tumors. Compound E will be administered as a slow IV push with a target activity of 2 MBq / kg ±10% (up to 200 MBq maximum administered activity). The target administered activity may be reduced if warranted, based on the effective sensitivity of the scanner; any adjustments must be approved by the sponsor.Compound C Therapy

[0315] To be considered eligible for treatment with Compound C, subjects must have tumor uptake of Compound E by PET scan with at least one measurable lesion (per RECIST v1.1) having an SUVmax higher than the SUVmean of the liver. Subjects meeting this criterion enrolled in the A9T-3202-01 study within the previous 4 weeks may be eligible for this study after approval by the Medical Monitor or designee.

[0316] Compound C will be supplied to the study site as a ready-to-use solution for injection in a single-dose container from which any of the planned or reduced doses described in this protocol may be prepared. Compound C will be administered as a constant-rate IV infusion on Day 1 of every cycle. The injection end time will be the completion of the syringe push of the Compound C, and not the end of any post-dose saline flush.

[0317] The regimen for dosing will be a single administration of Compound C on Day 1 of each 6 ± 1 week cycle, repeated for up to 6 cycles. Individual subjects may have their dose delayed, reduced, and / or discontinued.

[0318] The present invention has been described with regard to one or more embodiments.However, it will be apparent to persons skilled in the art that a number of variations and modifications can be made without departing from the scope of the invention as defined in the claims.

Claims

WHAT IS CLAIMED IS:

1. A method of treating melanoma, comprising administering to a subject in need thereof a combination of:(a) one or more checkpoint inhibitors, and(b) a radioconjugate comprising a melanocortin 1 receptor (MC1R) targeting peptide (MC1 RTP) linked to a CROWN, a CROWNGA, or a CROWN Amide chelator by a linker, or a pharmaceutically acceptable salt thereof, wherein:the MCR1TP is cyclized and comprises a sequence of Formula A or B:Xaa1-Xaa2a-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7a(A) (SEQ ID NO: 2) Xaa1-Xaa2b-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7b(B) (SEQ ID NO: 3) Xaa1is selected from the group consisting of norleucine (Nle), D-Nle, Ala, D-Ala, Leu, D-Leu, He, D-lle, Cys, D-Cys, Met, D-Met, Phe, D-Phe, Trp, D-Trp, Vai, D-Val, 3-(1-naphthyl)alanine (Nal), D-Nal, 3-(2-naphthyl)alanine (2-Nal), D-2-Nal, Gly, a-aminobutyric acid, norvaline, D-norvaline, homonorleucine, and D-homonorleucine;Xaa2ais selected from the group consisting of Cys, D-Cys, Asp, D-Asp, Glu, D-Glu, 2-aminoadipic acid (2-Aad), D-2-Aad, 3-aminoadipic acid (3-Aad), D-3-Aad, propargylglycine (Pra), D-Pra, homopropargylglycine (Hpg), D-Hpg, beta-homopropargylglycine (Bpg), and D-Bpg;Xaa2bis selected from the group consisting of Cys, D-Cys, Lys, D-Lys, Ornithine (Orn), D-Orn, 2,4-diaminobutyric acid (Dab), D-Dab, 2,3-diaminopropionic acid (Dap), D-Dap, Lys(N3), D-Lys(N3), Orn(N3), D-Orn(N3), Dab(N3), D-Dab(N3), Dap(N3), D-Dap(N3), 2-(5'-azidopentyl)alanine, D-2-(5'-azidopentyl)alanine, 2-(6'-azidohexyl)alanine, and D-2-(6'-azidohexyl)alanine;Xaa3is His;Xaa4is D-Phe;Xaa5is Arg;Xaa6is Trp;Xaa7ais selected from the group consisting of Cys, D-Cys, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, Lys(N3), D-Lys(N3), Orn(N3), D-Orn(N3), Dab(N3), D-Dab(N3), Dap(N3), D-Dap(N3), 2-(5’-azidopentyl)alanine, D-2-(5’-azidopentyl)alanine, 2-(6’-azidohexyl)alanine, and D-2-(6’-azidohexyl)alanine;Xaa7bis selected from the group consisting of Cys, D-Cys, Asp, D-Asp, Glu, D-Glu, 2-Aad, D-2-Aad, 3-Aad, D-3-Aad, Pra, D-Pra, Hpg, D-Hpg, Bpg, and D-Bpg;wherein one or more of Xaa3, Xaa5, Xaa6, and Xaa7ais alpha N-methylated in Formula A, and one or more of Xaa3, Xaa5, Xaa6, and Xaa7bis alpha N-methylated in Formula B; andwherein the MCR1TP is optionally C-terminally amidated.A9TH-038 / 01WQ 344158-22442. The method of claim 1 , wherein the radioconjugate comprises a radionuclide chelated to a compound of Formula I or II, or a stereoisomer or a pharmaceutically acceptable salt or solvate thereof:Formula I (SEQ ID NO: 4),Formula II (SEQ ID NO: 5),wherein the linker comprises one or more O, S, NR, C=O, C1-6 alkyl, C3-6 cycloalkyl, C1-6 heterocycloalkyl, aryl, or heteroaryl, or a combination thereof, wherein R is H or C1-3 alkyl; and wherein the linker optionally comprises an albumin binding moiety.

3. The method of claim 2, wherein the linker comprises one or more O, NR, C=O, C1-6 alkyl, C1-6 heterocycloalkyl, or a combination thereof, wherein R is H or C1-3 alkyl.

4. The method of claim 2, wherein the linker comprises one or more, wherein each of X and Y is independently CH or N.

5. The method of claim 4, wherein the linker comprises 4-amino-1-carboxymethyl-piperidine (Pip).

6. The method of claim 2, wherein the linker comprises one or more, wherein each of V and W is independently oxygen or NH.

7. The method of claim 2, wherein the linker further comprises one to three charge-modifying groups at either end of the linker.

8. The method of claim 7, wherein the charge-modifying group is an amino acid unit formed from a natural or unnatural amino acid.

9. The method of claim 8, wherein the charge-modifying group is 2-aminohexanedioic acid (Aad), aspartic acid (Asp), or glutamic acid (Glu).

10. The method of claim 2, wherein the linker is:H N NH(albumin-binding group)wherein R is H, C1-5 alkyl, or (CH2)nCO2H, and n is an integer of 1-3.

11. The method of claim 10, wherein the albumin-binding group has the following structure:wherein each R4is independently H, halogen, C1-5 alkyl, C1-5 alkoxy, or nitro.

12. The method of claim 2, wherein the linker is:H N NH(albumin-binding group)and the albumin-binding group has the following structure:R4wherein each R4is independently H, halogen, C1-5 alkyl, C1-5 alkoxy, or nitro.

13. The method of claim 12, wherein the albumin-binding group is / V-[4-(p-tolyl)butanoyl], 14. The method of claim 2, wherein the compound is:(SEQ ID NO: 46),(SEQ ID NO: 47),(SEQ ID NO: 48), or(SEQ ID NO: 49),or a stereoisomer or a pharmaceutically acceptable salt or solvate thereof.

15. The method of claim 2, wherein the radionuclide is selected from the group consisting of44Sc,47Sc,61Cu,64Cu,67Cu,67Ga,68Ga,72As,77As,86Y,90Y,89Zr, "Nb,94mTc,99mTc,105Rh,109Pd,111ln, 114m|n, 117mSn, 137QS;141QS>141Qe>142pr, 149pm, 149Tb152Tb155Tb161yb153Sm159Gd165Er, 166|_|O,175Yb,177Lu,186Re,188Re,198Au,199Au,211At,208Pb,212Pb,212Bi,218Bi,228Ra,224Ra,225Ac, and227Th.

16. The method of claim 15, wherein the radionuclide is149Tb,161Tb,177Lu,225Ac, or227Th.

17. The method of any one of claims 1 to 16, wherein the radioconjugate comprises225Ac chelated with(SEQ ID NO: 46), (SEQ ID NO: 47),(SEQ ID NO: 48), or(SEQ ID NO: 49),or a stereoisomer or a pharmaceutically acceptable salt or solvate thereof.

18. The method of any one of claims 1 to 17, wherein the method comprises administering the radioconjugate 1 to 20 times, 3 to 12 times, 4 to 10 times, or 4 to 8 times in a course of a treatment cycle.

19. The method of claim 18, wherein the method comprises administering the radioconjugate at an interval of 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, or 15 weeks.

20. The method of any one of claims 1 to 19, wherein the dose of the radioconjugate ranges from about 0.5 MBq to about 30 MBq, from about 1.5 MBq to about 18 MBq, from about 2 MBq to about 15 MBq, from about 3 MBq to about 20 MBq, from about 6 MBq to about 12 MBq, from about 9 MBq to about 11 MBq, from about 8 MBq to about 13 MBq, or from about 4 MBq to about 12 MBq.

21. The method of claim 20, wherein the dose of the radioconjugate is about 0.5 MBq, about 1 MBq, about 2 MBq, about 3 MBq, about 4 MBq, about 5 MBq, about 6 MBq, about 7 MBq, about 8 MBq, about 9 MBq, about 8 MBq, about 9 MBq, about 10 MBq, about 11 MBq, or about 12 MBq.

22. The method of any one of claims 1 to 21 , wherein the one or more checkpoint inhibitors are selected from a CTLA-4 inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a LAG-3 inhibitor, ora combination thereof.

23. The method of any one of claims 1 to 22, wherein the one or more checkpoint inhibitors are at least one CTLA-4 inhibitor and at least one PD-1 inhibitor or PD-L1 inhibitor.

24. The method of claim 22 or 23, wherein the one or more checkpoint inhibitors is selected from the group consisting of ipilimumab, tremelimumab, pembrolizumab, nivolumab, atezolizumab, cemiplimab, dostarlimab, retifanlimab, toripalimab, tislelizumab, camrelizumab, avelumab, spartalizumab, sintilimab, acrixolimab, sasanlimab, cosibelimab, and durvalumab.

25. The method of claim 24, wherein the one or more checkpoint inhibitors is selected from the group consisting of ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, toripalimab, retifanlimab, cemiplimab, and dostarlimab.

26. The method of claim 23, wherein the CTLA-4 inhibitor is tremelimumab and the PD-L1 inhibitor is durvalumab.

27. The method of claim 22, wherein the LAG-3 inhibitor is relatlimab and the PD-1 inhibitor is nivolumab.

28. The method of any one of claims 1 to 22, wherein the one or more checkpoint inhibitors is a single PD-1 inhibitor or more than one PD-1 inhibitors.

29. The method of claim 28, wherein the single PD-1 inhibitor is pembrolizumab, nivolumab, cemiplimab, dostarlimab, retifanlimab, toripalimab, spartalizumab, sintilimab, acrixolimab, sasanlimab, camrelizumab, or tislelizumab.

30. The method of claim 28 or 29, wherein the single PD-1 inhibitor is pembrolizumab, nivolumab, tislelizumab, toripalimab, dostarlimab, retifanlimab, or cemiplimab.

31. The method of claim 28, wherein the more than one PD-1 inhibitors is a combination of nivolumab and ipilimumab, a combination of pembrolizumab and ipilimumab, ora combination of durvalumab and tremelimumab.

32. The method of any one of claims 1 to 22, wherein the one or more checkpoint inhibitors is a single PD-L1 inhibitor.

33. The method of claim 32, wherein the single PD-L1 inhibitor is atezolizumab, avelumab, durvalumab, or cosibelimab.

34. The method of any one of claims 1 to 22, wherein the one or more checkpoint inhibitors is a single CTLA-4 inhibitor.

35. The method of claim 34, wherein the single CTLA-4 inhibitor is ipilimumab or tremelimumab.

36. The method of any one of claims 1 to 35, wherein the method comprises administering the one or more checkpoint inhibitors 1 to 20 times, 3 to 12 times, 4 to 10 times, or 4 to 8 times in a course of a treatment cycle.

37. The method of claim 36, wherein the method comprises administering the one or more checkpoint inhibitors comprises at an interval of 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, or 15 weeks.

38. The method of any one of claims 1 to 37, wherein the dose of the one or more checkpoint inhibitors ranges from about 1 mg to about 2000 mg, from about 100 mg to about 1000 mg, from about 200 mg to about 800 mg, or from about 600 mg to about 1200 mg.

39. The method of any one of claims 1 to 38, wherein the melanoma is metastatic cutaneous melanoma or metastatic uveal melanoma.

40. The method of any one of claims 1 to 38, wherein the subject has failed treatment with a PD-1 inhibitor, a PD-L1 inhibitor, or a combination thereof.

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