Radiolabeled melanocortin 1 receptor specific alpha-melanocyte stimulating hormone analogs for imaging or therapy

Abstract

The present invention relates to alpha-melanocyte stimulating hormone analogs targeting the melanocortin-1 receptor.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 539,948, filed September 22, 2023, the contents of which are incorporated herein by reference in their entirety for all purposes. Technical Field

[0003] This invention relates to α-melanocyte-stimulating hormone analogs that target melanocortin 1 receptors. Background Technology

[0004] Current imaging techniques used for metastatic melanoma (including cutaneous melanoma, amelanoma, and uveal melanoma) have limited sensitivity in detecting small metastatic lesions, early lymph node metastases, and liver metastases. Furthermore, current treatments for metastatic melanoma have achieved limited success in advanced stages.

[0005] The melanocortin 1 receptor (MC1R) is specifically expressed in cutaneous melanoma, amelanoma, and uveal melanoma. Low expression levels of MC1R in normal tissues make this protein an attractive target for radionuclide imaging and therapy. The endogenous ligand of MC1R binds to α-melanocyte-stimulating hormone (αMSH) with a sub-nanomolar binding affinity. However, αMSH also binds to other melanocortin receptors, including MC3R, MC4R, and MC5R. αMSH does not bind to MC2R, which is selectively activated by adrenocorticotropic hormone (ACTH).

[0006] Although peptide analogs of αMSH have been developed for imaging applications (e.g., those with the sequence DOTA-Pip-Nle-loop [Asp-His-D-Phe-Arg-Trp-Lys]-NH2), 68 Ga-labeled CCZ01048 (see Zhang et al., 2017 Theranostics 7(4):805-813) still requires higher selectivity for MC1R relative to other melanocortin receptors to reduce off-target accumulation of radiolabeled peptides targeting MC1R in vivo. The metabolic stability of peptide analogs is also important for achieving high tumor accumulation and long-term retention of radiolabeled peptide analogs in vivo for imaging MC1R-expressing tissues and / or the treatment of MC1R-related symptoms or diseases (e.g., melanoma, non-melanoma skin cancer, etc.).

[0007] Any of the foregoing information is not intended to be, nor should it be construed as, prior art opposing the present invention. Summary of the Invention

[0008] Various embodiments of this disclosure relate to a compound comprising a melanocortin 1 receptor (MC1R) targeting peptide (MC1RTP), a radiolabeled group, and a connector for binding the MC1RTP to the radiolabeled group.

[0009] This disclosure further relates to a compound or a salt thereof comprising MC1RTP connected via a connector to a CROWN chelator, wherein:

[0010] The MC1RTP is a circularized sequence containing formula A:

[0011] Xaa 1 -Xaa 2a -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7a (A)

[0012] Xaa 1 Select from the following groups: leucine (Nle), D-Nle, Ala, D-Ala, Leu, D-Leu, Ile, D-Ile, Cys, D-Cys, Met, D-Met, Phe, D-Phe, Trp, D-Trp, Val, D-Val, 3-(1-naphthyl)alanine (Nal), D-Nal, 3-(2-naphthyl)alanine (2-Nal), D-2-Nal, Gly, α-aminobutyric acid, valine, D-valine, high-leucine, and D-high-leucine;

[0013] Xaa 2a Select the following groups: Cys, D-Cys, Asp, D-Asp, Glu, D-Glu, 2-aminohexanoic acid (2-Aad), D-2-Aad, 3-aminohexanoic acid (3-Aad), D-3-Aad, propargylglycine (Pra), D-Pra, homopropargylglycine (Hpg), D-Hpg, β-homopropargylglycine (Bpg), and D-Bpg;

[0014] Xaa 3 It is His;

[0015] Xaa 4 It is D-Phe;

[0016] Xaa 5 It is Arg;

[0017] Xaa 6 It is Trp;

[0018] Xaa7a Select the following groups: 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;

[0019] One or more amino acid residues of the MC1RTP are α-N-methylated; and

[0020] The MC1RTP may optionally undergo C-terminal amidation.

[0021] This disclosure further relates to pharmaceutical compositions comprising compounds as disclosed herein.

[0022] This disclosure further relates to methods of treating cancer using compounds and compositions as disclosed herein.

[0023] This disclosure further relates to methods of treating melanoma using compounds and compositions as disclosed herein.

[0024] This overview of the invention does not necessarily describe all the features of the invention. Attached Figure Description

[0025] These and other features of the invention will become more apparent from the following description with reference to the accompanying drawings, wherein:

[0026] Figure 1 This demonstrates that in NRG mice carrying SK-MEL-1 tumors, in 225 Ac-marked CCZ01178 (at 15 kBq and 30 kBq) and 177 Tumor volume changes in a dose-escalation study of Lu-labeled CCZ01158 (at 20 MBq and 40 MBq).

[0027] Figure 2 Injection was shown 225 Ac-marked CCZ01178 (at 15 kBq and 30 kBq) or 177 Survival probability of NRG mice carrying SK-MEL-1 tumors with Lu-labeled CCZ01158 (at 20 MBq and 40 MBq). Detailed Implementation

[0028] General definition

[0029] As used herein, the terms “comprising,” “having,” “including,” and “containing,” and their grammatical variations, are inclusive or open-ended and do not exclude additional unlisted elements and / or method steps. If the term “consistently composed of” is used herein in conjunction with a compound, composition, use, or method, it indicates that additional elements and / or method steps may be present, but these additions do not materially affect the manner of action of the referenced compound, composition, or use. When the term “consisting of” is used herein in conjunction with a composition, use, or method, it excludes the presence of additional elements and / or method steps. In some embodiments, a compound, composition, use, or method described herein that includes certain elements and / or steps may also consist substantially of those elements and / or steps, and in other embodiments, it may consist substantially of those elements and / or steps, whether or not those embodiments are specifically mentioned. In some embodiments, a use or method described herein that includes certain elements and / or steps may also consist substantially of those elements and / or steps, and in other embodiments, it may consist substantially of those elements and / or steps, whether or not those embodiments are specifically mentioned.

[0030] The use of the indefinite article "a" to refer to an element does not preclude the possibility of more than one element, unless the context explicitly requires the presence of one and only one element. Unless otherwise explicitly stated, the singular forms "a," "an," and "the" include plural pronouns. When used in conjunction with the term "comprising," the use of "a" or "an" can mean "one," but it also corresponds to the meanings of "one or more," "at least one," and "one or more than one." The term "multiple" as used herein means more than one, such as two or more, three or more, four or more, etc.

[0031] In this disclosure, the representation of a range of numbers by endpoints includes all numbers contained in that range, including all full numbers, all integers, and, where appropriate, all fractional intermediate values ​​(e.g., 1 to 5 may include 1, 1.5, 2, 2.75, 3, 3.80, 4, and 5, etc.).

[0032] Unless otherwise stated, the terms “certain embodiments,” “various embodiments,” “an embodiment,” and similar terms include specific features of the embodiment described alone or in combination with any other embodiment or embodiment described herein, whether directly or indirectly referencing other embodiments, and whether said features or embodiments are described in the context of compounds, methods, products, uses, compositions, etc.

[0033] The term "subject" refers to an animal (e.g., a mammal or a non-mammal). A subject can be a human or a non-human primate. A subject can be a laboratory mammal (e.g., a mouse, rat, rabbit, hamster, etc.). A subject can be an agricultural animal (e.g., a horse, sheep, cattle, pig, camel, etc.) or livestock (e.g., a dog, cat, etc.). In some implementations, the subject is a human.

[0034] The compounds disclosed herein may also include their base-free forms, prodrugs, salts, or pharmaceutically acceptable salts. Unless otherwise stated, the compounds claimed and described herein are intended to include all racemic mixtures and all individual enantiomers or combinations thereof, whether or not they are expressly stated herein.

[0035] The compounds disclosed herein may be shown as having one or more charged groups, may be shown as having ionizable groups in an uncharged (e.g., protonated) state, or may be shown as having no specified charge. As those skilled in the art will understand, the ionization state of certain groups within the compounds (e.g., but not limited to CO2H, PO3H2, SO2H, SO3H, SO4H, OPO3H2, etc.) depends particularly on the pKa of that group and the pH at that position. For example, but not limited to, carboxylic acid groups (i.e., COOH) are generally understood to be deprotonated (and negatively charged) at neutral pH and most physiological pH values, unless the protonated state is stable (e.g., due to intramolecular H bonding). Similarly, OSO3H (i.e., SO4H) groups, SO2H groups, SO3H groups, OPO3H2 (i.e., PO4H2) groups, and PO3H groups are generally deprotonated (and negatively charged) at neutral and physiological pH values.

[0036] As used herein, the terms “salt” and “solvent” have their usual meanings in chemistry. Thus, when a compound is a salt or solvate, it associates with a suitable counterion. How to prepare salts or exchange counterions is well known in the art. Typically, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (e.g., but not limited to, Na, Ca, Mg, or K hydroxides, carbonates, bicarbonates, etc.) or by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water or an organic solvent or a mixture of both. The counterion can be altered, for example, by ion exchange techniques such as ion exchange chromatography. Unless a specific form is specifically indicated, all zwitterions, salts, solvates, and counterions are contemplated.

[0037] In some embodiments, the salt or counterion may be pharmaceutically acceptable, for example, for administration to a subject. More generally, for any pharmaceutical composition disclosed herein, non-limiting examples of suitable excipients include any suitable buffer, stabilizer, salt, antioxidant, complexing agent, tonic, cryoprotectant, lyophilization protectant, suspending agent, emulsifier, antimicrobial agent, preservative, chelating agent, binder, surfactant, wetting agent, non-aqueous mediator (such as fixative oil), or polymer for sustained or controlled release. See, for example, Berge et al. 1977. (J. Pharm Sci. 66:1-19) or Remington – The Science and Practice of Pharmacy, 21st edition (edited by Gennaro et al., Lippincott Williams & Wilkins Philadelphia).

[0038] As used in this article, “Xy-Xz” is expressed (where y and z are integers (e.g., X1-X). 15 X1-X 30 X1-X 100 "etc." refers to the number of carbons in a compound, R-group, or substituent (for alkyl and aryl groups, whether saturated or unsaturated), or the number of carbons and heteroatoms in a compound, R-group, or substituent (for heteroalkyl and heteroaryl groups, whether saturated or unsaturated). Heteroatoms can include any, some, or all possible heteroatoms. For example, in some embodiments, heteroatoms are selected from N, O, S, P, and Se. In some embodiments, heteroatoms are selected from N, O, S, and P. Such embodiments are non-limiting. Alkyl and aryl groups can alternatively be represented using the expression "Cy-Cz", where y and z are integers (e.g., C3-C). 15 wait).

[0039] Unless otherwise expressly stated, the terms “alkyl” and “heteroalkyl” each include any reasonable combination of the following: (1) saturated alkyl and unsaturated alkyl (e.g., alkenyl and ynyl); (2) straight-chain or branched; (3) acyclic or cyclic (aromatic or non-aromatic), the latter including polycyclic (fused rings, multiple unfused rings or combinations thereof); and (4) unsubstituted or substituted. For example, an alkyl or heteroalkyl (i.e., “alkyl / heteroalkyl”) can be saturated, branched and cyclic; or unsaturated, branched and cyclic; or straight-chain and unsaturated; or any other reasonable combination according to the skill of a person skilled in the art. If not specified, the size of the alkyl / heteroalkyl is a size that a person skilled in the art would consider reasonable. For example, but not limited to, if not specified, the size of the alkyl group can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51. 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 or more carbons, which is consistent with common knowledge to those skilled in the art. Additionally, but not limited to, unless otherwise specified, the size of the heteroalkyl group can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 5 2, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 or more carbon atoms and heteroatoms, which is consistent with common knowledge to those skilled in the art.

[0040] As used herein, in the context of alkyl / heteroalkyl compounds, the term "straight-chain" may be used as commonly understood by those skilled in the art, and generally refers to a chemical entity comprising a backbone or main chain that does not split into more than one continuous chain. Non-limiting examples of straight-chain alkyl groups include methyl, ethyl, n-propyl, and n-butyl.

[0041] As used herein, "cyclic" peptides / polypeptides can be used as commonly understood by those skilled in the art, and generally refers to peptides or polypeptides having a covalent bond between two amino acids within the peptide or polypeptide, such as between a carboxyl group and an amino terminus, between a carboxyl terminus and a side-chain amino group, between an amino terminus and a side-chain carboxyl group, or between side chains, to form a cyclic structure. For example, but not limited to, peptides can be cyclized by forming a lactam bridge (i.e., an amide bond) between a side-chain carboxylic ester of one amino acid residue (e.g., Asp, Glu) and an amine of another amino acid residue (e.g., Dap, Dab, Orn, Lys). In embodiments, a lactam bridge is formed between the side-chain carboxylic ester of Asp and the side-chain amine of Lys. Further details are provided herein.

[0042] As used herein, the term "branched" may be used as commonly understood by those skilled in the art, and generally refers to a chemical entity comprising a backbone or main chain that splits into more than one continuous chain. The portions of the backbone or main chain that split in more than one direction may be linear, cyclic, or any combination thereof. Non-limiting examples of branched alkyl groups include tert-butyl and isopropyl.

[0043] As used herein, when referring to a chemical entity, the term "saturated" may be used as commonly understood by those skilled in the art, and typically refers to a chemical entity containing only single bonds. Saturated C1-C 15 Non-limiting examples of alkyl groups may include methyl, ethyl, n-propyl, isopropyl, sec-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, tert-pentyl, n-hexyl, isohexyl, 1,2-dimethylpropyl, 2-ethylpropyl, 1-methyl-2-ethylpropyl, 1-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, tert-hexyl, n-heptyl, isoheptyl, sec-heptyl, tert-heptyl, n-octyl, isooctyl, sec-octyl, tert-octyl, n-nonyl, isonyl, sec-nonyl, tert-nonyl, n-decyl, isodel, sec-decyl, and tert-decyl. C2-C 15Non-limiting examples of alkenyl groups may include vinyl, allyl, isopropenyl, 1-propen-2-yl, 1-buten-1-yl, 1-buten-2-yl, 1-buten-3-yl, 2-buten-1-yl, 2-buten-2-yl, octenyl, and decenyl. C2-C 15 Non-limiting examples of alkynyl groups may include ethynyl, propynyl, butynyl, penynyl, hexynyl, hepynyl, octyynyl, nonynyl, and decyynyl. Non-limitingly, the saturated C1-C group defined above... 15 Alkyl, C2-C 15 alkenyl and C2-C 15 Alkyne groups are all encompassed in the term "X1-X" as used herein. 15 Within "alkyl". Without limitation, the term "X1-X" refers to... 15 "Heteroalkyl" will encompass the saturated C1-C as defined above. 15 Alkyl, C2-C 15 alkenyl and C2-C 15 Each of the alkynyl groups, wherein one or more carbon atoms are independently replaced by heteroatoms. Those skilled in the art will understand that various combinations of different heteroatoms can be used.

[0044] Unless otherwise expressly stated, the terms “aryl” and “heteroaryl” each include any reasonable combination of the following: (1) cyclic or polycyclic (fused ring, multiple unfused rings or combinations thereof); (2) aromatic (i.e., unsaturated ring) or non-aromatic (i.e., saturated ring); and (3) unsubstituted or substituted. Non-limiting examples of aryl or heteroaryl (i.e., “aryl / heteroaryl”) include: phenyl, naphthyl, thiophene, indole, pyridyl, etc. Unless otherwise specified, the size of aryl / heteroaryl is a size that would be reasonable to those skilled in the art. For example, but not limited to, if not specified, the size of the aryl group can be 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 or more carbons, which is consistent with common knowledge to those skilled in the art. Additionally, but not limited to, if not specified, the size of the heteroaryl group can be 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52. 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 or more carbon atoms and heteroatoms, which is consistent with common knowledge to those skilled in the art. It should be noted that aryl or heteroaryl groups can have all or only part of their backbone or main chain bonded in a manner that forms a 'loop,' ring, or cyclic structure of atoms bonded together. That is, aryl / heteroaryl groups can contain straight or branched chains of carbon / heteroatoms that are not part of a ring or loop.

[0045] For example, X3-X 18Aryl / heteroaryl groups can include, but are not limited to, saturated C3-C 18 cycloalkyl, C3-C 18 Cycloalkenyl, C3-C 18 Cycloalkynyl, C3-C 18 Aromatic aryl groups, wherein each X can independently be C, N, S, P, O, or Se, X3-X. 18 Non-aromatic heterocyclic groups and X3-X in which each X can independently be C, N, S, P, O or Se. 18 Aromatic heterocyclic groups. Saturated C3-C 18 Non-limiting examples of cycloalkyl groups may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl. (C3-C) 18 Non-limiting examples of cycloalkenyl groups may include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, and cyclodecenyl. C3-C 18 Non-limiting examples of aromatic aryl groups may include phenyl (Ph), pentalenyl, indole, naphthyl, and azulenyl. X3-X 18 Non-limiting examples of non-aromatic heterocyclic groups may include aziridinyl, azetidinyl, diazacyclic butyl, pyrrolyl, pyrrolinyl, piperidinyl, piperazinyl, imidazolinyl, pyrazolyl, imidazolinyl, phthalimide, succinimide, oxiranyl, tetrahydropyranyl, oxacyclic butyl, dioxyl, thiocyclic butyl, thiepinyl, morpholinyl, and oxothiocyclic pentyl. X3-X 18 Non-limiting examples of aromatic heterocyclic groups may include pyrrole, imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrazinyl, quinolinyl, isoquinolinyl, acridineyl, indolyl, isoindolyl, indolizinyl, purine, carbazole, indolazole, phthalazinyl, naphridinyl, quinoxolinyl, quinazolinyl, cenolinyl, pteridineyl, phenanthridinyl, phenazinyl, phenanthrolinyl, perimidinyl, furanyl, dibenzofuranyl, xanthenyl, benzofuranyl, thienyl, thianyl, benzothienyl, phosphorinyl, phosphinolinyl, phosphindolyl, thiazolyl, oxazolyl, and isoxazolyl. Unless otherwise stated, X1-X 18 Alkyl / heteroalkyl will particularly cover X3-X 18Aryl / heteroaryl, including groups as defined above.

[0046] As used herein, the term "substituted" is used as commonly understood by those skilled in the art and generally refers to a compound or chemical entity in which one chemical group is replaced by a different chemical group. Unless otherwise stated, a substituted alkyl group is an alkyl group in which one or more hydrogen atoms are each independently replaced by a non-hydrogen atom. For example, chloromethyl is a non-limiting example of a substituted alkyl group, and more specifically an example of a substituted methyl group. Aminoethyl is another non-limiting example of a substituted alkyl group, and more specifically an example of a substituted ethyl group. Unless otherwise stated, a substituted compound or group (e.g., alkyl, heteroalkyl, aryl, heteroaryl, etc.) may be substituted by any chemical group that would be reasonable to those skilled in the art. For example, but not limited to, hydrogen atoms bonded to carbon or heteroatoms (e.g., N) may be substituted with: halide ions (e.g., F, I, Br, Cl), amines, amides, oxo, hydroxyl, thiols, phosphate esters, phosphonates, sulfate esters, SO2H, SO3H, alkyl, heteroalkyl, aryl, heteroaryl, ketones, formaldehyde, carboxylic acid esters, formamides, nitriles, monohalomethyl, dihalomethyl, and trihalomethyl.

[0047] As used herein, the term "unsubstituted" is used as commonly understood by those skilled in the art. Non-limiting examples of unsubstituted alkyl groups include methyl, ethyl, tert-butyl, pentyl, etc. The expression "optionally substituted" is used interchangeably with the expression "unsubstituted or substituted".

[0048] In the structures provided herein, hydrogen may or may not be shown. In some embodiments, hydrogen (whether shown or implied) may be protium (i.e., 1 H), deuterium (i.e.) 2 H) or 1 H and 2 A combination. Used to... 1 H and 2 H-exchange methods are well known in the art. For solvents that can exchange hydrogen, 1 H and 2 The exchange of hydrogen atoms occurs readily in the presence of a suitable deuterium source, without the need for any catalyst. The use of acid, base, or metal catalysts, along with increases in temperature and pressure, can promote the exchange of non-exchangeable hydrogen atoms, typically involving all hydrogen atoms in the molecule. 1 H to 2 Exchange of H.

[0049] Unless otherwise stated, the term "peptide" as used herein may comprise proteinogenic and / or non-proteinogenic amino acid residues. Non-limiting examples of non-proteinogenic amino acids include: D-amino acids (including, but not limited to, any D-form of the following amino acids), ornithine (Orn), 3-(1-naphthyl)alanine (Nal), 3-(2-naphthyl)alanine (2-Nal), , valine, leucine (Nle), high leucine, β-(1,2,3-triazol-4-yl)-L-alanine, 1,2,4-triazol-3-alanine, Phe(4-F), Phe(4-Cl), Phe(4-Br), Phe(4-I), Phe(4-NH2), Phe(4-NO2), high arginine (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) or Trp(CHO), 2-aminohexanoic acid ( 2-Aad), 3-aminoadipic acid (3-Aad), propargyl glycine (Pra), homopropargyl glycine (Hpg), β-homopropargyl glycine (Bpg), 2,3-diaminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab), azidolysine (Lys(N3)), azido-ornithine (Orn(N3)), 2-amino-4-azidobutyric acid Dab(N3), Dap(N3), 2-(5'-azidopentyl)alanine, 2-(6'-azidohexyl)alanine, 4-amino-1-carboxymethyl-piperidine (Pip), 4-(2-aminoethyl)-1-carboxymethyl-piperazine (Acp).

[0050] If not specified as an L-amino acid or a D-amino acid, the amino acid should be understood as an L-amino acid.

[0051] Unless otherwise stated, amino acids can be modified by any modifications known in the art, which is consistent with common general knowledge for those skilled in the art. For example, but not limited to, C-terminal amino acid residues can be amidated, which means replacing the C-terminal carboxylic acid ester with an amide, i.e., –C(O)NH2 instead. Amide residues are identified by –NH2 (e.g., Lys-NH2, Trp-NH2, etc.). As another non-limiting example, amino acids can be methylated, for example, by N-methylation or α-N-methylation.

[0052] The term "Xaa" refers to any amino acid. The term "–Xaa"... 8 –Xaa 9 –Xaa 10 –” refers to three amino acids linked together by peptide bonds, namely Xaa 8 Xaa9 and Xaa 10 The term "–Xaa" 9 (Xaa 8 )–Xaa 10 –” refers to the same three amino acids, but through Xaa 9 C-terminus with Xaa 10 The amide bonds between the N-termini are linked together, where in Xaa 8 C-terminus and Xaa 9 Additional amide bonds are formed between the side-chain amines. Unless otherwise stated, "Xaa" can be any amino acid known to those skilled in the art, including proteogenic and non-proteogenic amino acids (e.g., but not limited to the non-proteogenic amino acids listed above).

[0053] For cyclized peptides, formula Xaa 1 -Ring(Xaa 2 -Xaa 3 -Xaa 4 )-Xaa 5 etc. refers to Xaa 2 and Xaa 4 The covalent linkage between the side chains (i.e., between the first and last amino acids in parentheses). Similarly, formula Xaa 1 -Ring(Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 ) refers to Xaa 2 and Xaa 5 Cyclic peptides with covalently linked side chains.

[0054] compound

[0055] The compounds presented herein include peptides that can be synthesized by any of the various methods established in the art. These methods include, but are not limited to, liquid-phase and solid-phase peptide synthesis using 9-fluorenylmethoxycarbonyl (Fmoc) and / or tert-butoxycarbonyl (Boc) chemical reactions, as well as other synthetic methods.

[0056] Solid-phase peptide synthesis methods and techniques are well-established in the art. For example, peptides can be synthesized by sequentially incorporating 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, the reactive side chains and α-amino groups of the amino acid are protected by suitable protecting groups to prevent reaction, allowing only the α-carboxyl group to react with functional groups (such as amino groups, hydroxyl groups, or alkyl halides) on the solid support. After coupling the C-terminal amino acid to the support, the protecting groups on the side chains of the amino acid and / or the α-amino group are selectively removed, thereby 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 and purified from the support. A non-limiting example of an instrument used for solid-phase peptide synthesis is the Aapptec Endeavor 90 peptide synthesizer.

[0057] The choice of resin determines whether the peptide will have a C-terminal carboxylic acid ester or a C-terminal amide (i.e., whether the C-terminus of the peptide is amidated). For example, but not limited to, once the peptide is cleaved, 4-(2′,4′-dimethoxyphenyl-Fmoc-aminomethyl)phenoxy resin (Rink amide resin) or 9-Fmoc-aminoxanthan-3-yloxy-Merrifield resin (Sieber amide resin) can be used for the C-terminal amide. Without limitation, once the peptide is cleaved, p-benzyloxybenzyl alcohol resin (Wang resin) or 2-chlorotriphenylmethyl chloride resin can be used for the C-terminal carboxylic acid ester. During use, the resin swells in solvents such as N,N-dimethylformamide (DMF), dichloromethane (DCM), or 1-methyl-2-pyrrolidone (NMP).

[0058] To allow for the coupling of additional amino acids, the Fmoc protecting group can be removed from the amino acid on the solid support, for example, under mild alkaline conditions, such as piperidine in DMF (20-50% v / v). The amino acid to be added must also have been activated for coupling (e.g., at the α-carboxylic acid ester). Non-limiting examples of activators include, but are not limited to, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureon hexafluorophosphate (HBTU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureon tetrafluoroborate (TBTU), 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureon hexafluorophosphate (HATU), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), and benzotriazol-1-yl-oxy-tris(pyrrolidinyl)phosphonium hexafluorophosphate (PyBOP). Racemization is minimized by using triazoles such as 1-hydroxy-benzotriazole (HOBt) and 1-hydroxy-7-aza-benzotriazole (HOAt) Coupling can be carried out in the presence of a suitable base (such as N,N-diisopropylethylamine (DIPEA / DIEA)). For long peptides, peptide synthesis and coupling can be used.

[0059] Peptide cyclization can be performed by any known method. Cyclization can be carried out on or outside the resin. Non-limiting examples of peptide cyclization include: forming a lactam bridge between a carboxyl-containing amino acid side chain (e.g., Asp, D-Asp, Glu, D-Glu, etc.) and an amino-containing amino acid side chain (e.g., Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, etc.); forming a 1,2,3-triazole between amino acid side chains containing an azide group (e.g., Lys(N3), D-Lys(N3), etc.) and an alkynyl group (e.g., Pra, D-Pra, etc.) via click chemistry; and forming disulfide bonds between Cys residue side chains. Because cyclization occurs between amino acid side chains, except for the reaction that forms a 1,2,3-triazole between the alkynyl and azide groups via click reaction, the protecting groups on these amino acids must be selectively removed before cyclization. Non-limiting examples of selectively removable protecting groups include acetamoxymethyl (Acm) (e.g., on Cys), 2-phenylisopropyl ester (O-2-PhiPr) (e.g., on Asp / Glu), and 4-methyltriphenylmethyl (Mtt), allyloxycarbonyl (alloc), 1-(4,4-dimethyl-2,6-dioxocyclohexyl-1-ylidene)ethyl (Dde) and 1-(4,4-dimethyl-2,6-dioxocyclohexyl-1-ylidene)-3-methylbutyl (ivDde) ​​(e.g., on Lys / Orn / Dab / Dap). The Acm group on Cys can be selectively removed by a DMF solution containing 2 equivalents of thallium(III) trifluoroacetate, while inducing cyclization via the formation of disulfide bonds. The O-2-PhiPr and Mtt protecting groups can be selectively deprotected under weakly acidic conditions, such as 2.5% trifluoroacetic acid (TFA) in DCM. The alloc protecting group can be selectively deprotected using tetra(triphenylphosphine)palladium(0) and phenylsilane in DCM. The Dde and ivDde protecting groups can be selectively deprotected using 2-5% hydrazine in DMF. Then, for example, by using the coupling reaction conditions described above, the deprotected side chains of Asp / Glu (L- or D-form) and Lys / Orn / Dab / Dap (L- or D-form) can be cyclized.

[0060] The peptide backbone amide can be N-methylated (i.e., α-aminomethylated). This can be achieved by directly using Fmoc-N-methylated amino acids during peptide synthesis. Alternatively, N-methylation can be carried out under Mitsunobu conditions. First, the free primary amine group is protected using a solution of 4-nitrobenzenesulfonyl chloride (Ns-Cl) and 2,4,6-trimethylpyridine (Calactin) in NMP. N-methylation can be achieved in the presence of triphenylphosphine, diisopropyl azodicarbonate (DIAD), and methanol. Subsequently, N-deprotection can be performed using mercaptoethanol and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in NMP. To couple the protected amino acid to the N-methylated α-amino group, HATU, HOAt, and DIEA can be used.

[0061] As further described below, chelating agents, linkers (peptide or non-peptide linkers), and / or albumin-binding groups can be coupled to the N-terminus of the peptide while the peptide is linked to a solid carrier. This is readily achieved when the chelating agents, linkers, and / or albumin-binding groups contain activated carboxylic esters (and protecting groups (if necessary)) to allow coupling onto a resin.

[0062] Once the peptide is fully synthesized on a solid-phase support, the desired peptide can be cleaved from the solid-phase support using suitable reagents such as TFA, triisopropylsilane (TIS), and water. Simultaneously, side-chain protecting groups such as Boc, pentamethyldihydrobenzofuran-5-sulfonyl (Pbf), triphenylmethyl (Trt), and tert-butyl (tBu) are removed (i.e., deprotection). The crude peptide can be precipitated and collected from solution by adding cold ether followed by centrifugation. Purification and characterization of the peptide can be performed using standard separation techniques, such as high-performance liquid chromatography (HPLC) based on peptide size, charge, and polarity. The identity of the purified peptide can be confirmed by mass spectrometry or other similar methods.

[0063] This disclosure provides a compound comprising a melanocortin 1 receptor (MC1R) targeting peptide (MC1RTP), a radiolabeled group, and a connector for binding the MC1RTP to the radiolabeled group. In some embodiments, the radiolabeled group is a CROWN chelating agent.

[0064] In some implementations, MC1RTP is α-N-methylated.

[0065] MC1RTP binds to MC1R under physiological conditions (e.g., in vivo) and, in some embodiments, is selective for MC1R relative to at least one other member of the melanocortin receptor (i.e., MC3R, MC4R, and / or MC5R). MC1RTP may be selective for MC1R relative to MC3R. MC1RTP may be selective for MC1R relative to MC4R. MC1RTP may be selective for MC1R relative to MC5R. MC1RTP may be selective for MC1R relative to any combination of MC3R, MC4R, and / or MC5R. MC1RTP may be selective for MC1R relative to MC3R, MC4R, and MC5R.

[0066] In some embodiments of this disclosure, MC1RTP comprises an amino acid sequence defined by Formula I or Formula II:

[0067] Xaa 1 -Xaa 2a -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7a (I); or

[0068] Xaa 1 -Xaa 2b -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7b (II).

[0069] In some embodiments, this disclosure provides a compound or a salt thereof comprising a melanocortin 1 receptor (MC1R) targeting peptide (MC1RTP) linked to a CROWN chelator via a linker, wherein:

[0070] The MC1RTP is a circularized sequence containing formula A:

[0071] Xaa 1 -Xaa 2a -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7a (A)

[0072] Xaa 1Select from the following groups: leucine (Nle), D-Nle, Ala, D-Ala, Leu, D-Leu, Ile, D-Ile, Cys, D-Cys, Met, D-Met, Phe, D-Phe, Trp, D-Trp, Val, D-Val, 3-(1-naphthyl)alanine (Nal), D-Nal, 3-(2-naphthyl)alanine (2-Nal), D-2-Nal, Gly, α-aminobutyric acid, valine, D-valine, high-leucine, and D-high-leucine;

[0073] Xaa 2a Select the following groups: Cys, D-Cys, Asp, D-Asp, Glu, D-Glu, 2-aminohexanoic acid (2-Aad), D-2-Aad, 3-aminohexanoic acid (3-Aad), D-3-Aad, propargylglycine (Pra), D-Pra, homopropargylglycine (Hpg), D-Hpg, β-homopropargylglycine (Bpg), and D-Bpg;

[0074] Xaa 3 It is His;

[0075] Xaa 4 It is D-Phe;

[0076] Xaa 5 It is Arg;

[0077] Xaa 6 It is Trp;

[0078] Xaa 7a Select the following groups: 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;

[0079] One or more amino acid residues of the MC1RTP are α-N-methylated; and

[0080] The MC1RTP may optionally undergo C-terminal amidation.

[0081] In some implementations, Xaa 1It is leucine (Nle), D-Nle, Ala, D-Ala, Leu, D-Leu, Ile, D-Ile, Cys, D-Cys, Met, D-Met, Phe, D-Phe, Trp, D-Trp, Val, D-Val, 3-(1-naphthyl)alanine (Nal), D-Nal, 3-(2-naphthyl)alanine (2-Nal), D-2-Nal, Gly, α-aminobutyric acid, D-α-aminobutyric acid, valine, D-valine, homoleucine, or D-homoleucine. In some embodiments, Xaa 1 It is Nle, Ala, Leu, Ile, Cys, Met, Phe, Trp, Val, Nal, 2-Nal, Gly, α-aminobutyric acid, valine, or homoleucine. In some embodiments, Xaa 1 It is Nle, Ala, Leu, Ile, Cys, Met, Phe, Trp, Val, Nal, 2-Nal, α-aminobutyric acid, valine, or homoleucine. In some embodiments, Xaa 1 It is Nle.

[0082] In some implementations, Xaa 2a It is Cys, D-Cys, Asp, D-Asp, Glu, D-Glu, 2-aminohexanoic acid (2-Aad), D-2-Aad, 3-aminohexanoic acid (3-Aad), D-3-Aad, propargylglycine (Pra), D-Pra, homopropargylglycine (Hpg), D-Hpg, β-homopropargylglycine (Bpg), or D-Bpg. In some embodiments, Xaa 7b It is Cys, Asp, Glu, 2-Aad, 3-Aad, Pra, Hpg, or Bpg. In some implementations, Xaa 2a It is Asp, Glu, Pra, or D-Pra. In some implementations, Xaa 2a It is Asp, Glu, or Pra. In some implementations, Xaa 2a It is ASP.

[0083] In some implementations, Xaa 2bThese are 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, or D-2-(6'-azidohexyl)alanine. In some embodiments, Xaa 2b It is Cys, Lys, Orn, Dab, Dap, Lys(N3), Orn(N3), Dab(N3), Dap(N3) or 2-(5'-azidopentyl)alanine, 2-(6'-azidohexyl)alanine. In some embodiments, Xaa 2b It is Lys, Orn, Dab, Dap, Lys(N3), Orn(N3), Dab(N3), Dap(N3), 2-(5'-azidopentyl)alanine or 2-(6'-azidohexyl)alanine. In some embodiments, Xaa 2b It's Lys.

[0084] In some implementations, Xaa 3 It is His, D-His, Pro, β-(1,2,3-triazol-4-yl)-DL-alanine, β-(1,2,3-triazol-4-yl)-L-alanine, β-(1,2,3-triazol-4-yl)-D-alanine, 1,2,4-triazol-3-alanine, or 1,2,4-triazol-3-D-alanine. In some embodiments, Xaa 3 It is His, Pro, β-(1,2,3-triazol-4-yl)-L-alanine or 1,2,4-triazol-3-alanine. In some embodiments, Xaa 3 It is His, β-(1,2,3-triazol-4-yl)-DL-alanine, or 1,2,4-triazol-3-alanine. In some embodiments, Xaa 3 It's His.

[0085] In some implementations, Xaa 4It is Phe, D-Phe, 2-Nal, D-2-Nal, Phe(4-F), D-Phe(4-F), Phe(4-Cl), D-Phe(4-Cl), 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, Xaa 4 It is D-Phe, D-2-Nal, D-Phe(4-F), D-Phe(4-Cl), D-Phe(4-Br), D-Phe(4-I), D-Phe(4-NH2), or D-Phe(4-NO2). In some embodiments, Xaa 4 It is Phe, D-Phe, 2-Nal, or D-2-Nal. In some implementations, Xaa 4 It is D-Phe or D-2-Nal. In some implementations, Xaa 4 It is D-Phe.

[0086] In some implementations, Xaa 5 It is Arg, D-Arg, high-arginine (hArg), D-hArg, Leu, D-Leu, 2-amino-4-guanidinylbutyric acid (Agb), D-Agb, 2-amino-3-guanidinylpropionic acid (Agp), or D-Agp. In some embodiments, Xaa 5 It is Arg, D-Arg, hArg, Leu, D-hArg, Agb, D-Agb, Agp, or D-Agp. In some implementations, Xaa 5 It is Arg, hArg, Leu, Agb, or Agp. In some implementations, Xaa 5 It's Arg.

[0087] In some implementations, Xaa 6 It is 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, Xaa 6 It is Phe, Trp, Trp(5-Br), Trp(5-OCH3), Trp(6-F), Trp(5-OH), or Trp(CHO). In some embodiments, Xaa 6 It is either Trp or D-Trp. In some implementations, Xaa 6It's Trp.

[0088] In some implementations, Xaa 7a These are 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, Xaa 7a It is 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, Xaa 7a It is Lys, Orn, Dab, Dap, Lys(N3), Orn(N3), Dab(N3), Dap(N3), 2-(5'-azidopentyl)alanine or 2-(6'-azidohexyl)alanine. In some embodiments, Xaa 7a It's Lys.

[0089] In some implementations, Xaa 7b It is 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 implementations, Xaa 7b It is Cys, Asp, Glu, 2-Aad, 3-Aad, Pra, Hpg, or Bpg. In some implementations, Xaa 7b It is Asp, Glu, Pra, or D-Pra. In some implementations, Xaa 7b It is ASP.

[0090] In some implementations, Xaa 1 、Xaa 2a 、Xaa 2b Xaa 3 Xaa 5 、Xaa 6 、Xaa 7a and Xaa 7b Each of them is an L-amino acid, and Xaa 4 It is a D-amino acid.

[0091] In some implementations, the MC1RTP sequence is essentially composed of the sequence defined by formula A, I, or II, where Xaa 1 Xaa 2a Xaa 2b Xaa 3 Xaa 4 Xaa 5 Xaa 6 Xaa 7a and Xaa 7b As defined for any combination of embodiments as defined in this disclosure. In some embodiments, the sequence of MC1RTP consists of a sequence defined by formula A, I, or II, wherein Xaa 1 Xaa 2a Xaa 2b Xaa 3 Xaa 4 Xaa 5 Xaa 6 Xaa 7a and Xaa 7b As defined for any combination of embodiments as defined in this disclosure. In some embodiments, the sequence of MC1RTP comprises, consists of, or is substantially composed of a sequence defined by Formula A or Formula I, wherein Xaa 1 Xaa 2a Xaa 3 Xaa 4 Xaa 5 Xaa 6 and Xaa 7a As defined for any combination of embodiments as defined in this disclosure. In some embodiments, the sequence of MC1RTP comprises, consists of, or is substantially composed of, the sequence defined by Formula II, wherein Xaa 1 Xaa 2b Xaa 3 Xaa 4 Xaa 5 Xaa 6 and Xaa 7b As defined for any combination of the embodiments defined in this disclosure.

[0092] In some implementations, the MC1RTP sequence comprises, consists of, or is substantially composed of, a sequence defined by Formula A or Formula I, wherein: Xaa 1 It is Nle, Ala, Leu, Ile, Cys, Met, Phe, Trp, Val, Nal, 2-Nal, α-aminobutyric acid, valine, or high-leucine; Xaa 2a It is Asp, Glu, Pra or D-Pra; Xaa3 It is His, β-(1,2,3-triazol-4-yl)-DL-alanine or 1,2,4-triazol-3-alanine; Xaa 4 It is Phe, D-Phe, 2-Nal, or D-2-Nal; Xaa 5 It is Arg, D-Arg, hArg, Leu, D-hArg, Agb, D-Agb, Agp, or D-Agp; Xaa 6 It is either Trp or D-Trp; and Xaa 7a It is Lys, Orn, Dab, Dap, Lys(N3), Orn(N3), Dab(N3), Dap(N3), 2-(5'-azidopentyl)alanine or 2-(6'-azidohexyl)alanine.

[0093] In some implementations, Xaa 1 It is Nle, Xaa 2a It's Asp, Xaa 3 It's His, Xaa 4 It's D-Phe, Xaa 5 It's Arg, Xaa 6 It is Trp, and Xaa 7 It is Lys. The sequence of MC1RTP can consist essentially of Nle-Asp-His-(D-Phe)-Arg-Trp-Lys, which is linear or cyclic, optionally C-terminal amidated, and α-N-methylated, as defined elsewhere in this disclosure. The sequence of MC1RTP can consist of Nle-Asp-His-(D-Phe)-Arg-Trp-Lys, which is linear or cyclic, optionally C-terminal amidated, and α-N-methylated, as defined elsewhere in this disclosure.

[0094] MC1RTP may or may not undergo C-terminal amidation (e.g., in Xaa). 7a or Xaa 7b (The text appears to be incomplete and contains errors. A more accurate translation would require the full context.) In some embodiments, MC1RTP is C-terminally amidated. In some embodiments, MC1RTP has a C-terminal carboxylic acid ester.

[0095] One or more amino acid residues of MC1RTP are α-N-methylated, including Xaa in the sequence defined by Formula A or Formula I. 3 Xaa 5 Xaa 6 and Xaa 7a Xaa in 1, 2, 3 or 4 and / or in the sequence defined by Equation II 3 Xaa 5 Xaa6 and Xaa 7b One, two, three, or four α-N-methylations are performed. In some embodiments, MC1RTP has only one, two, three, or four α-N-methylations. In some embodiments, Xaa in the sequence defined by Formula A or Formula I is N-methylated. 3 Xaa 5 Xaa 6 and Xaa 7a One or more of them are α-N-methylated. In some embodiments, Xaa in the sequence defined by Formula A or Formula I 5 and Xaa 7a It is α-N-methylated. In some embodiments, Xaa in the sequence defined by Formula II 5 and Xaa 7b It is α-N-methylated. In some embodiments, N-methylation is (N-Me-Xaa) 3 (N-Me-Xaa) 5 (N-Me-Xaa) 6 ) and (N-Me-Xaa 7a In some implementations, N-methylation is (N-Me-Xaa) 3 (N-Me-Xaa) 5 (N-Me-Xaa) 6 ) and (N-Me-Xaa 7b In some implementations, N-methylation is (N-Me-Xaa) 5 (N-Me-Xaa) 6 ) and (N-Me-Xaa 7a In some implementations, N-methylation is (N-Me-Xaa) 5 (N-Me-Xaa) 6 ) and (N-Me-Xaa 7b In some implementations, N-methylation is (N-Me-Xaa) 5 ) and (N-Me-Xaa 6 In some implementations, N-methylation is (N-Me-Xaa) 6 ) and (N-Me-Xaa 7a In some implementations, N-methylation is (N-Me-Xaa) 6 ) and (N-Me-Xaa 7b In some implementations, N-methylation is (N-Me-Xaa) 5 ) and (N-Me-Xaa 7a In some implementations, N-methylation is (N-Me-Xaa)5 ) and (N-Me-Xaa 7b In some implementations, the only N-methylation is (N-Me-Xaa). 6 ).

[0096] In some implementations, MC1RTP is linear. In some implementations, MC1RTP is cyclic. In some implementations, MC1RTP includes Xaa. 1 -Ring[Xaa 2a -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7a [,] is composed of or substantially composed of. In some implementations, MC1RTP includes a ring [Xaa] 1 -Xaa 2a -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7a [,] constitutes or is substantially composed of it. In some implementations, MC1RTP includes Xaa 1 -Ring[Xaa 2b -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7b [,] is composed of or substantially composed of. In some implementations, MC1RTP includes a ring [Xaa] 1 -Xaa 2a -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7b ], which is composed of or substantially composed of. In the aforementioned sequence, Xaa 1 Xaa 2a Xaa 2b Xaa 3 Xaa 4 Xaa 5 Xaa 6 Xaa 7a Xaa 7b It may have any alternative definitions presented in the preceding paragraphs or elsewhere in this disclosure.

[0097] MC1RTP can be achieved by adding Xaa to the sequence defined by equation A or equation I. 2aConnect to Xaa 7a The lactam bridge is cyclized by linking the side chains of Asp, D-Asp, Glu, D-Glu, 2-Aad, or D-2-Aad to the side chains of Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, or D-Dap. MC1RTP can be formed by cyclizing the side chains of Asp, D-Asp, Glu, D-Glu, 2-Aad, or D-2-Aad with the side chains of Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, or D-Dap in the sequence defined by Formula II. 2b Connect to Xaa 7b Cycling of the lactam bridge is formed by linking the side chains of Asp, D-Asp, Glu, D-Glu, 2-Aad or D-2-Aad with the side chains of Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap or D-Dap.

[0098] MC1RTP can be achieved by adding Xaa to the sequence defined by equation A or equation I. 2a Connect to Xaa 7a The 1,2,3-triazole is cyclized by linking the side chain of Pra, D-Pra, Hpg, D-Hpg, Bpg, or D-Bpg to 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. MC1RTP can be formed by adding Xaa to the sequence defined by Formula II. 2b Connect to Xaa 7b The 1,2,3-triazole is cyclized by linking the side chain of Pra, D-Pra, Hpg, D-Hpg, Bpg or D-Bpg to Lys(N3), D-Lys(N3), Orn(N3), D-Orn(N3), Dab(N3), D-Dab(N3), Dap(N3), D-Dap(N3), D-Dap(N3), 2-(5'-azidopentyl)alanine, D-2-(5'-azidopentyl)alanine, 2-(6'-azidohexyl)alanine or D-2-(6'-azidohexyl)alanine.

[0099] When Xaa 1 and Xaa 7a When both are Cys (D-form and / or L-form), MC1RTP can be achieved by adding Xaa to the sequence defined by Equation A or Equation I. 1 Connect to Xaa 7a The disulfide bonds undergo cyclization. When Xaa 2a and Xaa7a When both are Cys (D-form and / or L-form), MC1RTP can be achieved by adding Xaa to the sequence defined by Equation A or Equation I. 2a Connect to Xaa 7a The disulfide bonds undergo cyclization. When Xaa 1 and Xaa 7b When both are Cys (D-form or L-form), MC1RTP can be achieved by adding Xaa to the sequence defined by Equation II. 1 Connect to Xaa 7b The disulfide bonds undergo cyclization. When Xaa 2b and Xaa 7b When both are Cys (D-form or L-form), MC1RTP can be achieved by adding Xaa to the sequence defined by Equation II. 2b Connect to Xaa 7b The disulfide bonds are cyclized.

[0100] In some implementations, MC1RTP may comprise, consist of, or substantially consist of the following:

[0101] Xaa 1 -Ring[Xaa 2a -Xaa 3 -Xaa 4 -(N-Me-Xaa 5 )-(N-Me-Xaa 6 )-(N-Me-Xaa 7a )]-NH2;

[0102] Xaa 1 -Ring[Xaa 2a -Xaa 3 -Xaa 4 -(N-Me-Xaa 5 )-(N-Me-Xaa 6 )-Xaa 7a ]-NH2;

[0103] Xaa 1 -Ring[Xaa 2a -Xaa 3 -Xaa 4 -Xaa 5 -(N-Me-Xaa 6 )-(N-Me-Xaa 7a )]-NH2;

[0104] Xaa 1 -Ring[Xaa 2a -Xaa 3 -Xaa 4-(N-Me-Xaa 5 )-Xaa 6 -(N-Me-Xaa 7a )]-NH2;

[0105] Xaa 1 -cyclo[Xaa 2a -Xaa 3 -Xaa 4 -(N-Me-Xaa 5 )-Xaa 6 -Xaa 7a )]-NH2;

[0106] Xaa 1 -cyclo[Xaa 2b -Xaa 3 -Xaa 4 -(N-Me-Xaa 5 )-(N-Me-Xaa 6 )-(N-Me-Xaa 7b )]-NH2;

[0107] Xaa 1 -cyclo[Xaa 2b -Xaa 3 -Xaa 4 -(N-Me-Xaa 5 )-(N-Me-Xaa 6 )-Xaa 7b )]-NH2;

[0108] Xaa 1 -cyclo[Xaa 2b -Xaa 3 -Xaa 4 -Xaa 5 -(N-Me-Xaa 6 )-(N-Me-Xaa 7b )]-NH2;

[0109] Xaa 1 -cyclo[Xaa 2b -Xaa 3 -Xaa 4 -(N-Me-Xaa 5 [[ID=​​​​​​​​​​​​​​-(N-Me-Xaa 5 )-Xaa 6 -Xaa 7b ]-NH2;

[0111] Among them, Xaa 1 Xaa 2a Xaa 2b Xaa 3 Xaa 4 Xaa 5 Xaa 6 Xaa 7a and Xaa 7b This can be any alternative definition provided above. MC1RTP can be cyclized by forming lactam bridges, i.e., 1,2,3-triazoles or disulfide bonds. In some such embodiments, Xaa 2a It is Asp and Xaa 7a It is Lys, and in Xaa 2a With Xaa 7a A lactam bridge is formed between them. In some such embodiments, Xaa 2b It is Lys and Xaa 7b It is Asp, and in Xaa 2b With Xaa 7b A lactam bridge is formed between them. In some such embodiments, Xaa 2a It is Glu and Xaa 7a It is Orn, and in Xaa 2a With Xaa 7a A lactam bridge is formed between them. In some such embodiments, Xaa 2b It is Orn and Xaa 7b It is Glu, and in Xaa 2b With Xaa 7b Lactam bridges are formed between them.

[0112] In some embodiments, MC1RTP comprises an Nle-ring [Asp-His-(D-Phe)-Arg-Trp-Lys], wherein the MC1RTP is optionally C-terminally amidated, and wherein Xaa is in the sequence defined by Formula A or Formula I. 3 Xaa 5 Xaa 6 and Xaa 7a One, two, three, or four of them are α-N-methylated. In some embodiments, MC1RTP comprises, is composed of, or is substantially composed of:

[0113] Nle-ring [Asp-(N-Me-His)-(D-Phe)-(N-Me-Arg)-(N-Me-Trp)-(N-Me-Lys)];

[0114] Nle-ring [Asp-His-(D-Phe)-(N-Me-Arg)-(N-Me-Trp)-(N-Me-Lys)];

[0115] Nle-ring [Asp-His-(D-Phe)-(N-Me-Arg)-(N-Me-Trp)-Lys];

[0116] Nle-ring [Asp-His-(D-Phe)-Arg-(N-Me-Trp)-(N-Me-Lys)];

[0117] Nle-ring [Asp-His-(D-Phe)-(N-Me-Arg)-Trp-(N-Me-Lys)];

[0118] Nle-ring [Asp-His-(D-Phe)-(N-Me-Arg)-Trp-Lys];

[0119] Nle-cyclo[Asp-(N-Me-His)-(D-Phe)-(N-Me-Arg)-(N-Me-Trp)-(N-Me-Lys)]-NH2;

[0120] Nle-cyclo[Asp-His-(D-Phe)-(N-Me-Arg)-(N-Me-Trp)-(N-Me-Lys)]-NH2;

[0121] Nle-cyclo[Asp-His-(D-Phe)-(N-Me-Arg)-(N-Me-Trp)-Lys]-NH2;

[0122] Nle-cyclo[Asp-His-(D-Phe)-Arg-(N-Me-Trp)-(N-Me-Lys)]-NH2;

[0123] Nle-cyclic [Asp-His-(D-Phe)-(N-Me-Arg)-Trp-(N-Me-Lys)]-NH2; or

[0124] Nle-cyclic[Asp-His-(D-Phe)-(N-Me-Arg)-Trp-Lys]-NH2.

[0125] In some such implementations, MC1RTP is cyclized via a lactam bridge.

[0126] The connector can be attached to the N-terminus of MC1RTP. The connector can be any connector, such as, but not limited to, ethers, esters, thioethers, disulfides, thioesters, amides, carbamates, ureas, phosphate diesters, polyethylene glycol (PEG), peptides, polypeptides, alkyl groups (e.g., C1-C...). 10 C1-C 15 C1-C 20 C1-C 30 C1-C 50 C1-C 75 C1-C 100 C1-C 120 etc.), heteroalkyl groups (e.g., X1-X) 10 X1-X 15 X1-X 20 X1-X 30 X1-X 50 X1-X 75 X1-X 100 etc.), aryl (e.g., C3-C 10 C3-C 15 C3-C 20 C3-C 30 C3-C 50 C3-C 75 C3-C 100 C3-C 120 (etc.) or heteroaryl (e.g., X3-X) 10 X3-X 15 X3-X 20 X3-X 30 X3-X 50 X3-X 75 X3-X 100 X3-X 120 (etc.). Alkyl or heteroalkyl can be one or more of the following: branched or straight-chain; acyclic, cyclic or polycyclic; saturated or unsaturated; and unsubstituted or substituted. Aryl or heteroaryl can be one or more of the following: cyclic or polycyclic; aromatic or non-aromatic; and unsubstituted or substituted. Non-limitingly, in substituted embodiments, alkyl, heteroalkyl, aryl or heteroaryl can be substituted with one or more of the following: halide ions, amides, oxo, hydroxyl, thiols, phosphates and sulfates. In some embodiments, each X is independently C, N, O, P, Se or S. The halide ion can be –F, –Br, –I or –Cl. In some embodiments, the halide ion is –Br, –I or –Cl. In some embodiments, the linker is cationic. In some embodiments, the linker has a net neutral charge.

[0127] In some implementations, the connector is composed of C1-C120 The alkylene group is composed of, or is substantially composed of, an alkylene group that is: straight-chain or branched; saturated or unsaturated; and acyclic or cyclic (including polycyclic). In some embodiments, the connector is composed of X1-X 120 The heteroalkylene group is composed of or substantially composed of a heteroalkylene group, which can be: straight-chain or branched; saturated or unsaturated; and acyclic or cyclic (including polycyclic). In some such embodiments, the linker comprises a peptide. In some such embodiments, the linker is composed of or substantially composed of a peptide attached to the N-terminus of the MC1RTP. For example, the peptide can be 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 amino acid residues long. The peptide can contain proteogenic and / or non-proteogenic amino acids.

[0128] In some implementations, the linker is a linear peptide –Xaa, having 3 to 6 amino acid residues. 8 –Xaa 9 –(Xaa 10 ) 1-4 – The peptide is linked to the N-terminus of MC1RTP and a radiolabeled group (e.g., a CROWN chelator), wherein Xaa 8 Xaa 9 and Xaa 10 Each is an amino acid, independent of the others. In one implementation, the linker Xaa 8 –Xaa 9 –(Xaa 10 ) 1-4 – Through Xaa 10 The free C-terminus forms a bond and connects to the N-terminus of MC1RTP.

[0129] In some embodiments, the linker comprises an albumin-binding group. In some embodiments, the linker is a linear peptide –Xaa having 3 to 6 amino acid residues. 8 –Xaa 9 –(Xaa 10 ) 1-4 –, where Xaa 8 Xaa 9 and Xaa 10 Each is an amino acid independently. In these embodiments, the radiolabeled group (e.g., CROWN chelating agent) and the albumin-binding group are respectively bound to Xaa 8 Free N-terminus and Xaa 9 The side chain bond, or the radiolabeled group (e.g., CROWN chelating agent) and the albumin-binding group are respectively bonded to Xaa 9 The side chain and Xaa 8The free N-terminus is bonded. In one embodiment, the N-terminus of MC1RTP is bonded to the connector -Xaa. 8 –Xaa 9 –(Xaa 10 ) 1-4 –Xaa 10 C-terminal bonding. In one implementation, the connector-Xaa 8 –Xaa 9 –(Xaa 10 ) 1-4 – Through Xaa 10 The free C-terminus forms an amide bond and attaches to the N-terminus of MC1RTP. Xaa 8 Xaa 9 and each Xaa 10 It can be any amino acid independently, including proteogenic and / or non-proteogenic amino acids (including D-amino acids). In some embodiments, Xaa 8 It is Gly, Glu, D-Glu, Asp, D-Asp, 2-Aad, D-2-Aad, 3-Aad, or D-3-Aad. In some implementations, Xaa 9 It is Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, or D-Dap, any of which can form an amide bond with a carboxylic acid ester of a radiolabeled group or an albumin-binding group. In some embodiments, Xaa 8 It is Gly, Glu, or D-Glu. In some implementations, Xaa 9 It is Lys or D-Lys. In some such implementations, (Xaa) 10 ) 1-4 It is diglycine. In some implementations, (Xaa) 10 ) 1-4 It is p-aminomethylaniline-diethylene glycol (pABzA-DIG), 4-amino-(1-carboxymethyl)piperidine (Pip), 9-amino-4,7-dioxanonanoic acid (dPEG2), or 4-(2-aminoethyl)-1-carboxymethylpiperazine (Acp). In some embodiments, (Xaa) 10 ) 1-4 It's Pip.

[0130] In some implementations, the linker is a branched peptide – Xaa – having 3 to 6 amino acid residues. 9 (Xaa 8 )–(Xaa 10 ) 1-4– The peptide is linked to the N-terminus of MC1RTP and a radiolabeled group (e.g., a CROWN chelator), wherein Xaa 8 Xaa 9 and Xaa 10 Each is an amino acid, independent of the others. In one implementation, the linker –Xaa 9 (Xaa 8 )–(Xaa 10 ) 1-4 – Through Xaa 10 The free C-terminus forms a bond and connects to the N-terminus of MC1RTP.

[0131] In some embodiments, the linker comprises an albumin-binding group. In some embodiments, the linker is a branched peptide –Xaa having 3 to 6 amino acid residues. 9 (Xaa 8 )–(Xaa 10 ) 1-4 –, where Xaa 8 Xaa 9 and Xaa 10 Each is an amino acid independently. In these implementations, Xaa 8 C-terminus with Xaa 9 The side chain forms an amide, and the radiolabeled group (e.g., CROWN chelator) and the albumin-binding group are respectively bound to Xaa. 8 and Xaa 9 The free N-terminal bond, or the radiolabeled group (e.g., CROWN chelating agent) and the albumin-binding group, are respectively bound to Xaa. 9 and Xaa 8 Free N-terminal bonds. In these implementations, Xaa 9 Is it Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, or D-Dap, Xaa 8 C-terminus with Xaa 9 The side chain forms an amide, and the radiolabeled group and albumin-binding group are respectively associated with Xaa. 8 and Xaa 9 Free N-terminal bonds, or respectively with Xaa 9 and Xaa 8 Free N-terminal bonds. Xaa 8 and each Xaa 10 It can be any amino acid independently, including proteogenic and / or non-proteogenic amino acids (including D-amino acids). In some embodiments, Xaa 8It is Gly, Glu, D-Glu, Asp, D-Asp, 2-Aad, D-2-Aad, 3-Aad, or D-3-Aad. In some implementations, Xaa 8 It is Gly, Glu, or D-Glu. In some implementations, Xaa 9 It is Lys or D-Lys. In some such implementations, (Xaa) 10 ) 1-4 It is diglycine. In some implementations, (Xaa) 10 ) 1-4 It is p-aminomethylaniline-diethylene glycol (pABzA-DIG), 4-amino-(1-carboxymethyl)piperidine (Pip), 9-amino-4,7-dioxanonanoic acid (dPEG2), or 4-(2-aminoethyl)-1-carboxymethylpiperazine (Acp). In some embodiments, (Xaa) 10 ) 1-4 It's Pip.

[0132] In some implementations, the linker comprises a linear peptide –Xaa 8 –Xaa 9 –Xaa 10 –, where Xaa 8 Xaa 9 and Xaa 10 Each is an amino acid, and the radiolabeled group (e.g., CROWN chelating agent) and the albumin-binding group are respectively associated with Xaa. 8 Free N-terminus and Xaa 9 The side chain bond, or the radiolabeled group (e.g., CROWN chelating agent) and the albumin-binding group are respectively bonded to Xaa 9 The side chain and Xaa 8 The free N-terminus is bonded. In one embodiment, the N-terminus of MC1RTP is bonded to Xaa. 10 C-terminal bonding. In one implementation, the connector-Xaa 8 –Xaa 9 –Xaa 10 – Through Xaa 10 The free C-terminus forms an amide bond and attaches to the N-terminus of MC1RTP. In such embodiments, Xaa 10 It is –N(H)R 2 R 3 R 2 C(O) –, where each R 2 It does not exist independently, is methylene or ethylene, and R 3 It is –(CH2) n -,or Each X1 Independently, it is carbon or nitrogen, and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11. In some embodiments, n is 6-8. In some embodiments, n is 7. In some embodiments, an X 1 It is nitrogen. In other embodiments, two X... 1 All are nitrogen. In some implementations, X... 1 At least one nitrogen atom in Xaa is protonated to produce a cationic peptide. In some embodiments, Xaa 10 It is 4-amino-1-carboxymethyl-piperidine (Pip), 4-(2-aminoethyl)-1-carboxymethyl-piperazine (Acp), or -N(H)-(CH2). 2-15 C(O)- (e.g., 8-aminooctanoic acid (Aoc), etc.). In some embodiments, Xaa 10 It's Pip. Xaa 8 and Xaa 9 It can be any amino acid independently, including proteogenic or non-proteogenic amino acids (including D-amino acids). In some embodiments, Xaa 8 It is Gly, Glu, D-Glu, Asp, D-Asp, 2-Aad, D-2-Aad, 3-Aad, or D-3-Aad. In some implementations, Xaa 9 It is Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, or D-Dap, any of which can form an amide bond with a carboxylic acid ester of a radiolabeled group or an albumin-binding group. In some embodiments, Xaa 8 It is Gly, Glu, or D-Glu. In some implementations, Xaa 9 It is Lys or D-Lys.

[0133] In some implementations, the linker comprises a branched peptide – Xaa 9 (Xaa 8 )–Xaa 10 –, where Xaa 8 Xaa 9 and Xaa 10 Each is an amino acid, Xaa 8 C-terminus with Xaa 9 The side chain forms an amide, and the radiolabeled group (e.g., CROWN chelator) and the albumin-binding group are respectively bound to Xaa. 8 and Xaa 9 The free N-terminal bond, or the radiolabeled group (e.g., CROWN chelating agent) and the albumin-binding group are respectively bound to Xaa 9 and Xaa 8The free N-terminus is bonded. In one embodiment, the N-terminus of MC1RTP is bonded to Xaa. 10 C-terminal bonding. In one implementation, the connector –Xaa 9 (Xaa 8 )–Xaa 10 – Through Xaa 10 The free C-terminus forms a bond to the N-terminus of the MC1RTP. In some embodiments, the linker comprises a branched peptide –Xaa 9 (Xaa 8 )–Xaa 10 –, where Xaa 9 It is Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, or D-Dap, and Xaa 8 C-terminus with Xaa 9 The side chain forms an amide, wherein the radiolabeled group and the albumin-binding group are respectively associated with Xaa 8 and Xaa 9 Free N-terminal bonds, or respectively with Xaa 9 and Xaa 8 Free N-terminal bonds. Xaa 10 It is –N(H)R 2 R 3 R 2 C(O) –, where each R 2 It does not exist independently, is methylene or ethylene, and R 3 It is –(CH2) n -,or Each X 1 Independently, it is carbon or nitrogen, and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11. In some embodiments, n is 6-8. In some embodiments, n is 7. In some embodiments, an X 1 It is nitrogen. In other embodiments, two X... 1 All are nitrogen. In some implementations, X... 1 At least one nitrogen atom in Xaa is protonated to produce a cationic peptide. In some embodiments, Xaa 10 It is 4-amino-1-carboxymethyl-piperidine (Pip), 4-(2-aminoethyl)-1-carboxymethyl-piperazine (Acp), or -N(H)-(CH2). 2-15 C(O)- (e.g., 8-aminooctanoic acid (Aoc), etc.). In some embodiments, Xaa 10 It's Pip. Xaa 8It can be any amino acid, including proteogenic or non-proteogenic amino acids (including D-amino acids). In some embodiments, Xaa 8 It is Gly, Glu, D-Glu, Asp, D-Asp, 2-Aad, D-2-Aad, 3-Aad, or D-3-Aad. In some implementations, Xaa 8 It is Gly, Glu, or D-Glu. In some implementations, Xaa 9 It is Lys or D-Lys.

[0134] In some implementations, the connector is or In some implementations, the connector is In some implementations, the connector is Furthermore, the albumin-binding group is N-[4-(p-tolyl)butyryl].

[0135] Albumin-binding groups can have the following structures, where each R 4 Independent of H, halogen, C 1-5 Alkyl, C 1-5 Alkoxy or nitro:

[0136] .

[0137] In some implementation schemes, the three Rs 4 The group is H, and there are two R groups. 4 The group is independently I, F, Br, Cl, or methyl located at meta / meta, ortho / ortho, para / meta, meta / para, para / ortho, ortho / para, meta / ortho, or ortho / meta. In some embodiments, the four R groups are... 4 The group is H, and there is an R. 4 The group is I, F, Br, Cl, or methyl located at the para, meta, or ortho positions. In some embodiments, the albumin-binding group is N-[4-(iodophenyl)butyryl], N-[4-(fluorophenyl)butyryl], N-[4-(bromophenyl)butyryl], N-[4-(chlorophenyl)butyryl], or N-[4-(tolyl)butyryl]. In some embodiments, the albumin-binding group is N-[4-(tolyl)butyryl]. In some embodiments, the albumin-binding group is N-[4-(p-iodophenyl)butyryl], N-[4-(p-fluorophenyl)butyryl], N-[4-(p-bromophenyl)butyryl], N-[4-(p-chlorophenyl)butyryl], or N-[4-(p-tolyl)butyryl]. In some embodiments, the albumin-binding group is N-[4-(p-tolyl)butyryl].

[0138] In embodiments where the linker comprises a linear peptide, the albumin-binding group can be coupled to Xaa. 8 The α-amino group, and the radiolabeled group can be coupled to Xaa 9 The side chain. In other such embodiments, the radiolabeled group can be coupled to Xaa. 8 The α-amino group, and the albumin-binding group can be coupled to Xaa. 9 The side chain.

[0139] In embodiments where the linker comprises a branched peptide, the albumin-binding group may be coupled to Xaa. 8 The α-amino group, and the radiolabeled group can be coupled to Xaa 9 The α-amino group. In other such embodiments, the radiolabeled group can be coupled to Xaa. 8 The α-amino group, and the albumin-binding group can be coupled to Xaa. 9 α-amino group.

[0140] The radiolabeled group can be a radioisotope chelating agent. The chelating agent can be incorporated into the compound by coupling with the peptide moiety of the compound.

[0141] Non-limiting examples of radioisotope chelating agents include chelating agents selected from H4py4pa-phenyl-NCS, CROWN, HYNIC, N4, or HBED-CC. Exemplary non-limiting examples of radioisotope chelating agents and radioisotopes chelated by chelating agents are shown in Table 1. In alternative embodiments, the radioisotope chelating agent in the compound is one of those chelating agents listed above or in Table 1, or any other radioisotope chelating agent. Those skilled in the art can substitute another chelating agent for any of the chelating agents listed herein.

[0142] In one implementation, the radioisotope chelating agent is CROWN.

[0143] Table 1: Exemplary chelating agents and exemplary isotopes binding the chelating agents

[0144] Chelating agents Radionuclides H4py4pa-phenyl-NCS Ac-225 CROWN (2,2',2'',2'''-(1,10-dioxa-4,7,13,16-tetraazacyclooctadecane-4,7,13,16-tetrayl)tetraacetic acid) Bismuth-213Lu-177Ac-225Tb-149Tb-152Tb-155Tb-161Th-227 HYNIC Tc-99mTc-94m N4 (6-Carboxy-1,4,7,11-Tetraazaundecane) Tc-99mTc-94m HBED-CC Ga-68

[0145] In some implementations, the CROWN chelating agent has the following connectivity with the connector ( (Showing connectivity with the connector):

[0146] .

[0147] In some embodiments, the CROWN chelating agent connected to the connector has the following structure ( (This demonstrates connectivity with MC1RTP): .

[0149] In some embodiments, a radioisotope chelating agent is conjugated with a radioisotope. The conjugated radioisotope may be, but is not limited to, the following: 68 Ga、 61 Cu、 64 Cu、 67 Ga、 99m Tc, 111 In、 114m In、 44 Sc、 47 Sc、 86 Y、 90 Y、 89 Zr、 90 Nb, 177 Lu、 117m Sn、 165 Er、 227 Th、 225 Ac、 213 Bi、 212 Bi、 211 As、 203 Pb, 212 Pb, 166 Ho、 188 Re、 186 Re、 149 Pm, 159 Gd, 105 Rh、 109 Pd, 198 Au、 199 Au、 175 Yb、 142 Pr、 149 Tb, 152 Tb, 155 Tb, 161 Tb, etc. In some embodiments, the chelating agent is one of the chelating agents in Table 1, and the conjugated radioactive isotope is one of the radioactive isotopes shown in Table 1 as a binder for the chelating agent.

[0150] In some embodiments, the conjugated radioisotope is a therapeutic radioisotope (e.g., a beta emitter or an alpha emitter). Non-limiting examples of therapeutic radioisotopes include... 165 Er、 212 Bi、 213 Bi、 211 At、 166 Ho、 149 Pm, 159 Gd, 105 Rh、 109 Pd, 198 Au、199 Au、 175 Yb、 142 Pr、 177 Lu、 111 In、 203 Pb, 212 Pb, 47 Sc、 90 Y、 117m Sn、 153 Sm、 149 Tb, 152 Tb, 155 Tb, 161 Tb, 224 Ra、 225 Ac、 227 Th、 223 Ra、 77 As、 131 I, 64 Cu、 67 Cu, etc. In some implementations, the radioactive isotope is... 225 Ac.

[0151] In some embodiments, the conjugated radioisotopes are suitable for PET or SPECT imaging (e.g., positron emitters or gamma emitters). Non-limiting examples of positron- or gamma-emitting radioisotopes include... 68 Ga、 67 Ga、 61 Cu、 64 Cu、 99m Tc, 110m In、 111 In、 44 Sc、 86 Y、 89 Zr、 90 Nb, 18 F, 131 I, 123 I, 124 I or 72 As.

[0152] In some implementations, the conjugated radioactive isotopes are 213 Bi、 177 Lu、 225 Ac、 149 Tb, 152 Tb, 155 Tb, 161 Tb or 227 Th.

[0153] A compound having the following structure or a salt thereof is also provided.

[0154]

[0155] (CCZ01178),

[0156] The compound is optionally conjugated with a radioactive isotope. In some embodiments, the compound is conjugated with... 213 Bi、 177 Lu、 225 Ac、 149 Tb, 152 Tb, 155 Tb, 161 Tb or 227 Th conjugation. In some embodiments, the compound is conjugated with... 225 Ac conjugation. In some embodiments, the compound is 225 CCZ01178 marked with Ac.

[0157] In some implementations, the MC1RTPs are those disclosed in WO2019 / 222851, which is incorporated herein by reference in its entirety for all purposes.

[0158] Uses / Methods

[0159] This section incorporates all embodiments and combinations of features of the compounds described in the previous sections.

[0160] A pharmaceutical composition is also disclosed comprising a compound as defined in Part II and a pharmaceutically acceptable excipient, carrier, or diluent. The compound may be any embodiment (or combination of its features) as defined in the preceding sections. The compound may be conjugated with a therapeutic radioisotope (as defined in the preceding sections) or with a radioisotope suitable for PET or SPECT imaging (as defined in the preceding sections).

[0161] The compound can be used in the preparation of radioisotope-conjugated compounds. Therefore, a method for preparing radioisotope-conjugated compounds is provided, the method comprising conjugating a radioisotope as defined in the preceding sections with a radioisotope chelating agent of the compound as defined in the preceding sections. The compound can be any embodiment (or combination of features thereof) defined in the preceding sections. The radioisotope can be a therapeutic radioisotope (as defined in the preceding sections) or a radioisotope suitable for PET or SPECT imaging (as defined in the preceding sections).

[0162] In some implementations, this disclosure provides a method for treating cancer.

[0163] In some embodiments, this disclosure provides a method for treating melanoma.

[0164] In some embodiments, this disclosure provides a method of treating MC1R-related diseases, comprising administering to a subject any of the compounds disclosed herein. In some embodiments, this disclosure provides the use of any of the compounds disclosed herein in the manufacture of a medicament for treating MC1R-related diseases or symptoms.

[0165] In some embodiments, the MC1R-related disease or symptom is a cancer that expresses MC1R. In some embodiments, the cancer is melanoma or non-melanoma skin cancer. For example, but not limited to, MC1R is specifically expressed in cutaneous melanoma, non-melanoma, and uveal melanoma. In some embodiments, the cancer that expresses MC1R is melanoma or non-melanoma skin cancer. In some embodiments, the cancer that expresses MC1R is primary melanoma or metastatic melanoma. In some embodiments, the cancer that expresses MC1R is uveal melanoma. In some embodiments, the cancer that expresses MC1R is melanoma.

[0166] In some embodiments of methods for treating cancer, administration of the compound of the present disclosure having a CROWN chelator prolongs the survival of a subject when compared to administration of a compound having a DOTA chelator (but not a CROWN chelator) (where the remainder of the compound is identical (i.e., the same connector and the same MC1RTP)). In some embodiments, the survival is prolonged by at least 3 months, at least 6 months, at least 9 months, or at least 12 months. In some embodiments, the survival is prolonged by at least 1 year, at least 2 years, at least 3 years, at least 4 years, or at least 5 years.

[0167] In some implementation methods of cancer treatment, when combined with the application of... 177 Lu-labeled DOTA chelator (not) 225 When compared to compounds containing an Ac-labeled CROWN chelator (where the remainder of the compound is identical (i.e., the same connector and the same MC1RTP)), administration of the compound of this disclosure having the CROWN chelator prolongs the survival of the subject. In some embodiments, the survival is prolonged by at least 3 months, at least 6 months, at least 9 months, or at least 12 months. In some embodiments, the survival is prolonged by at least 1 year, at least 2 years, at least 3 years, at least 4 years, or at least 5 years.

[0168] In some embodiments of methods for treating cancer, the application of the compound of the present disclosure with a CROWN chelator is more effective in reducing tumor size or slowing cancer progression when compared to the application of a compound with a DOTA chelator (but not a CROWN chelator) (where the rest of the compound is the same (i.e., the same connector and the same MC1RTP)).

[0169] In some implementation methods of cancer treatment, when combined with the application of... 177 Lu DOTA chelating agent (not 225 When applied to compounds containing the Ac-labeled CROWN chelator (where the remainder of the compound is the same (i.e., the same connector and the same MC1RTP)), the application of the compound of this disclosure having the CROWN chelator is more effective in reducing tumor size or slowing cancer progression.

[0170] In some embodiments, this disclosure provides a method for imaging tissue expressing MC1R in a subject, wherein the method includes: administering any of the compounds described herein to the subject; and imaging the subject's tissue using PET or SPECT. When the tissue is diseased tissue (e.g., cancer expressing MC1R), MC1R-targeted therapy can then be selected to treat the subject. In some embodiments of any of the methods disclosed herein, the compounds are administered in the form of a pharmaceutical composition. In some embodiments, the tissue expressing MC1R is cancerous tissue. In some embodiments, the cancer is melanoma or non-melanoma skin cancer. In some embodiments, the cancer is primary melanoma or metastatic melanoma. In some embodiments, the cancer is uveal melanoma.

[0171] Without limitation, the compounds disclosed herein or pharmaceutical compositions comprising such compounds may be administered intravenously to a subject or by subcutaneous or intradermal injection around the initial tumor site (e.g., to detect lymphatic spread).

[0172] Example

[0173] The invention is further illustrated in the following embodiments.

[0174] Example 1: Synthesis and radiolabeling of CCZ01178 ([4-(p-tolylphenyl)butyryl]-Gly-Lys(CROWN)-Pip-Nle-cyclo[Asp-His-D-Phe-N-Me-Arg-Trp-N-Me-Lys]-NH2) and CCZ01158 ([4-(p-tolylphenyl)butyryl]-Gly-Lys(DOTA)-Pip-Nle-cyclo[Asp-His-D-Phe-N-Me-Arg-Trp-N-Me-Lys]-NH2)

[0175]

[0176] CCZ01178

[0177] CCZ01158

[0178] CCZ01178 was synthesized according to the modified procedures disclosed in WO2019 / 222851 and WO2021 / 168567, the contents of each of which are hereby incorporated in their entirety for all purposes. CCZ01158 was synthesized according to WO2019 / 222851.

[0179] [ 225 Ac]Ac-CCZ01178 and [ 225 The radiolabeled Ac]Ac-CCZ01158

[0180] CCZ01178 and CCZ01158 are used 225 Radiolabeling with AcCl3. See WO2021 / 168567. For example, an aliquot of the CCZ01178 precursor (1 mM, 1 nmol, 0.9 µL) was dissolved in 0.2 M NaOAc (pH 5.5, 223 µL) and EtOH (10%, 34 µL), followed by the dissolution of 0.86 MBq. 225 AcCl3 (85 µL). React the mixture at room temperature for 20 minutes. Further dilute the reaction mixture in formulation buffer.

[0181] [ 225 Ac]Ac-CCZ01158 was prepared in a manner similar to that described above, wherein the mixture was heated to 95°C during the reaction.

[0182] [ 177 Radiolabeled Lu]Lu-CCZ01158

[0183] CCZ01158 177 Radiolabeling with LuCl3. See Bratanovic et al., J. Nucl. Med. 2022, 63, 424-430, which is incorporated herein by reference in its entirety for all purposes. For example, an aliquot of the CCZ01158 precursor (1 mM, 0.7 nmol, 0.7 µL) was dissolved in 0.2 M NaOAc (pH 5.5, 114 µL) and ethanol (10%, 13 µL), followed by the dissolution of 62.2 MBq. 177 Add LuCl3 (2.3 µL) and heat to 95 °C for 15 minutes. Further dilute the reaction mixture in formulation buffer.

[0184] Example 2: Biodistribution

[0185] Under anesthesia, NRG mice carrying SK-MEL-1 human melanoma were injected with 15-30 kBq of [the drug / method / etc.] via the tail vein. 225 Ac]Ac-CCZ01178 or 225Ac-labeled CCZ01158. Mice were re-anesthetized and euthanized by CO2 inhalation at different time points, such as 1, 3, 4, 20, 24, 70, 119 and / or 120 h post-injection. Blood was rapidly aspirated and organs of interest were harvested, rinsed with 1× PBS (pH 7.4) and aspirated. Each organ was then weighed and the radioactivity of the collected tissues was measured using a WallacWIZARD2 gamma counter (Perkin Elmer), normalized to the injection dose using a standard curve, and expressed as a percentage of the injection dose per gram of tissue (%ID / g). Table 2 summarizes [ 225 Biodistribution data of Ac]Ac-CCZ01178 at 1, 3, 20, 70 and 119 h post-injection.

[0186] Table 2. 225 Biodistribution of Ac]Ac-CCZ01178 in NRG mice carrying SK-MEL-1 human melanoma at 1, 3, 20, 70, and 119 h post-injection. Values ​​are expressed as %ID / g (mean ± standard deviation), n = 4.

[0187]

[0188] Example 3. Dose escalation study

[0189] In mice carrying SL-MEL-1, [ 225 Ac]Ac-CCZ01178 (at 15 kBq and 30 kBq) and [ 177 Lu]Lu-CCZ01158 (at 20 MBq and 40 MBq) was used in dose escalation studies.

[0190] SK-MEL-1 human melanoma mice were injected with saline (control), [ 225 Ac]Ac-CCZ01178 (approximately 15 or 30 kBq / mouse) or [ 177 Lu-CCZ01158 (approximately 20 or 40 MBq / mouse). Tumor size and body weight were measured every 2–4 days from the date of injection. The endpoint was defined as weight loss > 15%, tumor ulceration, or tumor volume > 1000 mm. 3 (Volume = width × width × length / 2, measured with calipers).

[0191] Figure 1 The changes in tumor volume over time are shown, and Figure 2 Survival curves for different treatment groups are shown.

[0192] Example 4: Comparison of biodistribution 24 h after injection

[0193] Under anesthesia, NRG mice carrying SK-MEL-1 human melanoma were injected with 15-30 kBq of [the drug / method / etc.] via the tail vein. 225 Ac]Ac-CCZ01178 or [ 225 Ac]Ac-CCZ01158. 24 h post-injection, mice were re-anesthetized and euthanized by CO2 inhalation. Blood was rapidly drawn, and organs of interest were harvested, rinsed with 1× PBS (pH 7.4), and aspirated. Each organ was then weighed, and the radioactivity of the collected tissues was measured using a Wallac WIZARD2 gamma counter (Perkin Elmer), normalized to the injection dose using a standard curve, and expressed as a percentage of the injection dose per gram of tissue (%ID / g). Table 3 summarizes […]. 225 Ac]Ac-CCZ01178 and [ 225 Biodistribution data of Ac]Ac-CCZ01158 24 h after injection.

[0194] Table 3. 225 Ac]Ac-CCZ01178 and [ 225 Biodistribution of Ac]Ac-CCZ01158 in NRG mice carrying SK-MEL-1 human melanoma at 24 h post-injection. Values ​​are expressed as %ID / g (mean ± standard deviation), n = 3 or 4.

[0195]

[0196]

[0197] All references are incorporated accordingly.

[0198] The invention has been described with respect to one or more embodiments. However, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the scope of the invention as defined in the claims.

Claims

1. A compound or a salt thereof, wherein the compound comprises a melanocortin 1 receptor (MC1R) targeting peptide (MC1RTP) linked to a CROWN chelator via a linker, wherein: The MC1RTP is a circularized sequence containing formula A: Yeah 1 -No 2a -No 3 -No 4 -No 5 -No 6 -No 7a (A) Xaa 1 Select from the following groups: leucine (Nle), D-Nle, Ala, D-Ala, Leu, D-Leu, Ile, D-Ile, Cys, D-Cys, Met, D-Met, Phe, D-Phe, Trp, D-Trp, Val, D-Val, 3-(1-naphthyl)alanine (Nal), D-Nal, 3-(2-naphthyl)alanine (2-Nal), D-2-Nal, Gly, α-aminobutyric acid, valine, D-valine, high-leucine, and D-high-leucine; Xaa 2a Select the following groups: Cys, D-Cys, Asp, D-Asp, Glu, D-Glu, 2-aminohexanoic acid (2-Aad), D-2-Aad, 3-aminohexanoic acid (3-Aad), D-3-Aad, propargylglycine (Pra), D-Pra, homopropargylglycine (Hpg), D-Hpg, β-homopropargylglycine (Bpg), and D-Bpg; Xaa 3 It is His; Xaa 4 It is D-Phe; Xaa 5 is Arg; Xaa 6 It is Trp; Xaa 7a Select the following groups: 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; One or more amino acid residues of the MC1RTP are α-N-methylated; and The MC1RTP may optionally undergo C-terminal amidation.

2. The compound of claim 1, wherein the MC1RTP is obtained by passing Xaa 2a Connect to Xaa 7a Cyclolated lactam bridges.

3. The compound of claim 2, wherein Xaa 2a It is Asp and Xaa 7a It is Lys; and the lactam bridge connects the side chains of Asp and Lys.

4. The compound according to any one of claims 1 to 3, wherein Xaa 1 It is ortholeucine (Nle), Xaa 2a It's Asp, Xaa 3 It's His, Xaa 4 It's D-Phe, Xaa 5 It's Arg, Xaa 6 It is Trp, and Xaa 7a It's Lys.

5. The compound according to any one of claims 1 to 4, wherein Xaa 3 、Xaa 5 、Xaa 6 and Xaa 7a One or more of them are α-N-methylated.

6. The compound according to any one of claims 1 to 5, wherein only Xaa 5 and Xaa 7a It is α-N-methylated.

7. The compound of any one of claims 1 to 6, wherein the connector comprises an albumin-binding group.

8. The compound of claim 7, wherein the linker is a linear peptide –Xaa having 3 to 6 amino acid residues. 8 –Xaa 9 –(Xaa 10 ) 1-4 –, where Xaa 8 Xaa 9 and Xaa 10 Each is an amino acid, and among them: The N-terminus of the MC1RTP and Xaa 10 Free C-terminal bonds; and The CROWN chelating agent and the albumin-binding group are respectively bound to Xaa 8 Free N-terminus and Xaa 9 Side chain bonding, or The CROWN chelating agent and the albumin-binding group are respectively bound to Xaa 9 The side chain and Xaa 8 Free N-terminal bonds.

9. The compound of claim 8, wherein the CROWN chelating agent and the albumin-binding group are respectively bound to Xaa 9 The side chains and Xaa 8 The free N-terminal bond.

10. The compound of claim 8 or 9, wherein: Xaa 8 It is Gly, Glu, or D-Glu; and Xaa 9 It is Lys or D-Lys.

11. The compound according to any one of claims 8 to 10, wherein (Xaa) 10 ) 1-4 It is p-aminomethylaniline-diethylene glycol (pABzA-DIG), 4-amino-(1-carboxymethyl)piperidine (Pip), 9-amino-4,7-dioxanonanoic acid (dPEG2) or 4-(2-aminoethyl)-1-carboxymethylpiperazine (Acp).

12. The compound according to any one of claims 8 to 11, wherein (Xaa) 10 ) 1-4 It's Pip.

13. The compound according to any one of claims 1 to 6, wherein the connector is: or .

14. The compound according to any one of claims 7 to 13, wherein the albumin-binding group has the following structure: , Each R 4 Independent of H, halogen, C 1-5 Alkyl, C 1-5 Alkyl or nitro groups.

15. The compound according to any one of claims 1 to 13, wherein the connector is: , Furthermore, the albumin-binding group has the following structure: , Each R 4 It can be independently H, I, Br, F, Cl, -OH, -OCH3, -NH2, -NO2 or -C1-C6 alkyl.

16. The compound of any one of claims 7 to 15, wherein the albumin-binding group is N-[4-(p-tolyl)butyryl].

17. The compound of any one of claims 1 to 16, wherein the CROWN chelating agent is conjugated with a radioisotope.

18. The compound of any one of claims 1 to 17, wherein the CROWN chelating agent is... 213 Bi、 177 Lu、 225 Ac、 149 Tb, 152 Tb, 155 Tb, 161 Tb or 227 Th affix.

19. The compound of any one of claims 1 to 18, wherein the CROWN chelating agent is... 225 Ac suffix.

20. A compound having the following structure: , or its salt.

21. The compound of claim 20, wherein it is in contact with... 213 Bi、 177 Lu、 225 Ac、 149 Tb, 152 Tb, 155 Tb, 161 Tb or 227 Th affix.

22. The compound of claim 20 or 21, wherein it is combined with... 225 Ac suffix.

23. A method of treating melanoma, comprising administering a compound as described in any one of claims 1 to 22.

24. The method of claim 23, wherein the melanoma is a metastatic cutaneous melanoma or a metastatic uveal melanoma.

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