WO2024206972A1

WO2024206972A1 - Compounds and combinations for diagnosing and treating melanoma and methods related to the same

Info

Publication number: WO2024206972A1
Application number: PCT/US2024/022449
Authority: WO
Inventors: Yubin Miao
Original assignee: University of Colorado System; University of Colorado Colorado Springs
Current assignee: University of Colorado System; University of Colorado Colorado Springs
Priority date: 2023-03-31
Filing date: 2024-04-01
Publication date: 2024-10-03
Anticipated expiration: 2025-09-30

Abstract

The present inventive concept relates to compounds and combinations for diagnosing and treating melanoma and methods related to the same involving combining MC1R-TRT and ICIs for melanoma treatment and provide novel treatments for metastatic melanoma. This inventive concept provides clinicians with novel valuable imaging tools to identify MC1R-positive patients who will benefit from the treatments, determine patient-specific dosimetry for safe and efficacious doses, and monitor patient responses to MC1R-TRT and ICIs treatments. This inventive concept will pave the way for use of this novel treatment in FDA-approved clinical trials, provide patients with personalized diagnoses and treatments, enhance diagnosis, treatment, and a cure for metastatic melanoma patients.

Description

Attorney Docket No.151077-00046WO COMPOUNDS AND COMBINATIONS FOR DIAGNOSING AND TREATING MELANOMA AND METHODS RELATED TO THE SAME RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Patent Application No. 63/493,358, filed on March 31, 2023. The entire content of which is hereby incorporated by reference in its entirety. STATEMENT OF GOVERNMENT SUPPORT [0002] This invention was made with government support under Grant no. R01CA225837 and R01CA269221 awarded by the National Institutes of Health. The government has certain rights in the invention. RESERVATION OF COPYRIGHT [0003] This disclosure contains material that is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure as it appears in the U.S. Patent and Trademark Office patent file or records, but otherwise reserves any and all copyright rights. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING [0004] A Sequence Listing XML file, submitted pursuant 37 C.F.R. §§ 1.831–835, entitled 151077-00046WO_ST26.xml, 30,802 bytes in size, created on March 29, 2024, and filed electronically, is provided in lieu of a paper copy. The entire content of the Sequence Listing XML file is incorporated herein by reference in its entirety. FIELD OF THE INVENTION [0005] The present inventive concept describes the development of novel theranostic peptides for imaging-guided melanocortin-1-receptor-targeted radionuclide therapy (MC1R-TRT), and the combination of MC1R-TRT with immune checkpoint Attorney Docket No.151077-00046WO inhibitors (ICIs) for melanoma treatment. Novel theranostic peptides can be used for imaging-guided MC1R-TRT, and the combinations of MC1R-TRT and ICIs can treat melanoma more effectively than MC1R-TRT only. BACKGROUND OF THE INVENTION [0006] Malignant melanoma is the most lethal form of skin cancer with an increasing incidence in the United States. Unfortunately, no curative treatment exists for metastatic melanoma. Despite the significant advances of molecularly targeted treatments (BRAF-, CTLA-4- and PD-1-targeted therapies) in treating metastatic melanoma over the past decade, the 5-year survival is only 35% for metastatic melanoma patients. Thus, there is an urgent need to develop alternative treatment strategies for metastatic melanoma. [0007] New FDA-approved molecularly-targeted treatments, namely Vemurafenib (BRAF inhibitor), Ipilimumab [cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor] and Nivolumab [programmed death-1 receptor (PD-1) inhibitor], have improved the overall survival of metastatic melanoma patients by months (11-19). However, the response to Vemurafenib is transient, with most patients eventually having recurrence and relapse (14-15). The overall response rate for Ipilimumab is <11.1% (16-17). Although Nivolumab exhibited a median overall survival of 16.8 months, the median progression- free survival (PFS) was only 9.7 months (18). The 5-year survival is only 35% for metastatic melanoma patients (19). Thus, there is an urgent need to develop alternative treatments for metastatic melanoma. [0008] Recently, the combination of radionuclide therapy and immunotherapy to augment the immune response against tumor has been evaluated in preclinical studies (20-23). For instance, it has been reported that the combination of VLA-4-targeted ¹⁷⁷Lu- LLP2A and immunotherapy (anti-PD-1, anti-PD-L1, anti-CTLA-4) significantly delayed B16/F10 melanoma growth (21). It has also been found that the combination of 50 μCi of ⁹⁰Y-NM600 (an alkylphosphocholine analog) with anti-CTLA-4 and anti-PD-L1 resulted in 66% complete tumor response in B78 melanoma-bearing C57 mice (22). Li et al. found that the combination of 111 μCi of MC1R-targeted ²¹²Pb-VMT01 with anti-CTLA-4 and anti-PD-1 led to 43% complete tumor response in B16/F10 melanoma-bearing C57 mice (23). Nevertheless, although these promising results underscore the promise of the Attorney Docket No.151077-00046WO combination of receptor-targeted alpha radionuclide therapy and immune checkpoint inhibitors for melanoma treatment, there still remains a need to further develop novel therapeutics and diagnostics, such as theranostics that combine radionuclide imaging and radiation therapy which target specific biological pathways, for melanoma diagnosis and treatment. SUMMARY OF THE INVENTION [0009] Aspects of the present inventive concept include a compound or compounds according to a chemical structure: Y¹–X–(ABC)–CycMSH_hex(KD) wherein:Y¹ includes a radiometal chelator or an optical tag; X is absent, or is a –NH–(CH₂)₇–(C=O)– group; (ABC) is selected from the group consisting of GlyGlyNle, GlyGlyGly, GlySerGlyNle, and PEG2Nle when X is absent, or is Nle when X is a –NH–(CH2)7–(C=O)– group; CycMSH_hex(KD) is a cyclic peptide including the general structure:

[0010] wherein: W is C–H from Lys or Orn, wherein j is 3 if W is from Orn or j is 4 if W is from Lys; X¹ is L- or D-Phe, Tyr, or Trp; Y is Arg or Lys; Z is Trp, Phe, or Tyr; Z¹ is Asp(CONH2) or Glu(CONH2); and Z² is a side chain –(C=O)– from the Asp or Glu of Z¹, or a pharmaceutically acceptable salt thereof. In some aspects, Y¹ includes a DOTA, NOTA, NODAGA, HYNIC, DO3AM, TCMC-pBz-NCS, or PSC group, or Y¹ is a Cy5.5 group [0011] Another aspect provides a pharmaceutical composition including an effective amount of a compound of the present inventive concept and a radioisotope, and a pharmaceutically acceptable carrier, additive, or excipient. Aspects pharmaceutical composition may further include at least one agent in addition to the compounds of the inventive concept, or the pharmaceutical composition including compounds of the Attorney Docket No.151077-00046WO present inventive concept may be capable of being co-administered with at least one agent. aspects of the at least one agent include, e.g., DTIC, IL-2, alpha-interferon, and immune checkpoint inhibitors (ICIs), such as, e.g., (anti-PD-1 + anti-CTLA-4) or (anti- PD-L1 + anti-CTLA-4). [0012] Another aspect provides a method of treating melanoma in a subject in need thereof comprising administering to said patient an effective amount of a compound or pharmaceutical composition of the present inventive concept. [0013] Another aspect provides a method of diagnosing the presence, absence, or extent of melanoma in a subject including: administering an imaging-effective amount of the compound or pharmaceutical composition of the present inventive concept; imaging the subject to determine if tissue in the subject exhibits elevated expression of melanocortin-1 receptors (MC1Rs); and diagnosing the patient as having melanoma if the tissue exhibits elevated expression of MC1Rs in comparison to a threshold and/or with a standard. [0014] Another aspect provides a method of monitoring therapy of a subject in the treatment of melanoma including: administering an imaging effective amount of a compound of the inventive concept to a subject undergoing melanoma treatment; imaging said patient to determine if tissue in the patient exhibits elevated expression of MSH receptors; and comparing the results of the imaging to a threshold and/or with a standard. [0015] Another aspect provides uses of the compound or composition of the inventive concept in manufacture of a medicament for treating melanoma in a subject, in manufacture of a medicament for diagnosing the presence, absence, or extent of melanoma in a subject, and in manufacture of a medicament for monitoring therapy of a subject in the treatment of melanoma. BRIEF DESCRIPTION OF THE DRAWINGS [0016] FIG.1 depicts a synthetic scheme for a peptide of the inventive concept from the intermediate (tBu)₃DOTA–Gly–Gly–Nle–Lys(Mtt)–His(Trt)–D-Phe–Arg(Pbf)– Trp(Boc)–Asp(O-2-PhiPr) (SEQ ID NO:1), synthesized on an H₂N-Sieber amide resin, to Attorney Docket No.151077-00046WO prepare DOTA–GlyGly–Nle–CycMSH_hex(KD) (SEQ ID NO:2, with DOTA group attached). [0017] FIG.2 depicts an in-human study on a melanoma patient with metastases in brain (BM), lung (LM), connective tissue (CM), and intestine (IM) using MC1R-targeted ⁶⁸Ga-DOTA–GlyGly–Nle–CycMSH_hex (SEQ ID NO:3, complexed with ⁶⁸Ga) as an imaging probe. [0018] FIG.3 depicts the strategy to combine MC1R-targeted radionuclide therapy (MC1R-TRT) with a peptide of the inventive concept (SEQ ID NO:2, with DOTA group attached, complexed with ²⁰³Pb/²¹²Pb) and immune checkpoint inhibitors to treat melanoma. [0019] FIG.4 depicts a ²²⁴Ra/²¹²Pb generator decay chain.²¹²Pb (T1/2 = 10.6 h) decays to ²¹²Bi (T1/2 = 60.6 mins) via a β-decay, then further decays to stable ²⁰⁸Pb through two α-decays and two β-decays that can be used for therapy. [0020] FIG.5 depicts biodistribution of ²⁰³Pb-DOTA–GlyGly–Nle–CycMSH_hex (SEQ ID NO:3, complexed with ²⁰³Pb) in B16/F1 melanoma-bearing C57 mice at 2, 4, 24 h post- injection; Coronal SPECT/CT image of a B16/F1 melanoma-bearing mouse at 2 h post- injection of ²⁰³Pb-DOTA–GlyGly–Nle–CycMSH_hex. Co-injection of peptide blockade (pink columns) blocked 95% of melanoma uptake. [0021] FIG.6 depicts the effect of substituting the –GlyGly– linker of DOTA–GlyGly– Nle–CycMSH_hex(KD) (SEQ ID NO:2, with DOTA group attached) with an 8- aminooctanoic acid- (Aoc) linker (SEQ ID NO:4, with DOTA group attached to Nle N- terminal of SEQ ID NO:4 through Aoc linker) dramatically enhancing the MC1R binding affinity of DOTA–(linker)–Nle–CycMSH_hex(KD) peptides. [0022] FIG.7A depicts the general structure of a radiometal chelator/optical tag– linker–Nle–CycMSH_hex(KD) peptides/compounds (SEQ ID NO:4, with optical tag/radiometal chelator attached to –Nle–CycMSH_hex(KD) through a linker) of the inventive concept. [0023] FIG.7B depicts exemplary radiometal chelators (DOTA, NOTA, NODAGA, HYNIC, DO3AM, TMC-pBz-NCS, and PSC) and an optical tag (Cy5.5) included in peptides/compounds of the inventive concept. Attorney Docket No.151077-00046WO [0024] FIG.7C depicts exemplary peptide, PEG, and Aoc linkers included in the peptides/compounds of the inventive concept. [0025] FIG.8 depicts structures of DOTA–GlyGly–Nle–CycMSH_hex(KD) (SEQ ID NO:2, with DOTA group attached) and control peptides (SEQ ID NOS:5–9): used in analysis of properties of the compounds of the inventive concept. [0026] FIG.9 depicts melanocortin-1 receptor (MC1R) binding affinities of DOTA– GlyGly–Nle–CycMSH_hex(KD) and control peptides depicted in FIG.8 on B16/F1 melanoma cells. [0027] FIG.10A depicts the structure of Cyanine5.5 (Cy5.5)-GlyGly–Nle– CycMSH_hex(KD) (SEQ ID NO:2, with Cy5.5 group attached). [0028] FIG.10B depicts the receptor binding affinity of Cy5.5-GlyGly–Nle– CycMSHhex(KD) on B16/F1 melanoma cells. [0029] FIG.11 depicts the MC1R staining of B16/F1 and B16/F10 melanoma tumors by Cy5.5-GlyGly–Nle–CycMSHhex(KD) and commercial fluorescein isothiocyanate (FITC)-MC1R antibody. [0030] FIG.12 depicts the radioactive HPLC profile of ¹¹¹In-DOTA–GlyGly–Nle– CycMSH_hex(KD). [0031] FIG.13 depicts the cellular internalization and efflux of ¹¹¹In-DOTA–GlyGly– Nle–CycMSH_hex(KD) on M21 melanoma cells. [0032] FIG.14 depicts the biodistribution of ¹¹¹In-DOTA–GlyGly–Nle– CycMSHhex(KD) in B16/F1 melanoma-bearing C57 mice at 0.5, 2, 4 and 24 h post- injection, and SPECT/CT image of a B16/F1 melanoma-bearing mouse at 2 h post- injection of ¹¹¹In-DOTA–GlyGly–Nle–CycMSH_hex(KD). Co-injection of peptide blockade (black columns) blocked 91% of melanoma uptake (p<0.05). [0033] FIG.15 depicts the biodistribution of ²⁰³Pb-DOTA–GlyGly–Nle– CycMSH_hex(KD) (SEQ ID NO:2 with DOTA group attached and complexed with ²⁰³Pb) in B16/F1 melanoma-bearing C57 mice at 0.5, 2, 4 and 24 h post-injection, and coronal SPECT/CT image of a B16/F1 melanoma-bearing mouse at 2 h post-injection of ²⁰³Pb- DOTA–GlyGly–Nle–CycMSH_hex(KD). Co-injection of peptide blockade (black columns) blocked 92% of melanoma uptake (p<0.05). Attorney Docket No.151077-00046WO DETAILED DESCRIPTION [0034] The present inventive concept will now be described with reference to the following embodiments. As is apparent by these descriptions, this inventive concept can be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the inventive concept to those skilled in the art. For example, features illustrated with respect to one embodiment can be incorporated into other embodiments, and features illustrated with respect to a particular embodiment can be deleted from that embodiment. In addition, numerous variations and additions to the embodiments suggested herein will be apparent to those skilled in the art in light of the instant disclosure, which do not depart from the instant inventive concept. [0035] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this inventive concept belongs. The terminology used in the description of the inventive concept herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the inventive concept. [0036] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. [0037] The compositions of the present inventive concept may be suitable for and formulated for parenteral, oral, inhalation spray, topical (i.e., both skin and mucosal surfaces, including airway surfaces), rectal, nasal, buccal (e.g., sub-lingual), vaginal or implanted reservoir administration, etc. where the most suitable route in any given case will depend on the nature and severity of the condition being treated in combination with the drug profile of the compound described herein as would be understood by one of ordinary skill in the art. [0038] For topical administration, suitable forms include, but are not limited to an ointment, cream, emulsion, microemulsion, a gel, a dispersion, a suspension, a foam, an aerosol, a liquid, a droplet, and suitable transdermal delivery systems known in the art, such as patches and bandages, dressing, gauze and the like including the Attorney Docket No.151077-00046WO medicament described herein. Topical administration may further include articles of clothing such as socks or hosiery including the medicament described herein. [0039] The term “parenteral” as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraperitoneal, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. [0040] Compositions for injection will include the active ingredient together with suitable carriers including propylene glycol-alcohol-water, isotonic water, sterile water for injection (USP), emulPhor™-alcohol-water, cremophor-EL™, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil, with other additives for aiding solubility or preservation may also be included, or other suitable carriers known to those skilled in the art. Accordingly, these carriers may be used alone or in combination with other conventional solubilizing agents such as ethanol, propylene glycol, or other agents known to those skilled in the art. [0041] Compositions for oral administration may be, for example, solid preparations such as tablets, sugar-coated tablets, hard capsules, soft capsules, granules, powders, gelatins, and the like, with suitable carriers and additives being starches, sugars, binders, diluents, granulating agents, lubricants, disintegrating agents and the like. Because of their ease of use and higher patient compliance, tablets and capsules represent the most advantageous oral dosage forms for many medical conditions. [0042] Similarly, compositions for liquid preparations include solutions, emulsions, dispersions, suspensions, syrups, elixirs, and the like with suitable carriers and additives being water, alcohols, oils, glycols, preservatives, flavoring agents, coloring agents, suspending agents, and the like. [0043] Where the compounds described herein are to be applied in the form of solutions or injections, the compounds may be used by dissolving or suspending in any conventional diluent. The diluents may include, for example, physiological saline, Ringer's solution, an aqueous glucose solution, an aqueous dextrose solution, an alcohol, a fatty acid ester, glycerol, a glycol, an oil derived from plant or animal sources, a paraffin and the like. These preparations may be prepared according to any conventional method known to those skilled in the art. Attorney Docket No.151077-00046WO [0044] Compositions for nasal administration may be formulated as aerosols, drops, powders and gels. Aerosol formulations typically comprise a solution or fine suspension of the active ingredient in a physiologically acceptable aqueous or non-aqueous solvent. Such formulations are typically presented in single or multidose quantities in a sterile form in a sealed container. The sealed container can be a cartridge or refill for use with an atomizing device. Alternatively, the sealed container may be a unitary dispensing device such as a single use nasal inhaler, pump atomizer or an aerosol dispenser fitted with a metering valve set to deliver a therapeutically effective amount, which is intended for disposal once the contents have been completely used. When the dosage form comprises an aerosol dispenser, it will contain a propellant such as a compressed gas, air as an example, or an organic propellant including a fluorochlorohydrocarbon or fluorohydrocarbon. [0045] Compositions suitable for buccal or sublingual administration include tablets, lozenges, gelatins, and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth or gelatin and glycerin. [0046] In particular embodiments, the present inventive concept provides a pharmaceutical formulation including the compound described herein wherein the pharmaceutical formulation is a parenteral formulation. In some embodiments, the parenteral formulation is an intravenous formulation. In some embodiments the parenteral formulation is an intraperitoneal formulation. In other embodiments, the present inventive concept provides a pharmaceutical formulation including the compound described herein wherein the pharmaceutical formulation is an oral formulation. [0047] According to the present inventive concept, methods of the inventive concept include administering an effective amount of a composition of the present inventive concept as described above to the subject. The effective amount of the composition, the use of which is in the scope of present inventive concept, will vary somewhat from subject to subject, and will depend upon factors such as the age and condition of the subject and the route of delivery. Such dosages can be determined in accordance with routine pharmacological procedures known to those skilled in the art. A composition of the present inventive concept can comprise the active agents in an amount ranging Attorney Docket No.151077-00046WO from a lower limit from about 0.01, 0.05, 0.10, 0.50, 1.0, 5.0, or 10% to an upper limit ranging from about 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 96, 97, 98, 99, or 100% by weight of the composition. In some embodiments, the active agents include from about 0.05 to about 95% by weight of the composition. In other embodiments, the active agents can include from about 0.05 to about 60% by weight of the composition. In still other embodiments, the active agents include from about 0.05 to about 10% by weight of the composition. Definitions [0048] The following terms are used to describe the present inventive concept. In the event that a term is not specifically defined herein, that term is accorded its commonly understood meaning within the context of its use by those of ordinary skill in the art. It is understood that the definitions of the terms which are used to describe the present inventive concept are interpreted in a manner consistent with the present inventive concept and within the context of a particular term's use in describing the present inventive concept in one or more embodiments. [0049] As used herein, “a” or “an” or “the” can mean one or more than one. Also as used herein, “and/or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”). [0050] Furthermore, the term “about,” as used herein when referring to a measurable value such as an amount of a compound or agent of this inventive concept, dose, time, temperature, and the like, is meant to encompass variations of 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the specified amount. [0051] The terms “comprise,” “comprises” and “comprising” as used herein, specify the presence of the stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. [0052] As used herein, the transitional phrase “consisting essentially of” means that the scope of a claim is to be interpreted to encompass the specified materials or steps recited in the claim and those that do not materially affect the basic and novel Attorney Docket No.151077-00046WO characteristic(s) of the claimed invention. Thus, the term “consisting essentially of” when used in a claim of this invention is not intended to be interpreted to be equivalent to “comprising.” [0053] Nevertheless, the term "comprising" also may encompass the presence of the stated features, integers, steps, operations, elements, and/or components included by transitional phrases "consisting essentially of," as well as the transitional phrase "consisting of," wherein the scope of a claim is interpreted to encompass only the specified materials or steps recited in the claim. [0054] A “subject” as used herein can be a human subject and can include, but is not limited to, a patient. The subject may be male or female and may be of any race or ethnicity, including, but not limited to, Caucasian, African-American, African, Asian, Hispanic, Indian, etc. The subject may be of any age, including newborn, neonate, infant, child, juvenile, adolescent, adult, and geriatric. In some embodiments, the subject is over 30, 40, 50, 60, 70, 80 or 90 years of age. A subject can also include an animal subject, including mammalian subjects such as canines, felines, bovines, caprines, equines, ovines, porcines, rodents (e.g., rats and mice), lagomorphs, primates (including non-human primates), etc., for prevention and treatment purposes as well as veterinary medicine and/or pharmaceutical drug development purposes. A subject, according to embodiments of the present inventive concept, can be experiencing melanoma or susceptible or at risk for melanoma. [0055] The term “compound” is used herein to refer to any specific chemical compound disclosed herein. Within its use in context, the term generally refers to a single oligopeptide, or an oligopeptide bonded to a DOTA group optionally complexed with a radioisotope, but in certain instances may also refer to components/portions of such compounds, intermediates used to synthesize such compounds, stereoisomers and/or optical isomers (including racemic mixtures) of disclosed compounds. The term compound shall include, where applicable, any and all relevant pharmaceutically acceptable salts thereof. [0056] The term “neutral amino acid” is an amino acid which has an uncharged sidechain at physiological pH. Neutral amino acids for use according to the present inventive concept include, for example, glycine, alanine, valine, leucine, isoleucine, Attorney Docket No.151077-00046WO norleucine, methionine, phenylalanine, serine, threonine and tyrosine. In some embodiments, neutral amino acids for use according to the present inventive concept include glycine, alanine, valine, leucine, isoleucine and norleucine. The term “negatively charged amino acid” is an amino acid which has a negatively charged sidechain at physiological pH. Negatively charged amino acids for use according to the present inventive concept include glutamic acid and aspartic acid, both of which contain a plurality of carboxylate anions (in contrast to free/protonated carboxylic acids) at physiological pH. [0057] The term “chelate,” “chelator” or “chelating agent” is used to describe a moiety (as represented by Y¹ in structures presented herein) which is functionally capable of complexing or “chelating” a radioisotope as otherwise described herein. Each is appropriately chemically linked (via covalent linkers or directly to Cyclic peptides as otherwise described herein). Exemplary chelators for use in the present invention, which are well known in the art, include the following: Polyaminocarboxylates, Such as EDTA: ethylenediaminetetraacetic acid DTPA: diethylenetriaminepentaacetic acid Polyaminocarboxylic Macrocycles, Such as: DOTA: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid NOTA: 1,4,7-triazacyclononane-1,4,7-triacetic acid NODAGA: 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid HYNIC: 6-hydrazinonicotinic acid DO3AM: 2-[4,7,10-tris(2-amino-2-oxoethyl)-1,4,7,10-tetrazacyclododec-1- yl]acetic acid TCMC-pBz-NCS: 2-[4,7,10-tris(2-amino-2-oxoethyl)-6-[(4- isothiocyanatophenyl)methyl]-1,4,7,10-tetrazacyclododec-1-yl]acetamide PSC: [4-(Carbamoylmethyl)-7,10-bis(carboxymethyl)-1,4,7,10-tetraaza-1- cyclododecyl]acetic acid [0058] In some embodiments, the chelator is DOTA, NOTA, or HYNIC. In some embodiments, the chelator is DOTA. In some embodiments, when the radioisotope Attorney Docket No.151077-00046WO included is Cu or Ga, the chelator is NOTA. In some embodiments, when the radioisotope included is Tc or Re, the chelator is HYNIC or NOTA. [0059] Chelates, chelators or chelating agents are generally bi- or multidentate ligands which generally produce a binding or complexation (complex) of a metal radioisotope as otherwise described herein. The ligand or chelator forms a chelate complex with the substrate. The term, without limitation, is used to describe complexes in which the metal ion is bound to two or more atoms of the chelating agent by whatever means (e.g., coordinate binding or complexation) occurs when a radioisotope and chelate group complex within each other in compounds according to the present invention. It is noted here that when a chelator is complexed to a radioisotope as used herein, the chelate complex structure is represented in a generic, nonlimiting sense, such that bonds which are represented may occur between a radioisotope and the chelating agent, as well as additional bonds (such as between carbonyl/carboxyl groups) which are not specifically represented, but which are understood/determined to be bonded within the context of the chelate complex (to accommodate that different radioisotopes may bind differently to different chelate groups). [0060] The term “DOTA” is used as an abbreviation for 1,4,7,10- tetraazacyclododecane-1,4,7,10-tetraacetic acid, a chelator for use in the present invention, which chemical structure (bonded in compounds according to the present invention) is represented as follows:

[0061] Chelators, such as, but not limited to DOTA, may be complexed with a radioisotope R_i according to the present inventive concept. Attorney Docket No.151077-00046WO [0062] "CycMSH_hex(KD)" or "cyclic peptide(KD)," "cycpeptide(KD)," or "cyclic MSH_hex(KD)" refers to cyclic peptides, wherein the sidechain amino group of an N- terminal lysine residue is cyclized with the sidechain carboxyl group of a C-terminal aspartic acid residue, which are bound optionally through a linker, e.g., a peptide (comprising 1, 2, 3 or 4 amino acid residues), PEG, or 8-octanoic acid linker to, e.g., DOTA or other chelator, or an optical tag, e.g., Cy5.5, according to the present inventive concept. The linker may be bound to the cyclic peptide through the N-terminal amino group of the N-terminal lysine residue. In some embodiments, the linker includes norleucine (Nle) that is bound to the N-terminal amino group of the N-terminal lysine residue of the cyclic peptide. [0063] The term “radical” is used to describe a group which is covalently bonded to another group in compounds according to the present inventive concept. [0064] The term “acylated” is used to describe an acyl group which may be used, where appropriate, at a terminal amine group of compounds of the present invention. The term “acyl” as used herein refers a group at a terminal amine position of an amino acid which contains a C₀ to C₂₀ linear, branched, or cyclic alkyl chain. The acyl group at a terminal amine position, results in an amide linkage, which, after administration, may be cleaved. [0065] The term “melanoma” is used to describe a malignant tumor of melanocytes which are found predominantly in skin but also in the bowel and the eye (see uveal melanoma), even though melanoma can be found in any part of the body. Melanoma is a form of cancer that begins in melanocytes, the cells that make skin pigment, or melanin. It may begin in a mole (skin melanoma), but can also begin in other pigmented tissues. There are several types of melanoma, defined by where they first appear, including skin and eye melanoma and in rare instances in the GI tract or lymph nodes. [0066] Melanoma is one of the rarer types of skin cancer but causes the majority of skin cancer related deaths. Malignant melanoma is a serious type of skin cancer. It is due to uncontrolled growth of pigment cells, called melanocytes. Despite many years of intensive laboratory and clinical research, the sole effective cure is surgical resection of the primary tumor before it achieves a Breslow thickness greater than 1 mm. Attorney Docket No.151077-00046WO [0067] Around 160,000 new cases of melanoma are diagnosed worldwide each year. About 48,000 melanoma related deaths occur worldwide per year. Malignant melanoma accounts for 75 percent of all deaths associated with skin cancer. The treatment includes surgical removal of the tumor; adjuvant treatment; chemo- and immunotherapy, or radiation therapy. The severity of melanoma is often characterized by the Clark level, which are for thin tumors and describe how deeply the cancer has spread into the skin, and the Breslow depth, which refers to the microscopic depth of tumor invasion. [0068] The following stages are identified in the progression of the melanoma disease state. Melanoma progresses from an early stage (in situ) through an invasive stage, a high risk melanoma stage, a regional metastatic stage and a distant metastatic stage with varying degrees of survivability, as set forth below. Melanoma Stages: Stage 0: Melanoma in Situ (Clark Level I), 99.9% Survival Stage I/II: Invasive Melanoma, 85-95% Survival T1a: Less than 1.00 mm primary, w/o Ulceration, Clark Level II-III T1b: Less than 1.00 mm primary, w/Ulceration or Clark Level IV-V T2a: 1.00-2.00 mm primary, w/o Ulceration Stage II: High Risk Melanoma, 40-85% Survival T2b: 1.00-2.00 mm primary, w/Ulceration T3a: 2.00-4.00 mm primary, w/o Ulceration T3b: 2.00-4.00 mm primary, w/Ulceration T4a: 4.00 mm or greater primary w/o Ulceration T4b: 4.00 mm or greater primary w/Ulceration Stage III: Regional Metastasis, 25-60% Survival N1: Single Positive Lymph Node N2: 2-3 Positive Lymph Nodes OR Regional Skin/In-Transit Metastasis N3: 4 Positive Lymph Nodes OR Lymph Node and Regional Skin/In Transit Metastases Stage IV: Distant Metastasis, 9-15% Survival M1a: Distant Skin Metastasis, Normal LDH Attorney Docket No.151077-00046WO M1b: Lung Metastasis, Normal LDH M1c: Other Distant Metastasis OR Any Distant Metastasis with Elevated LDH Based Upon AJCC 5-Year Survival with Proper Treatment [0069] Traditional therapy of melanoma involves a number of treatment options. These generally include surgery, chemotherapy, radiation therapy and immunotherapy (IL-2, other). In the case of surgery, treatment can vary and can include local excision, wide local excision, lymphadenectomy, sentinel lymph node biopsy and skin grafting. In the case of chemotherapy, a standard chemotherapeutic agent dacarbazine (DTIC) is administered to the patient in order to treat the cancer, generally through cancer cell death. In the case of radiation therapy, radiation is used as a palliative rather than a cure for melanoma. Radiation relieves bone pain and other symptoms caused by metastases to the bones, brain, and organs such as the liver. Although not curative, radiation treatment is being investigated for more widespread use in controlling other symptoms of skin cancer. In the case of immunotherapy (biologic treatment), a patient's natural immune system is raised, or other immune compositions (IL-2) are administered to the patient against the cancer. [0070] “Metastatic melanoma” refers to a progressed form of melanoma wherein the original cancer has metastasized to another area of the skin (regional or distant) or to other non-skin tissue (e.g., lungs, liver, brain, lymph system). Metastatic melanoma describes when melanoma has spread into surrounding healthy tissue and through the bloodstream, or lymphatic system, to other parts of the body. If melanoma spreads to these other areas, the cancer cells in the new tumor are still melanoma cells but the disease is called metastatic melanoma. [0071] Unlike early stages of melanoma, which can be treated successfully with early diagnosis, the prognosis for patients diagnosed with metastatic melanoma is poor, with survival rates of six to nine months. Prior to 2011, the FDA only approved two types of therapies for metastatic melanoma, interleukin 2 (IL-2) and DTIC. The methods of treatment for metastatic melanoma include radiation, immunotherapy, chemotherapy and palliative surgery. Vemurafenib (BRAF inhibitor) and ipilimumab (CTLA-4 inhibitor) were approved in 2011, and Nivolumab (PD-1 inhibitor) was approved in 2014 by US FDA for treating Attorney Docket No.151077-00046WO metastatic melanoma. However, the 5-year survival is only 35% for metastatic melanoma patients (19). [0072] The term “imaging,” “molecular imaging” or “radioimaging is used to describe methods that use the nuclear properties of matter in diagnosis and therapy, pursuant to the present invention. More specifically, the present invention relies on molecular imaging because it produces images that reflect biological processes that take place at the cellular and subcellular level. [0073] Molecular imaging is a discipline that unites molecular biology and in vivo imaging. It enables the visualization of the cellular function and the follow-up of the molecular process in living organisms without perturbing them. The multiple and numerous potentialities of this field are applicable to the diagnosis and treatment of diseases such as cancer, in the present invention, in particular, melanoma, including metastatic melanoma. This technique also contributes to improving the treatment of these disorders by optimizing the pre-clinical and clinical tests of new medication. This approach also has a major economic impact due to earlier and more precise diagnosis. [0074] Molecular imaging differs from traditional imaging in that probes labeled biomarkers are used to help image particular targets or pathways. Biomarkers interact chemically with their surroundings and in turn alter the image according to molecular changes occurring within the area of interest. This process is markedly different from previous methods of imaging which primarily imaged differences in qualities such as density or water content. This ability to image fine molecular changes opens up an incredible number of exciting possibilities for medical application, including early detection and treatment of disease, in particular, melanoma and metastatic melanoma according to the present inventive concept. [0075] There are a number of different imaging modalities that can be used for noninvasive molecular imaging, using compounds according to the present invention. Each has different strengths and weaknesses and some are more adept at imaging multiple targets or sites than others. This is important in instances where metastatic melanoma is suspected. The modalities which can be used in the present invention are varied and in the present invention principally include single photon emission computed tomography (SPECT) and positron emission tomography (PET), discussed below. Attorney Docket No.151077-00046WO [0076] The main purpose of SPECT when used in melanoma imaging pursuant to the present invention is to measure the distribution of radioisotope in skin tissue, in particular, those skin regions and other tissues where melanoma, including metastatic melanoma, is suspected. The development of computed tomography in the 1970s allowed mapping of the distribution of the radioisotopes in tissue, and led to the technique now called SPECT. [0077] The imaging agent used in SPECT emits gamma rays, as opposed to the positron emitters used in PET. There are a number of radioisotopes (such as ^99mTc, ¹¹¹In, ¹²³I, ²⁰¹Tl, ⁶⁷Ga, and ²⁰³Pb, among other gamma ray emitters) that can be used in the present invention and imaged with SPECT technology. In SPECT, where possible, by rotating the gamma camera around the area to be analyzed, a three-dimensional image of the distribution of the radiotracer may be obtained by employing filtered back projection or other tomographic techniques. The radioisotopes used in SPECT have relatively long half-lives (a few hours to a few days) making them easy to produce and relatively cheap in comparison to other radioisotopes. This represents the major advantage of SPECT as an imaging technique, as it is significantly cheaper than PET or other imaging methods such as magnetic resonance imaging (MRI). However, SPECT sometimes lacks exceptional spatial (i.e., where exactly the particle is) or temporal (i.e., did the contrast agent signal happen at a particular millisecond or not) resolution. [0078] Another imaging technique which finds particular use in the present invention is positron emission tomography (PET). In PET, a molecule is tagged with a positron emitting isotope. These positrons (β particles) interact with nearby electrons, emitting two 511,000 eV photons, directed 180 degrees apart in opposite directions. These photons are then detected by the scanner which can estimate the density of positron annihilations in a specific area. When enough interactions and annihilations have occurred, the density of the original molecule may be measured in that area. Typical radioisotopes include ¹¹C, ¹³N, ¹⁵O, ¹⁸F, ⁶⁴Cu, ⁶²Cu, ¹²⁴I, ⁷⁶Br, ⁸²Rb and ⁶⁸Ga, among others. In some embodiments, the radioisotope may be ⁶⁶Ga, ⁶⁸Ga, ⁶⁴Cu, or ⁸⁶Y. One of the major disadvantages of PET is that most of the radioisotopes must be made with a cyclotron, thus making the use of PET, in certain instances prohibitively expensive. Most of these probes also have a half life measured in minutes and hours, thus forcing Attorney Docket No.151077-00046WO the cyclotron, in many instances, to be on site. These factors can make PET sometimes prohibitively expensive, except in certain cases, which the present invention addresses in certain aspects. PET imaging does have many advantages though. First and foremost is its sensitivity: a typical PET scanner can detect between 10⁻¹¹ mol/L to 10⁻¹² mol/L concentrations. [0079] The term “effective” is used, to describe an amount of a compound, component or composition, which produces an intended effect when used within the context of its use, which may be a diagnostic method, a therapeutic method, a method to monitor the progression of therapy or other method (chemical synthesis) pursuant to the present invention. In the case of therapeutic methods, an effective amount for treating melanoma, including metastatic melanoma, is that amount which shrinks cancerous tissue (e.g., tumor), produces a remission, prevents further growth of the tumor and/or reduces the likelihood that the cancer in its early stages (in situ or invasive) does not progress further to metastatic melanoma. [0080] Noted here is that within the context of the use of the present invention, the patient will be receiving a radiation dose, which provides guidance to the amount of compound which is considered effective when used within the context of its use. A patient undergoing a nuclear medicine procedure will receive a radiation dose. Under present international guidelines it is assumed that any radiation dose, however small, presents a risk. The radiation doses delivered to a patient in a nuclear medicine investigation present a very small risk of side effects, including inducing cancer in the patient. In this respect it is similar to the risk from X-ray investigations except that the dose is delivered internally rather than from an external source such as an X-ray machine. [0081] The radiation dose from a diagnostic nuclear medicine procedure is expressed as an effective dose with units of sieverts (usually given in millisieverts, mSv). The effective dose resulting from an investigation is influenced by the amount of radioactivity administered in megabecquerels (MBq), the physical properties of the radiopharmaceutical used, its distribution in the body and its rate of clearance from the body. Attorney Docket No.151077-00046WO [0082] Effective doses can range from 6 μSv (0.006 mSv) for a 3 MBq chromium-51 EDTA measurement of glomerular filtration rate to 37 mSv or more for a 150 MBq thallium-201 non-specific tumour imaging procedure. The common bone scan with 600 MBq of technetium-99m-MDP has an effective dose of 3 mSv. Formerly, units of measurement were the Curie (Ci), being 3.7E10 Bq, and also 1.0 grams of radium (Ra- 226); the rad (radiation absorbed dose), now replaced by the Gray; and the rem (röntgen equivalent man), now replaced with the Sievert. The rad and rem are essentially equivalent for almost all nuclear medicine procedures, and only alpha radiation will produce a higher Rem or Sv value, due to its much higher relative biological effectiveness (RBE). [0083] The term “coadministration” or “combination therapy” is used to describe a therapy in which at least two active compounds (one of which is a compound according to the present inventive concept) in effective amounts are used to treat melanoma, including metastatic melanoma as otherwise described herein at the same time. Although the term coadministration preferably includes the administration of two active compounds to the patient at the same time, it is not necessary that the compounds be administered to the patient at the same time, although effective amounts of the individual compounds will be present in the patient at the same time. Compounds according to the present inventive concept may be administered with one or more compounds including a chemotherapeutic agent such as dacarbazine (DTIC), an immunotherapeutic agent such as, e.g., IL-2 and/or α-interferon, and/or an immune checkpoint inhibitor (ICI) or inhibitors (ICIs), capable of blocking, e.g., PD-1, PD-L1, and/or CTLA4 and enable T cells to kill melanoma cells, such as, e.g., (anti-PD-1 + anti- CTLA-4) or (anti-PD-L1 + anti-CTLA-4), among other compounds. [0084] The term “treating” or “successfully treating” when used in the context of treating melanoma, including metastatic melanoma, shall include shrinking a tumor, curing melanoma, including melanoma which has metastasized (by causing a remission of the cancer in the patient) or reducing the likelihood or preventing the spread of the melanoma into other organs. Melanoma, including metastatic melanoma, may be treated using compounds according to the present invention alone, or in combination with other methods and/or compounds including surgery, chemotherapy (such as the Attorney Docket No.151077-00046WO use of the chemotherapeutic agent dacarbazine or DTIC), radiation therapy (i.e., with agents other than the present therapeutic compositions) and immunotherapy (IL-2 and/or α-interferon, or an ICI or ICIs, e.g., (anti-PD-1 + anti-CTLA-4) or (anti-PD-L1 + anti-CTLA-4)). Compositions [0085] In embodiments of the inventive concept, the basic compound and in particular, the radiometal chelator group as described above, is complexed with a radioisotope for purposes of being used in the diagnosis or therapy of melanoma, including metastatic melanoma, the invention relates to compounds and their pharmaceutically acceptable salts. [0086] Compounds and methods for diagnosing and treating melanoma have been described previously, for example, in U.S. Patent Nos.8,986,651, 10,047,135, and 10,464,985, incorporated herein by reference. Embodiments of the present inventive concept relate to novel therapeutic and diagnostic agents, such as theranostic agents, for the diagnosis and treatment of melanoma, for example, but not limited to, metastatic melanoma. In some embodiments, the agents of the inventive concept include theranostics including peptides for targeting the melanocortin-1 receptor (MC1R). In- human results clearly demonstrate MC1R as a clinically relevant molecular target (50). In some embodiments, the peptides of the inventive concept may be for use in imaging- guided melanocortin-1-receptor-targeted radionuclide therapy (MC1R-TRT) for melanoma treatment. In some embodiments, the peptides of the inventive concept may be for use in MC1R-TRT in combination with immune checkpoint inhibitors (ICIs) for melanoma treatment. In some embodiments, the combination of MC1R-TRT and ICIs may be used to treat melanoma more effectively than may be accomplished with MC1R-TRT only. [0087] Other embodiments of the present inventive concept include novel imaging tools (for example, a ²⁰³Pb-peptide) to identify MC1R-positive patients who can benefit from the treatments, determine patient-specific dosimetry for safe and efficacious doses, and monitor patient response to treatments (MC1R-TRT and ICIs). Embodiments of the present inventive concept can provide patients with personalized Attorney Docket No.151077-00046WO diagnoses and treatments that enhance the opportunity to cure metastatic melanoma patients. [0088] Embodiments of the present inventive concept include novel peptides, for example, DOTA–Linker–Nle–CycMSH_hex(KD) peptides, and the novel peptides associated with radionuclides, such as ²⁰³Pb and/or ²¹²Pb (²⁰³Pb/²¹²Pb-DOTA–Linker– Nle–CycMSHh_ex(KD) peptides), that can be used for imaging-guided MC1R-TRT and in combination with ICIs for melanoma treatment. Although synthesis and radiolabeling methods used in preparation of embodiments of the present inventive concept are conventional, the DOTA–Linker–Nle–CycMSH_hex(KD) peptides of the present inventive concept are novel and exhibit superior characteristics than those presently available. The theranostic approach of the inventive concept is innovative in that it uses novel MC1R-targeted DOTA–Linker–Nle–CycMSH_hex(KD) peptides to precisely deliver imaging-guided alpha radiation (²¹²Pb decays to ²¹²Bi, the decay of ²¹²Bi yields α- particles) to melanoma for treatment, as well as is innovative in that it uses a diagnostic ²⁰³Pb-peptide to enhance the success of treatment by selecting MC1R-positive patients. The combinations of MC1R-TRT and ICIs of the inventive concept are further innovative in taking advantage of additive therapeutic effects of MC1R-TRT and ICIs on melanoma, enhancing the opportunity for cure to metastatic melanoma patients. [0089] Embodiments of the present inventive concept relate to compounds of the general structure: (Y¹)_q–X_m–(ABC)_n–CycMSH_hex(KD) [0090] wherein: [0091] Y¹ is a chelate/chelating group, wherein Y¹ optionally associates, incorporates and/or complexes with a radioisotope, or is an optical tag; [0092] X is absent, or is: an amino acid residue, for example, a neutral amino acid, such as norleucine (Nle), leucine (leu), isoleucine (Ile), glycine (Gly), or alanine (Ala), which may be optionally acylated at its amino terminal end; or an amino acid linker comprising an alkylene group or an ethylene glycol containing group of the chemical structure: Attorney Docket No.151077-00046WO –NH–(CH2)_p–(C=O)– –NH–(CH2)_s–(CH2CH2O)_k–(CH2)_i–(C=O)–; [0093] ABC is an amino acid linker, wherein: [0094] A is absent or a neutral or negatively charged amino acid at physiological pH which is optionally acylated at its amino terminal end; [0095] B is a neutral or negatively charged amino acid at physiological pH which is optionally acylated at its amino terminal end; and [0096] C is absent or a neutral or negatively charged amino acid at physiological pH; [0097] m is an integer from 0 to 250; [0098] n is 0 or 1; [0099] p is an integer from 0 to 20; [00100] s is an integer from 0 to 10; [00101] k is an integer from 0 to 10; [00102] i is an integer from 0 to 10; [00103] q is 0 or 1; and [00104] CycMSH_hex(KD) is a cyclic peptide comprising six amino acids of the general structure:

[00105] wherein: [00106] W is a C–H group from a lysine of ornithine residue, wherein the alkylene amine sidechain from the lysine (Lys) or ornithine (Orn) and an alkylene carboxylic acid sidechain of Z¹ are bonded together to form an amide linkage; Attorney Docket No.151077-00046WO [00107] X¹ is L- or D- phenylalanine (Phe), tyrosine (Tyr), or tryptophan (Trp); [00108] Y is arginine (Arg) or lysine (Lys); [00109] Z is Trp, Phe, or Tyr; [00110] Z¹ is Asp(CONH2) or Glu(CONH2); [00111] Z² is a side chain –(C=O)– from the Asp or Glu of Z¹; [00112] j is 3 if W is the C–H group from Orn or 4 if W is the C–H group from Lys, [00113] or a pharmaceutically acceptable salt thereof, [00114] wherein said compound, or pharmaceutically acceptable salt thereof, is optionally complexed with at least one radioisotope. [00115] In some embodiments, X is Nle. In some embodiments, X is Gly. In some embodiments, the amino acid X is C2–C20 acylated at the amino terminal. In some embodiments, X is a –NH–(CH2)7–(C=O)– (8-aminooctanoic acid) group. [00116] In some embodiments, when X is absent, ABC is GlyGlyNle, GlyGlyGlyNle, GlySerGlyNle, or PEG2Nle. In some embodiments, when ABC is Nle if X is a –NH– (CH2)7–(C=O)– group. [00117] In some embodiments, m is 0–5. In some embodiments, m is 0 or 1. In some embodiments, n is 0 or 1. In some embodiments, n is 1. In some embodiments, p is 0– 10. In some embodiments, p is 7. In some embodiments, k is 1 or 2. In some embodiments, i is 1 or 2. In some embodiments, s is 0, 1, or 2. In some embodiments, s is 0. In some embodiments, q is 0 or 1. In some embodiments, q is 1. [00118] In some embodiments, X¹ is D-Phe. [00119] In some embodiments, Y is Arg. [00120] In some embodiments, Z is Trp. [00121] In some embodiments, Z¹ is Asp, and Z² is the side chain –(C=O)– from the Asp of Z¹. [00122] In some embodiments, j is 4, and W is the C–H from Lys. [00123] In some embodiments, the at least one radioisotope is a polyvalent cationic radioisotope. In some embodiments, the radioisotope is selected from the group consisting of ⁸⁶Y, ⁹⁰Y, ¹¹¹In, ¹⁷⁷Lu, ²²⁵Ac, ²¹²Bi, ²¹³Bi, ⁶⁶Ga, ⁶⁷Ga, ⁶⁸Ga, ⁶⁴Cu, ⁶⁷Cu, ⁷¹As, ⁷²As, ⁷⁶As, ⁷⁷As, ⁶⁵Zn, ⁴⁸V, ²⁰³Pb, ²⁰⁹Pb, ²¹²Pb, ¹⁶⁶Ho, ¹⁴⁹Pm, ¹⁵³Sm, ²⁰¹Tl, ¹⁸⁸Re, ¹⁸⁶Re, and ^99mTc. In some embodiments, the radioisotope is ²⁰³Pb and/or ²¹²Pb. In some Attorney Docket No.151077-00046WO embodiments, the radioisotope may be for imaging/diagnosis, for example, detecting/selecting for MC1R-positive patients. in some embodiments, the radioisotope may be for treatment, for example, melanoma treatment. [00124] In some embodiments, a compound of the inventive concept incorporates or is complexed with a radioisotope, for example, as otherwise set forth herein. In some embodiments Y¹ is a radiometal chelator, and is a radical (a group, linked to a linker or peptide as otherwise set forth herein) of 1,4,7,10-tetraazacyclododecane-1,4,7,10- tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 1,4,7- triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA), 6-hydrazinonicotinic acid (HYNIC), 2-[4,7,10-tris(2-amino-2-oxoethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetic acid (DO3AM), 2-[4,7,10-tris(2-amino-2-oxoethyl)-6-[(4-isothiocyanatophenyl)methyl]- 1,4,7,10-tetrazacyclododec-1-yl]acetamide (TCMC-pBz-NCS), or [4-(Carbamoylmethyl)- 7,10-bis(carboxymethyl)-1,4,7,10-tetraaza-1-cyclododecyl]acetic acid (PSC). Other chelating groups/moieties that can complex with radioisotopes include those described, for example, in U.S. Patent Nos.8,986,651, 10,047,135, and 10,464,985. [00125] In some embodiments, Y¹ is an optical tag, for example, a radical (a group, linked to a linker or peptide as otherwise set forth herein) of a salt of 6-[(2E)-1,1- dimethyl-2-[(2E,4E)-5-(1,1,3-trimethylbenzo[e]indol-3-ium-2-yl)penta-2,4- dienylidene]benzo[e]indol-3-yl]hexanoic acid (Cy5.5). [00126] In some embodiments, Y¹ is a DOTA radical, i.e., a DOTA group, according to the structure: [00127] In some embodiments, CycMSH_hex(KD) is a cyclic peptide comprising six amino acids of the general structure:

Attorney Docket No.151077-00046WO [00128] wherein: [00129] W is a C–H group from a lysine or ornithine residue, wherein the alkylene amine sidechain from the lysine (Lys) or ornithine (Orn) residue and an alkylene carboxylic acid sidechain of Z¹ are bonded together to form an amide linkage; [00130] X¹ is L- or D-phenylalanine (Phe), tyrosine (Tyr), or tryptophan (Trp); [00131] Y is arginine (Arg) or lysine (Lys); [00132] Z is Trp, Phe, or Tyr; [00133] Z¹ is Asp(CONH2) or Glu(CONH2); and [00134] j is 3 if W is the C–H group from Orn or 4 if W is the C–H group from Lys. [00135] In some embodiments, CycMSH_hex(KD) is a cyclic peptide comprising six amino acids of the general structure:

[00136] wherein X¹, Y, and Z are defined as described hereinabove. [00137] In some embodiments, CycMSH_hex(KD) is a cyclic peptide comprising six amino acids according to the structure:

(SEQ ID NO:10). Attorney Docket No.151077-00046WO [00138] In some embodiments, the N-terminal amino acid (Orn or Lys of CycMSH_hex(KD)) is linked to Nle. [00139] In some embodiments of the above-described compounds, n is 0, or when n is 1, ABC may be a one, two, or three amino acid unit linker (A or C may be absent) wherein one, and in certain embodiments, two or three (in some embodiments, no more than two) of the amino acid units are negatively charged at physiological pH, e.g. aspartic or glutamic acid, for example, glutamic acid. In some embodiments, ABC may include a polar amino acid, for example, serine. In other embodiments, ABC is a three amino acid unit linker wherein no more than one, i.e., zero or one of the amino acid units is negatively charged at physiological pH, and the other amino acid units are neutral at physiological pH. In some embodiments, the neutral amino acid is norleucine, leucine, glycine or alanine, for example, norleucine or glycine. In some embodiments, ABC is norleucine (Nle). [00140] In some embodiments, X, when present, X may be a neutral amino acid, for example, norleucine, leucine, glycine, or alanine, or an alkylene or ethylene glycol containing amino acid linker according to the structure: –NH–(CH2)_p–(C=O)– or –NH–(CH₂)_s–(CH₂CH₂O)_k–(CH₂)_i–(C=O)–, [00141] as shown above, where p, s, k and i are as otherwise described hereinabove. It is noted that compounds according to the present invention which contain an ABC amino acid linker (as opposed to those without a linker, i.e., n is 0) and especially a linker having at least one negatively charged amino acid (e.g., aspartic acid or glutamic acid), often exhibit less renal uptake and consequently enhanced pharmacokinetics (longer half-life in vivo) than do compounds according to the present invention which do not contain such linkers. AB linkers (where C is absent) wherein A is glycine or alanine, especially glycine and wherein B is glutamic acid or aspartic acid may also be preferred. In still other embodiments, ABC linkers wherein A is glycine, serine or norleucine, B is glycine, glutamic acid or aspartic acid and C is glutamic acid (especially when B is Attorney Docket No.151077-00046WO glycine) or norleucine (when B is glutamic acid or glycine) may also be preferred. In still other embodiments, when A and C are each absent, B is norleucine (Nle), leucine or isoleucine. In some embodiments, ABC is norleucine (Nle), for example, when m is 0, or X is a PEG linker (e.g., a PEG2 linker), or an 8-octanoic acid (Aoc) linker as otherwise described herein. [00142] Accordingly, in some embodiments, ABC may be GlyGly, GlyGlyGly, GlySerGly, Nle, GlyGlyNle, SerGlyNle, GluGlyNle, AspGlyNle, GlyGluNle, or NleGlyGlu. In some embodiments, XABC groups (i.e., where m and n are both 1) may include, for example, GlyGlyNle, GlyGlyGlyNle, GlySerGlyNle, GlyAspGlyNle, GlyGluGlyNle, PEG₂Nle, and AocNle linkers. [00143] In some embodiments, Y¹ is a DOTA, NOTA, NODAGA, HYNIC, DO3AM, TCMC-pBz-NCS, or PSC group, optionally complexed with a radioisotope as otherwise described herein. [00144] In some embodiments, Y¹ is a DOTA group, optionally complexed with a radioisotope as otherwise described herein. [00145] In some embodiments, compounds according to the present inventive concept, DOTA–X_m–(ABC)_n–CycMSH_hex(KD), are represented by the chemical structure:

[00146] In some embodiments, compounds according to the present inventive concept, DOTA–GlyGly–Nle–CycMSH_hex(KD), are represented by the chemical structure: Attorney Docket No.151077-00046WO

[00147] In some a to present concept, DOTA–GlyGly–Nle–CycMSH_hex(KD) is represented by the chemical structure:

[00148] In some embodiments, compounds according to the present inventive concept, DOTA–(CH₂)₇–(C=O)–Nle–CycMSH_hex(KD) are represented by the chemical structure, wherein X is a –NH–(CH2)7–(C=O)– (8-amino octanoic acid, Aoc) group and ABC is Nle: Attorney Docket No.151077-00046WO

[00149] In some embodiments, a compound according to the present inventive concept, DOTA–NH–(CH₂)₇–(C=O)–Nle–CycMSH_hex(KD) is represented by the chemical structure:

[00150] In some embodiments, the present inventive concept relates to the above compounds, including pharmaceutically acceptable salts, wherein the compound, especially the Y group, is complexed with a radioisotope (which may be a neutral species or a cationic species, and is preferably a polyvalent cationic species) selected from the group consisting of ⁸⁶Y, ⁹⁰Y, ¹¹¹In, ¹⁷⁷Lu, ²²⁵Ac, ²¹²Bi, ²¹³Bi, ⁶⁶Ga, ⁶⁷Ga, ⁶⁸Ga, ⁶⁴Cu, ⁶⁷Cu, ⁷¹As, ⁷²As, ⁷⁶As, ⁷⁷As, ⁶⁵Zn, ⁴⁸V, ²⁰³Pb, ²⁰⁹Pb, ²¹²Pb, ¹⁶⁶Ho, ¹⁴⁹Pm, ¹⁵³Sm, ²⁰¹Tl, ¹⁸⁸Re, ¹⁸⁶Re, and ^99mTc. [00151] In some embodiments, Y¹ is a radiometal chelator, for example, a DOTA moiety, which may be complexed with a radioisotope R_i, wherein R_i is a radioisotope Attorney Docket No.151077-00046WO (which may be a neutral species or a cationic species, and is preferably a polyvalent cationic species) selected from the group consisting of ⁸⁶Y, ⁹⁰Y, ¹¹¹In, ¹⁷⁷Lu, ²²⁵Ac, ²¹²Bi, ²¹³Bi, ⁶⁶Ga, ⁶⁷Ga, ⁶⁸Ga, ⁶⁴Cu, ⁶⁷Cu, ⁷¹As, ⁷²As, ⁷⁶As, ⁷⁷As, ⁶⁵Zn, ⁴⁸V, ²⁰³Pb, ²⁰⁹Pb, ²¹²Pb, ¹⁶⁶Ho, ¹⁴⁹Pm, ¹⁵³Sm, ²⁰¹Tl, ¹⁸⁸Re, ¹⁸⁶Re, and ^99mTc. [00152] Radioisotopes may be selected based on the physical half-life, the decay mode (alpha, beta, auger, gamma, X-ray) and the energy of the radioisotope. In diagnostic aspects of the present invention, in some embodiments, radioisotopes include, for example, ¹¹¹In, ⁸⁶Y, ⁶⁶Ga, ⁶⁷Ga, ²⁰³Pb, ²¹²Pb, ⁶⁴Cu, and ^99mTc. [00153] In embodiments where compounds are to be analyzed using positron emission tomography or PET imaging, they are labeled with a positron emitting radioisotopes such as: ¹⁸F, ⁶⁶Ga, ⁶⁸Ga, ⁶⁴Cu, ⁸⁶Y, or other polyvalent, cationic radiometals that decay by positron emission. In other embodiments, the compounds may be analyzed using single photon emission computed tomography or SPECT imaging when labeled with a gamma radiation emitting radioisotope which preferably includes ¹¹¹In, ⁶⁷Ga, ^99mTc and ²⁰³Pb, or other gamma emitting radioisotopes as described herein. [00154] The present inventive concept relates to compounds and/or compositions which may be used to prepare imaging/therapeutic agents or as imaging/therapeutic agents (when complexed with a radioisotope) for diagnosing and treating melanoma, including metastatic melanoma as otherwise described herein. Compounds according to the present invention which are complexed with an appropriate radioisotope may be used to diagnose the existence and/or extent of melanoma, including metastatic melanoma, monitor therapy as a therapeutic aid of melanoma, including metastatic melanoma, and in certain instances, function as a therapeutic agent (peptide targeted radiation) for the treatment of melanoma, including metastatic melanoma. [00155] The present inventive concept also relates to pharmaceutical compositions comprising an effective amount of a compound for diagnostic and/or therapeutic purposes in combination with a pharmaceutically acceptable carrier, additive or excipient in pharmaceutical dosage form. For diagnostic purposes pharmaceutical compositions are formulated generally in parenteral dosage form, especially for intravenous administration, although oral or topical formulations may be useful in certain Attorney Docket No.151077-00046WO instances. In the case of the use of compounds according to the present inventive concept for therapeutic purposes, the compositions are formulated preferably in parenteral or topical dosage forms, although orally administered dosage forms are also useful. [00156] The compounds of the present inventive concept may, in accordance with the inventive concept, be administered in single or divided doses by the oral, parenteral or topical routes. Administration of the active compound may range from a single intravenous injection to continuous (intravenous drip) to several oral administrations per day (for example, Q.I.D.) and may include oral, topical, parenteral, intramuscular, intravenous, sub-cutaneous, transdermal (which may include a penetration enhancement agent), buccal, sublingual and suppository administration, among other routes of administration. Enteric coated oral tablets may also be used to enhance bioavailability of the compounds from an oral route of administration. The most effective dosage form will depend upon the pharmacokinetics of the particular agent chosen as well as the severity of disease in the patient. Administration of compounds according to the present inventive concept as sprays, mists, or aerosols for intra-nasal, intra-tracheal or pulmonary administration may also be used. The present inventive concept therefore also is directed to pharmaceutical compositions comprising an effective amount of compound according to the present inventive concept, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient. [00157] The amount of compound used is that amount effective within the context of the administration, whether that administration is for diagnostic purposes or therapeutic purposes. A suitable oral dosage for a compound according to the present inventive concept would be in the range of about 0.01 mg to 10 g or more per day, preferably about 0.1 mg to about 1 g per day. In parenteral formulations, a suitable dosage unit may contain from 0.1 to 250 mg of said compounds, which may be administered from one to four times per day (for diagnostic purpose, preferably once in a bolus dose), whereas for topical administration, formulations containing 0.01 to 1% active ingredient are preferred. It should be understood, however, that the dosage administration from patient to patient will vary and the dosage for any particular patient will depend upon the Attorney Docket No.151077-00046WO clinician's judgment, who will use as criteria for fixing a proper dosage the size and condition of the patient as well as the patient's response to the drug. [00158] When the compounds of the present inventive concept are to be administered by the oral route, they may be administered as medicaments in the form of pharmaceutical preparations which contain them in association with a compatible pharmaceutical carrier, additive or excipient material. Such carrier material can be an inert organic or inorganic carrier material suitable for oral administration. Examples of such carrier materials are water, gelatin, talc, starch, magnesium stearate, gum arabic, vegetable oils, polyalkylene-glycols, petroleum jelly and the like. [00159] The pharmaceutical preparations can be prepared in a conventional manner and finished dosage forms can be solid dosage forms, for example, tablets, dragees, capsules, and the like, or liquid dosage forms, for example solutions, suspensions, emulsions and the like. [00160] The pharmaceutical preparations may be subjected to conventional pharmaceutical operations such as sterilization. Further, the pharmaceutical preparations may contain conventional adjuvants such as preservatives, stabilizers, emulsifiers, flavor-improvers, wetting agents, buffers, salts for varying the osmotic pressure and the like. Solid carrier material which can be used include, for example, starch, lactose, mannitol, methyl cellulose, microcrystalline cellulose, talc, silica, dibasic calcium phosphate, and high molecular weight polymers (such as polyethylene glycol). [00161] For parenteral use, a compound according to the present inventive concept can be administered in an aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable oil or a mixture of liquids, which may contain bacteriostatic agents, antioxidants, preservatives, buffers or other solutes to render the solution isotonic with the blood, thickening agents, suspending agents or other pharmaceutically acceptable additives. Additives of this type include, for example, tartrate, citrate and acetate buffers, ethanol, propylene glycol, polyethylene glycol, complex formers (such as EDTA), antioxidants (such as sodium bisulfite, sodium metabisulfite, and ascorbic acid), high molecular weight polymers (such as liquid polyethylene oxides) for viscosity regulation and polyethylene derivatives of sorbitol anhydrides. Preservatives may also be added if necessary, such as benzoic acid, Attorney Docket No.151077-00046WO methyl or propyl paraben, benzalkonium chloride and other quaternary ammonium compounds. In certain preferred diagnostic and/or therapeutic embodiments, compounds according to the present inventive concept are administered intravenously in sterile saline solution. [00162] The compounds of this inventive concept may also be administered as solutions for nasal application and may contain in addition to the compounds of this inventive concept suitable buffers, tonicity adjusters, microbial preservatives, antioxidants and viscosity-increasing agents in an aqueous vehicle. Examples of agents used to increase viscosity are polyvinyl alcohol, cellulose derivatives, polyvinylpyrrolidone, polysorbates or glycerin. Preservatives added may include benzalkonium chloride, chloro-butanol or phenylethyl alcohol, among numerous others. [00163] Additionally, the compounds provided by the inventive concept can be administered by suppository. [00164] In certain aspects according to the present inventive concept, where various cancers are to be treated, the compounds may be co-administered with at least one other anti-cancer agent, such as a chemotherapeutic agent, for example, dacarbazine (DTIC), or an immunotherapeutic agent, for example, such as IL-2 and/or α-interferon, or an ICI or ICIs as otherwise described herein. In addition, compounds according to the present inventive concept may be administered prior to, during or after surgery to remove melanoma tissue. [00165] Preparation of compounds according to the present inventive concept proceeds using standard synthetic chemical techniques which are readily available in the art. Synthetic methods for obtaining compounds related to the present inventive concept may be found in the examples section of the present specification. These methods can serve as guides for obtaining compounds according to the present inventive concept. In general, the present compounds may be made by condensing an activated DOTA or other chelating group (containing a leaving group or using a coupling agent to facilitate the binding of the carboxyl group on DOTA or other chelating group to the amine terminal group of the amino acid linker (including, in certain cases, the lysine side chain amine group) or, in the case where the linker is absent directly to the amine group of the cyclic peptide (CycMSH_hex(KD)) The radionuclide may be complexed to the Attorney Docket No.151077-00046WO chelate (DOTA) group either before or after the activated chelate (DOTA) group is condensed onto the linker-Cyclic peptide or directly onto the Cyclic peptide (linker not present). The linker-cyclic peptide and/or the cyclic peptide with no linker is synthesized using conventional peptide synthesis (as otherwise described in the examples section or using methods readily available in the art using protecting group chemistry) and the various condensation and other reactions, etc. are readily performed using methods described herein or otherwise as readily known in the art. See, e.g., FIG.1 for an exemplary synthetic approach, or as previously described (45). Other approaches will be readily recognized to those of ordinary skill in the art. [00166] Once the compounds are synthesized, they may be formulated in pharmaceutical dosage form using conventional pharmaceutical formulation methods readily available in the art by simply admixing compounds with chosen carriers, additives and/or excipients, depending upon the dosage form to be used and depending upon the use (diagnostic or therapeutic) of the compositions. Methods [00167] In the diagnostic method according to the present inventive concept, a compound according to the present inventive concept is administered to a patient, and evidence of elevated expression of MC1Rs in tissue of said patient through standard well-known nuclear imaging techniques, especially radiation (radionuclide) imaging, including scintigraphic imaging, and especially single photon emission computed tomography (SPECT) and positron emission tomography (PET) in comparison to a normal standard, is indicative of a disease state (melanoma) and extent of disease state (metastasis) in the tissue of the patient. The nuclear imaging techniques useful in the present diagnostic methods are well known in the art. In general, elevated levels of radiation emanating from a diagnosed tissue is evidence of elevated MSH receptor activity and indicative of a disease state or condition (melanoma and/or metastatic melanoma) wherein these receptors are found at elevated levels. Methods of diagnosing the existence and/or extent (stage) of melanoma, including metastatic melanoma, are therefore additional aspects of the present inventive concept. Thus, a diagnostic method of diagnosing the existence or absence of melanoma in a patient at Attorney Docket No.151077-00046WO risk for melanoma comprises administering to said patient a compound according to the present inventive concept; imaging said patient to determine if tissue in said patient exhibits elevated expression of MC1Rs; and diagnosing said patient as having melanoma, including metastatic melanoma if said tissue evidences elevated expression of MSH receptors in comparison to a standard. [00168] Methods of monitoring the treatment of melanoma, including metastatic melanoma in conjunction with traditional or experimental melanoma therapy is an additional aspect of the inventive concept. In this aspect, a patient's response to therapy is monitored using the methods according to the present inventive concept. In this method, a patient is monitored before and after therapy by administering compound according to the present inventive concept and determining (through imaging diagnostics as otherwise described herein) the extent of expression of melanocyte stimulating hormone receptors in tissues of a patient before therapy and after therapy and comparing the expression levels with each other and/or with a standard (predetermined value) to determine the extent of reduction of cancer tissue which occurred pursuant to the therapeutic intervention. [00169] Methods of treating melanoma represent a further embodiment of the inventive concept. In this embodiment, compounds according to the present inventive concept as described above may be administered to a patient known to have melanoma and/or metastatic melanoma in effective amounts in order to reduce cancer tissue and otherwise treat the patient's cancer through targeted radiation therapy. The present therapeutic methods may be used alone or in combination with other treatment methods (surgery, chemotherapy, radiation therapy and/or immunotherapy (IL-2, α-interferon, and ICIs) for melanoma/metastatic melanoma as otherwise disclosed herein. In some embodiments of the therapeutic methods of the present inventive concept, compounds according to the present inventive concept are complexed with a radioisotope, for example, ⁶⁷Cu, ⁹⁰Y, ¹⁷⁷Lu, ¹⁸⁶Re, ¹⁸⁸Re, ²¹²Bi, ²¹³Bi, ²¹²Pb, ¹⁴⁹Pm, ¹⁶⁶Ho and ¹⁵³Sm and are administered to the patient (intravenously or topically, i.e., directly onto the melanoma tissue in the skin of the patient) in order to target the malignant melanoma tumor, including metastatic melanoma tissue with radiation therapy. Attorney Docket No.151077-00046WO [00170] The following examples are provided to assist in describing the present inventive concept. The details of these examples and the general description of the examples are for description purposes only and should be seen or taken to limit the scope of the inventive concept in any way. EXAMPLES Example 1. Melanocortin-1 receptor (MC1R) is a clinically relevant molecular target for developing novel MC1R-targeted theranostic (diagnostic and therapeutic) peptides for melanoma. [00171] Melanocortin-1 receptor (MC1R) is a G protein-coupled receptor (24-30) which is over-expressed on >80% of melanotic and amelanotic human metastatic melanoma (29). The MC1R densities are 7,000 and 2,880 receptors/cell for B16/F1 and B16/F10 murine melanoma cells (31, 32), and 5,700 and 1,280 receptors/cell for TXM13 and M21 human melanoma cells (33). Meanwhile, human keratinocytes and fibroblasts do not show detectable MC1R expressions, whereas melanocytes display relatively low MC1R levels (<700 receptors/cell) (27). Thus, the MC1R is a distinct molecular target for developing novel MC1R-targeted theranostic peptides for melanoma. [00172] Wild-type alpha-melanocyte-stimulating hormone (α-MSH) is a linear peptide (Ac–Ser¹–Tyr²–Ser³–Met⁴–Glu⁵–His⁶–Phe⁷–Arg⁸–Trp⁹–Cys¹⁰–Lys¹¹–Pro¹²–Val¹³–NH₂, SEQ ID NO:11). The motif of His⁶–Phe⁷–Arg⁸–Trp⁹ (SEQ ID NO:12) is the MC1R binding sequence. Radiolabeled α-MSH peptides for melanoma imaging have been developed previously (34–49). CycMSH_hex peptides have been described previously (see, e.g., US Patent Nos.8,603,435, 8,986,651, 9,393,330, and 9,493,537).⁶⁸Ga– DOTA–GlyGly–Nle–CycMSH_hex (SEQ ID NO:3, complexed with ⁶⁸Ga) can target MC1Rs for positron emission tomography (PET) imaging of melanoma metastases in brain, lung, connective tissue and intestine of a patient (FIG.2). These human results clearly demonstrate the feasibility of using a MC1R-targeted CycMSH_hex peptide for human melanoma imaging (50). Attorney Docket No.151077-00046WO Strategy to combine MC1R-targeted radionuclide therapy (MC1R-TRT) with immune checkpoint inhibitors (ICIs) for melanoma treatment [00173] DOTA–GlyGly–Nle–CycMSH_hex (SEQ ID NO:3) is cyclized by the Asp-Lys (DK) lactam (FIG.2) and displays 2.1 nM MC1R binding affinity on B16/F1 melanoma cells (50). However, switching from Asp-Lys (DK) to Lys-Asp (KD) cyclization improved the MC1R binding affinity of DOTA–GlyGly–Nle–CycMSH_hex(KD) (SEQ ID NO:2 with DOTA group attached) to 0.12 nM, an 8.3-fold improvement in binding affinity as compared to DOTA–GlyGly–Nle–CycMSH_hex described previously. Moreover, the replacement of –GlyGly– with an 8-aminooctanoic acid (–Aoc–) linker further improved the MC1R binding affinity of DOTA–AocNle–CycMSH_hex(KD) (SEQ ID NO:4 with DOTA group attached through an –Aoc– linker) to 0.032 nM. Such remarkable improvements on MC1R has lead us to develop novel theranostic ²⁰³Pb/²¹²Pb-DOTA–Linker–Nle– CycMSH_hex(KD) (SEQ ID NO:4, with DOTA group attached through a linker and complexed with ²⁰³Pb/²¹²Pb) peptides for imaging-guided MC1R-targeted radionuclide therapy (MC1R-TRT), and then combine MC1R-TRT with immune checkpoint inhibitors [ICIs: (anti-PD-1 + anti-CTLA-4) or (anti-PD-L1 + anti-CTLA-4)] for melanoma treatment (FIG.3). [00174] Novel theranostic ²⁰³Pb/²¹²Pb-DOTA–Linker–Nle–CycMSH_hex(KD) peptides can be used for imaging-guided MC1R-targeted radionuclide therapy (MC1R-TRT), and the combinations of MC1R-TRT and ICIs [(anti-PD-1 + anti-CTLA-4) or (anti-PD-L1 + anti-CTLA-4)] can treat melanoma more effectively than MC1R-TRT only (FIG.3). Through our initial studies, we have determined that the linker is a key factor in the peptide due to its favorable effect on MC1R binding affinity. Thus, linkers that improve melanoma uptake and modify the clearance properties of ²⁰³Pb/²¹²Pb-DOTA–Linker– Nle–CycMSH_hex(KD) peptides are used, and the therapeutic efficacies of the selected ²¹²Pb-DOTA–Linker–Nle–CycMSH_hex(KD) (SEQ ID NO:4 with DOTA group attached through a linker and complexed with ²¹²Pb) peptide with ICIs on human melanoma- bearing mice are examined (FIG.3). [00175] The research design takes advantage of 1). MC1R-targeted delivery of new theranostic ²⁰³Pb/²¹²Pb-DOTA–Linker–Nle–CycMSH_hex(KD) peptides to melanoma cells for imaging-guided MC1R-TRT.2). Combinations of MC1R-TRT and ICIs to improve the Attorney Docket No.151077-00046WO therapeutic efficacy of melanoma. High MC1R-specific B16/F1 melanoma uptake of ²⁰³Pb-DOTA–GlyGly–Nle–CycMSH_hex(KD) (SEQ ID NO:2 with DOTA attached and complexed with ²⁰³Pb) has been demonstrated herein.²⁰³Pb (T_1/2 = 51.9 h, 279 keV γ- emissions for imaging) and ²¹²Pb (T1/2 = 10.6 h, ²¹²Pb decays to ²¹²Bi, the decay of ²¹²Bi yields 6.1 and 8.8 MeV α-particles for therapy) are matched-pair theranostic radionuclides that share identical radiolabeling chemistry. The ²⁰³Pb-peptide (SEQ ID NO:2 with DOTA group attached and complexed with ²⁰³Pb) imaging can be used to identify MC1R-positive patients for therapy and obtain patient-specific dosimetry, whereas the ²¹²Pb-peptide (SEQ ID NO:2 with DOTA group attached and complexed with ²¹²Pb) can be used as targeted alpha therapy for MC1R-positive patients. The follow-up ²⁰³Pb-peptide imaging after treatments can monitor patient response and guide physicians to modify the therapy regimens accordingly. Second, ²¹²Pb is an attractive alpha therapy radionuclide that can be readily obtained from a ²²⁴Ra/²¹²Pb generator (FIG.4). Alpha-particles are helium ions (5-9 MeV) with high linear energy transfer (LET) over short path lengths (30-90 µm) (51, 52). Only a few α-particle traversals per cell are needed to cause cell death (53). Importantly, the cytotoxicity of α- particle is independent of dose rate (52) and unaffected by tissue oxygen level (54), which allows effective irradiation to hypoxic tumors. High LET of α-particles in short range can yield highly specific destruction within tumors, while minimizing collateral damage of healthy tissues. Essentially, ²¹²Pb serves as an “in vivo generator” to produce therapeutic alpha-particles via ²¹²Bi decay. Third, the remarkable improved melanoma uptake of our ²⁰³Pb-peptide (FIG.5) and the promising survival of B16/F10 melanoma mice treated by ²¹²Pb-VMT01 and ICIs (23) underscore the potential of the combinations of MC1R-TRT and ICIs for improving melanoma treatment. Theranostic peptide development [00176] MC1R-targeted theranostic ²⁰³Pb/²¹²Pb-DOTA–GlyGly–Nle–CycMSH_hex peptides have been developed and combined MC1R-TRT and ICIs for melanoma treatment (FIG.2). The peptide design builds upon the DOTA–GlyGly–Nle– CycMSH_hex(KD) peptide identified. Results below represent the evaluation of ²⁰³Pb- DOTA–GlyGly–Nle–CycMSH_hex in B16/F1 murine melanoma-bearing mice, the dramatic Attorney Docket No.151077-00046WO improvement on B16/F1 tumor uptake of ²⁰³Pb-DOTA–GlyGly–Nle–CycMSH_hex(KD) due to Lys-Asp (KD) cyclization, and the favorable effect of 8-aminooctanoic acid (–Aoc–) linker on the MC1R binding affinity of DOTA–Aoc–Nle–CycMSH_hex(KD). These results are discussed below. ²⁰³Pb-DOTA–GlyGly–Nle–CycMSHh_ex exhibited high MC1R-mediated melanoma uptake [00177] Building on the success of ⁶⁸Ga-DOTA–GlyGly–Nle–CycMSH_hex (FIG.2), we further developed ²⁰³Pb-DOTA–GlyGly–Nle–CycMSH_hex to take advantage of theranostic properties of the²⁰³Pb/²¹²Pb pair. DOTA–GlyGly–Nle–CycMSH_hex displayed a 2.1 nM MC1R binding affinity on B16/F1 melanoma cells (MC1R-positive).²⁰³Pb-DOTA–GlyGly– Nle–CycMSH_hex (FIG.5) was readily prepared with >98% radiolabeling yield, stable in mouse serum for 4 h.²⁰³Pb-DOTA–GlyGly–Nle–CycMSH_hex exhibited high B16/F1 melanoma uptake (12.6 ± 2.3 %ID/g at 2 h post-injection) and prolonged tumor retention (9.4 ± 2.2 and 6.4 ± 0.4 %ID/g at 4 and 24 h post-injection). Co-injection of 6.1 nmol of NDP-MSH blockade (competing MC1Rs) blocked 95% of the tumor uptake at 2 h post- injection (p<0.05), demonstrating that the melanoma uptake was MC1R-mediated. The B16/F1 melanoma lesions were clearly visualized using ²⁰³Pb-DOTA–GlyGly–Nle– CycMSH_hex as an imaging probe at 2 h post-injection (FIG.5). Accumulation of ²⁰³Pb- DOTA–GlyGly–Nle–CycMSH_hex was low (<1.3 %ID/g at 2, 4 and 24 h post-injection) in normal organs except kidneys (5.0 ± 1.5 %ID/g at 2 h post-injection), that were the major excretion pathways of ²⁰³Pb-DOTA–GlyGly–Nle–CycMSH_hex. Co-injection of NDP-MSH blockade did not reduce the renal uptake, indicating that the renal uptake was not MC1R-mediated (non-specific). The Lys-Asp (KD) cyclization dramatically improves the melanoma uptake of ²⁰³Pb-DOTA–GlyGly–Nle–CycMSHhex(KD) as compared ²⁰³Pb-DOTA–GlyGly–Nle– CycMSHhex cyclized by Asp-Lys (DK) [00178] The MC1R-binding moiety –His–D-Phe–Arg–Trp- was cyclized through an Asp-Lys (DK) lactam in DOTA–GlyGly–Nle–CycMSH_hex (SEQ ID NO:3, FIG.5), and displayed a 2.1 nM MC1R binding affinity on B16/F1 melanoma cells. When examining Attorney Docket No.151077-00046WO how His, D-Phe, Arg and Trp each affected the MC1R binding affinity of DOTA–GlyGly– Nle–CycMSH_hex, the Asp-Lys (DK) cyclization to Lys-Asp (KD) cyclization was also switched to examine whether such cyclization also affected the MC1R binding affinity. Surprisingly, the Lys-Asp (KD) cyclization improved the MC1R binding affinity of DOTA– GlyGly–Nle–CycMSH_hex(KD) (SEQ ID NO:2 with DOTA group attached) by 8.3-fold, to 0.12 nM, compared to DOTA–GlyGly–Nle–CycMSH_hex (SEQ ID NO:3). [00179] ²⁰³Pb-DOTA–GlyGly–Nle–CycMSH_hex(KD) was prepared and its melanoma targeting on B16/F1 melanoma-bearing C57 mice was examined.²⁰³Pb-DOTA–GlyGly– Nle–CycMSH_hex(KD) was readily prepared with >98% radiolabeling yield, and was stable in mouse serum for 4 h.²⁰³Pb-DOTA–GlyGly–Nle–CycMSH_hex(KD) exhibited high B16/F1 melanoma uptake (22.6 ± 5.0 %ID/g at 2 h post-injection) and prolonged tumor retention (14.4 ± 5.8 and 9.5 ± 3.9 %ID/g at 4 and 24 h post-injection). Co-injection of 6.1 nmol of NDP-MSH blockade (competing MC1Rs) blocked 92% of the tumor uptake at 2 h post-injection (p<0.05), demonstrating that the melanoma uptake was MC1R- mediated. The B16/F1 melanoma lesions were clearly visualized using ²⁰³Pb-DOTA– GlyGly–Nle–± (KD) as an imaging probe at 2 h post-injection (FIG.5). Accumulation of ²⁰³Pb-DOTA–GlyGly–Nle–CycMSH_hex(KD) was low (<2.2 %ID/g at 2, 4 and 24 h post- injection) in normal organs except kidneys (8.9 ± 1.9 %ID/g at 2 h post-injection), that were the major excretion pathways of ²⁰³Pb-DOTA–GlyGly–Nle–CycMSH_hex(KD). The B16/F1 melanoma uptake of ²⁰³Pb-DOTA–GlyGly–Nle–CycMSH_hex(KD) was 1.8, 1.5 and 1.5 times the tumor uptake of ²⁰³Pb-DOTA–GlyGly–Nle–CycMSH_hex at 2, 4 and 24 h post-injection. Favorable effect of 8-aminooctanoic acid (–Aoc–) linker in enhancing the MC1R binding affinity of DOTA–AocNle–CycMSHhex(KD) [00180] An 8-aminooctanoic acid (–Aoc–) linker was introduced between the DOTA and Nle–CycMSH_hex (KD) to examine the linker effect on MC1R binding affinity. Interestingly, the substitution of –GlyGly- linker with –Aoc– linker improved the MC1R binding affinity of DOTA–AocNle–CycMSH_hex(KD) by 3.8-fold (SEQ ID NO:4 with DOTA group attached, 0.032 nM) as compared to DOTA–GlyGly–Nle–CycMSH_hex(KD) (SEQ ID NO:2 with DOTA group attached, 0.12 nM, FIG.6). Such dramatic improvement in Attorney Docket No.151077-00046WO MC1R binding affinity suggested the favorable effect of –Aoc– hydrocarbon linker on MC1R binding affinity. [00181] Despite the profound effect of –Aoc– linker in improving the MC1R binding affinity, it is yet to be determined whether the –Aoc– linker yields the highest melanoma uptake and optimal clearance properties for ²⁰³Pb/²¹²Pb-DOTA–Linker–Nle– CycMSH_hex(KD) peptides. Meanwhile, the link length may affect the melanoma uptake and clearance property in our previous work (46, 47). Hence, novel DOTA–Linker–Nle– CycMSH_hex(KD) peptides with various linkers to improve melanoma uptake and modify clearance properties of ²⁰³Pb/²¹²Pb-DOTA–Linker–Nle–CycMSH_hex(KD) peptides are evaluated for imaging-guided MC1R-TRT, and then combined MC1R-TRT with ICIs for melanoma treatment. [00182] The novel theranostic ²⁰³Pb/²¹²Pb-DOTA–Linker–Nle–CycMSH_hex(KD) peptides can be used for imaging-guided MC1R-targeted alpha radionuclide therapy (MC1R-TRT), and the combinations of MC1R-TRT and ICIs [(anti-PD-1 + anti-CTLA-4) or (anti-PD-L1 + anti-CTLA-4)] can treat melanoma more effectively than MC1R-TRT only (FIG.2). [00183] The present inventive concept further combines MC1R-TRT and ICIs for melanoma treatment. Development and evaluation of novel ²⁰³Pb/²¹²Pb-DOTA–Linker– Nle–CycMSH_hex(KD) peptides in human melanoma xenografts and metastases are performed, and therapeutic efficacies of single-dose and double-dose regimens of MC1R-TRT and ICIs on melanoma xenografts and metastases are examined, as outlined and presented below. Part 1 [00184] 1. Non-radioactive Pb-conjugated peptide synthesis, purification, and characterization; In vitro competitive receptor binding. [00185] 2. Radiolabeling, serum stability, internalization, and efflux of ²⁰³Pb/²¹²Pb- peptides. [00186] 3. Biodistribution and dosimetry of ²⁰³Pb/²¹²Pb-peptides. [00187] 4. Maximum tolerated dose (MTD) determination and therapeutic efficacy examination. Attorney Docket No.151077-00046WO Part 2 [00188] Therapeutic efficacy of single-dose regimen MC1R-TRT + 3 × ICIs in flank tumor-bearing mice. [00189] Therapeutic efficacy of double-dose regimen 2 × {MC1R-TRT + 3 × ICIs} in flank tumor-bearing mice. [00190] Therapeutic efficacy of double-dose regimen 2 × {MC1R-TRT + 3 × ICIs} in metastatic tumor-bearing mice. [00191] Data analysis. Example 2. Properties of compounds CycMSHhex(KD) [00192] FIG.7A depicts a general structure of an exemplary optical tag/radiometal chelator-linker-Nle–CycMSH_hex(KD) compound. FIG.7B depicts exemplary radiometal chelators, and FIG.7C depicts exemplary linkers that may be included with the compounds shown in FIG.7A. [00193] The properties of DOTA–GlyGly–Nle–CycMSH_hex(KD) (SEQ ID NO:2 with DOTA group attached), including a DOTA radiometal chelator, a Gly–Gly-Nle linker, and the cyclic hexapeptide CycMSH_hex(KD) (SEQ ID NO:10) wherein the sidechain amino group of an N-terminal lysine residue is cyclized with the sidechain carboxyl group of a C-terminal aspartic acid residue, were compared 5 control peptides (FIG.8), wherein the MC1R binding sequence His–DPhe–Arg–Trp was scrambled to yield the control 1 peptide (SEQ ID NO:5, and Ala is used to replace each amino acid of the receptor binding sequence of His–DPhe–Arg–Trp to generate the control 2 to control 5 peptides (SEQ ID NOS:6–9), respectively. [00194] Melanocortin-1 receptor (MC1R) binding affinities of DOTA–GlyGly–Nle– CycMSH_hex(KD) and control peptides were determined on B16/F1 melanoma cells (FIG. 9). DOTA–GlyGly–Nle–CycMSH_hex(KD) displayed 0.12 ± 0.01 nM receptor binding affinity. The Lys-Asp (KD) cyclization improved the MC1R binding affinity of DOTA– GlyGly–Nle–CycMSHhex(KD) to 0.12 nM by 8.3-fold as compared to DOTA–GlyGly– Nle–CycMSH_hex, which was cyclized by Asp-Lys lactam, wherein the sidechain carboxyl group of an N-terminal aspartic acid residue is cyclized with a sidechain amino group of Attorney Docket No.151077-00046WO a C-terminal lysine residue. The structural changes of the control peptides and DOTA– GlyGly–Nle–CycMSHhex(KD) dramatically reduce the receptor binding affinities of the control peptides. [00195] FIG.10A depicts the structure of Cyanine5.5 (Cy5.5)-GlyGly–Nle– CycMSHhex(KD) (SEQ ID NO:2 with Cy5.5 group attached), including a Cy5.5 optical tag, a Gly-Gly-Nle linker, and the cyclic hexapeptide CycMSH_hex(KD) (SEQ ID NO:10) as described for DOTA–GlyGly–Nle–CycMSH_hex(KD). The receptor binding affinity for Cy5.5-GlyGly–Nle–CycMSHhex(KD) on B16/F1 melanoma cells is shown in FIG.10B. Cy5.5-GlyGly–Nle–CycMSHhex(KD) displayed 1.85 ± 0.36 nM receptor binding affinity. [00196] FIG.11 shows the MC1R staining of B16/F1 and B16/F10 melanoma tumors by Cy5.5-GlyGly–Nle–CycMSHhex(KD) (SEQ ID NO:2) and commercial fluorescein isothiocyanate (FITC)-MC1R antibody. The MC1R staining on B16/F1 and B16/F10 melanoma tumors co-localized between Cy5.5-GlyGly–Nle–CycMSHhex(KD) and FITC- MC1R antibody. [00197] FIG.12 shows the radioactive HPLC profile of ¹¹¹In-DOTA–GlyGly–Nle– CycMSH_hex(KD) (SEQ ID NO:2 with DOTA attached and complexed with ¹¹¹In). The retention time of ¹¹¹In-DOTA–GlyGly–Nle–CycMSH_hex(KD) was 17 min. [00198] FIG.13 shows the cellular internalization and efflux of ¹¹¹In-DOTA–GlyGly– Nle–CycMSH_hex(KD) on M21 melanoma cells. [00199] FIG.14 shows the biodistribution of ¹¹¹In-DOTA–GlyGly–Nle–CycMSH_hex(KD) in B16/F1 melanoma-bearing C57 mice at 0.5, 2, 4 and 24 h post-injection, and SPECT/CT image of a B16/F1 melanoma-bearing mouse at 2 h post-injection of ¹¹¹In- DOTA–GlyGly–Nle–CycMSH_hex(KD). Co-injection of peptide blockade (black columns) blocked 91% of melanoma uptake (p<0.05). [00200] ¹¹¹In-DOTA–GGNle–CycMSHhex(KD) exhibited high B16/F1 melanoma uptake (28.68 ± 5.15 %ID/g at 2 h post-injection) and prolonged tumor retention (26.80 ± 2.99 and 9.90 ± 1.37 %ID/g at 4 and 24 h post-injection). Co-injection of 6.1 nmol of NDP- MSH blockade (competing MC1Rs) blocked 91% of the tumor uptake at 2 h post- injection (p<0.05), demonstrating that the melanoma uptake was MC1R-mediated. The B16/F1 melanoma lesions were clearly visualized using ¹¹¹In-DOTA–GGNle– CycMSHhex(KD) as an imaging probe at 2 h post-injection. Attorney Docket No.151077-00046WO [00201] FIG.15 shows the biodistribution of ²⁰³Pb-DOTA–GlyGly–Nle– CycMSHhex(KD) (SEQ ID NO:2 with DOTA group attached and complexed with ²⁰³Pb) in B16/F1 melanoma-bearing C57 mice at 0.5, 2, 4 and 24 h post-injection, and coronal SPECT/CT image of a B16/F1 melanoma-bearing mouse at 2 h post-injection of ²⁰³Pb- DOTA–GlyGly–Nle–CycMSHhex(KD). Co-injection of peptide blockade (black columns) blocked 92% of melanoma uptake (p<0.05). [00202] ²⁰³Pb-DOTA–GGNle–CycMSH_hex(KD) exhibited high B16/F1 melanoma uptake (22.6 ^ 5.0 %ID/g at 2 h post-injection) and prolonged tumor retention (14.4 ^ 5.8 and 9.5 ^ 3.9 %ID/g at 4 and 24 h post-injection). Co-injection of 6.1 nmol of NDP- MSH blockade (competing MC1Rs) blocked 92% of the tumor uptake at 2 h post- injection (p<0.05), demonstrating that the melanoma uptake was MC1R-mediated. The B16/F1 melanoma lesions were clearly visualized using ²⁰³Pb-DOTA–GGNle– CycMSHhex(KD) as an imaging probe at 2 h post-injection. 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Metastatic melanoma imaging with an ¹¹¹In-labeled lactam bridge-cyclized alpha-melanocyte stimulating hormone peptide. Nucl Med Biol 36:267-276 (2009). 33. Miao Y, Whitener D, Feng W, Owen NK, Chen J, Quinn TP. Evaluation of the human melanoma targeting properties of radiolabeled alpha-melanocyte stimulating hormone peptide analogues. Bioconjug Chem 14:1177-1184 (2003). 34. Chen J, Cheng Z, Owen NK, Hoffman TJ, Miao Y, Jurisson SS, Quinn TP. Evaluation of an 1¹¹In-DOTA-rhenium cyclized α-MSH analog: a novel cyclic-peptide analog with improved tumor-targeting properties. J Nucl Med 42:1847-1855 (2001). 35. Cheng Z, Chen J, Miao Y, Owen NK, Quinn TP, Jurisson SS. Modification of the structure of a metallopeptide: synthesis and biological evaluation of ¹¹¹In labeled DOTA conjugated rhenium cyclized alpha-MSH analogs. J Med Chem 45:3048-3056 (2002). Attorney Docket No.151077-00046WO 36. Froidevaux S, Calame-Christe M, Tanner H, Sumanovski L, Eberle AN. 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[00203] Although the foregoing subject matter has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be understood by those skilled in the art that certain changes and modifications can be practiced within the scope of the appended claims.

Claims

Attorney Docket No.151077-00046WO THAT WHICH IS CLAIMED: 1. A compound according to a chemical structure: Y¹–X–(ABC)–CycMSH_hex(KD) wherein: Y¹ comprises a radiometal chelator or an optical tag; X is absent, or is a –NH–(CH2)7–(C=O)– group; (ABC) is selected from the group consisting of GlyGlyNle, GlyGlyGlyNle, GlySerGlyNle, and PEG₂Nle when X is absent, or is Nle when X is a –NH–(CH₂)₇– (C=O)– group; CycMSH_hex(KD) is a cyclic peptide comprising the general structure:

wherein: W is C–H from Lys or Orn, wherein j is 3 if W is from Orn or j is 4 if W is from Lys; X¹ is L- or D-Phe, Tyr, or Trp; Y is Arg or Lys; Z is Trp, Phe, or Tyr; Z¹ is Asp(CONH2) or Glu(CONH2); and Z² is a side chain –(C=O)– from the Asp or Glu of Z¹, or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1, wherein: X¹ is D-Phe; Y is Arg; and Attorney Docket No.151077-00046WO Z is Trp. 3. The compound of claim 1 or 2, wherein: W is C–H from Lys; Z¹ is Asp(CONH2); and Z² is the side chain –(C=O)– from Asp of Z¹. 4. The compound of any one of claims 1–3, wherein Y¹ comprises a DOTA, NOTA, NODAGA, HYNIC, DO3AM, TCMC-pBz-NCS, or PSC group as a radiometal chelator, or Y¹ comprises a Cy5.5 group as an optical tag. 5. A compound according to a chemical structure:

wherein: Y¹ comprises a DOTA, NOTA, NODAGA, HYNIC, DO3AM, TCMC-pBz-NCS, or PSC group, or Y¹ is a Cy5.5 group; X is absent, or is a –NH–(CH₂)₇–(C=O)– group; and (ABC) is selected from the group consisting of GlyGlyNle, GlyGlyGlyNle, GlySerGlyNle, and Peg₂Nle when X is absent, or is Nle when X is a –NH–(CH₂)₇– (C=O)– group, or a pharmaceutically acceptable salt thereof. 6. The compound of any one of claims 1–5, wherein Y¹ comprises a DOTA, NOTA, NODAGA, HYNIC, DO3AM, TCMC-pBz-NCS, or PSC group. Attorney Docket No.151077-00046WO 7. The compound of claim 6, wherein Y¹ incorporates or complexes with a radioisotope selected from the group consisting of ⁸⁶Y, ¹¹¹In, ²²⁵Ac, ²¹²Bi, ²¹³Bi, ⁷¹As, ⁷²As, ⁷⁶As, ⁷⁷As, ⁶⁵Zn, ⁴⁸V, ²⁰³Pb, ²⁰⁹Pb, ²¹²Pb, ¹⁶⁶Ho, ¹⁴⁹Pm, ¹⁵³Sm, ⁶⁷Ga, ⁶⁸Ga, ⁶⁴Cu, ⁶⁷Cu, ¹⁸⁸Re, ¹⁸⁶Re, and ^99mTc. 8. The compound of claim 6 or 7, wherein Y¹is a DOTA group. 9. The compound of claim 8, wherein the compound is complexed with a radioisotope selected from the group consisting of ⁶⁷Ga, ⁶⁸Ga, ⁸⁶Y, ¹¹¹In, ²²⁵Ac, ²¹²Bi, ²¹³Bi, ⁷¹As, ⁷²As, ⁷⁶As, ⁷⁷As, ⁶⁵Zn, ⁴⁸V, ²⁰³Pb, ²⁰⁹Pb, ²¹²Pb, ¹⁶⁶Ho, ¹⁴⁹Pm, and ¹⁵³Sm. 10. The compound of any one of claims 6–9, wherein the compound is complexed with ¹¹¹In. 11. The compound of any one of claims 6–9, wherein the compound is complexed with ²⁰³Pb or ²¹²Pb. 12. The compound of claim 11, wherein the compound is complexed with ²⁰³Pb. 13. The compound of claim 11, wherein the compound is complexed with ²¹²Pb. 14. The compound of claim 6, wherein Y¹ is a NOTA group. 15. The compound of claim 14, wherein the compound is complexed with a radioisotope selected from the group consisting of ⁶⁷Ga, ⁶⁸Ga, ⁶⁴Cu, ⁶⁷Cu, ¹⁸⁶Re, ¹⁸⁸Re, and ^99mTc. 16. The compound of claim 6, wherein Y¹ is a HYNIC group. Attorney Docket No.151077-00046WO 17. The compound of claim 16, wherein the compound is complexed with a radioisotope selected from the group consisting of ¹⁸⁶Re, ¹⁸⁸Re, and ^99mTc 18. The compound of any one of claims 1–5, wherein Y¹ is a Cy5.5 group. 19. The compound of any one of claims 1–18, wherein X is absent, and ABC is a GlyGlyNle group. 20. The compound of any one of claims 1–18, wherein X is: –NH–(CH₂)₇–(C=O)– and ABC is a Nle group. 21. A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1–20 and a radioisotope, and a pharmaceutically acceptable carrier, additive, or excipient. 22. The pharmaceutical composition of claim 21, for use in the diagnosis and/or treatment of melanoma. 23. The pharmaceutical composition of claim 21 or 22, wherein the composition further comprises an effective amount of at least one agent selected form the group consisting of DTIC, IL-2, and alpha-interferon. 24. The pharmaceutical composition of claim 21 or 22, wherein the composition is capable of being co-administered with at least one agent selected from the group consisting of DTIC, IL-2, and alpha-interferon. Attorney Docket No.151077-00046WO 25. The pharmaceutical composition of claim 21 or 22, wherein the composition further comprises an effective amount of an immune checkpoint inhibitor (ICI) or inhibitors (ICIs). 26. The pharmaceutical composition of claim 25, wherein the ICI or ICIs is (anti-PD-1 + anti-CTLA-4) or (anti-PD-L1 + anti-CTLA-4). 27. The pharmaceutical composition of claim 21 or 22, wherein the composition is capable of being co-administered an ICI or ICIs. 28. The pharmaceutical composition of claim 27, wherein the ICI or ICIs is (anti-PD-1 + anti-CTLA-4) or (anti-PD-L1 + anti-CTLA-4). 29. A method of treating melanoma in a subject in need thereof comprising administering to said patient an effective amount of a compound or pharmaceutical composition of any one of claims 1–28. 30. A method of diagnosing the presence, absence, or extent of melanoma in a subject comprising: administering an imaging-effective amount of the compound or pharmaceutical composition of any one of claims 1–28; imaging the subject to determine if tissue in the subject exhibits elevated expression of MC1Rs; and diagnosing the patient as having melanoma if the tissue exhibits elevated expression of MC1Rs in comparison to a threshold and/or with a standard. 31. A method of monitoring therapy of a subject in the treatment of melanoma comprising: administering an imaging effective amount of a compound or pharmaceutical composition of any one of claims 1–28 to a subject undergoing melanoma treatment; Attorney Docket No.151077-00046WO imaging said patient to determine if tissue in the patient exhibits elevated expression of MSH receptors; and comparing the results of the imaging to a threshold and/or with a standard. 32. The method of claim 31, wherein the therapy of the patient is continued, modified, or terminated based upon comparing the results of the imaging to a threshold and/or with a standard and whether the patient exhibits elevated expression of MC1Rs. 33. Use of the compound or pharmaceutical composition of any one of claims 1–28 in manufacture of a medicament for treating melanoma in a subject. 34. Use of the compound or pharmaceutical composition of any one of claims 1–28 in manufacture of a medicament for diagnosing the presence, absence, or extent of melanoma in a subject. 35. Use of the compound or pharmaceutical composition of any one of claims 1–28 in manufacture of a medicament for monitoring therapy of a subject in the treatment of melanoma.