Background

[PubMed]

Malignant melanoma is the most deadly form of skin cancer (1). Early and accurate diagnosis is necessary for surgery and successful treatment (2). The melanocortin (MC) system is a neuropeptide network of the skin, and it is involved in pigmentation regulation, cortisol production, and many other physiological processes (3). Most cutaneous cell types express MC receptors, pro-opiomelanocortin (POMC), and prohormone convertases, and they also release MCs. Melanotropin-stimulating hormones (α-, β-, and γ-MSH) are derived from POMC by the proteolytic action of prohormone convertases. There are five MC receptors (MC1R to MC5R), which belong to the G-protein−coupled receptor superfamily, and these receptors have been found to be overexpressed in melanoma cells (4, 5). α-MSH (Ac-Ser¹-Tyr²-Ser³-Met⁴-Glu⁵-His⁶-Phe⁷-Arg⁸-Trp⁹-Gly¹⁰-Lys¹¹-Pro¹²-Val¹³-NH₂), produced by the brain and the pituitary gland, is a tridecapeptide (13 amino acids) and is the most potent melanotropic peptide (6) in the regulation of skin pigmentation via MC1R.

Positron emission tomography (PET) imaging with [¹⁸F]fluoro-2-deoxy-2-d-glucose ([¹⁸F]FDG) in cancer has been approved by United States Food and Drug Administration with many on-going clinical trials. Although [¹⁸F]FDG is effective in the detection of melanoma, it is not melanoma-specific and some melanoma cells do not take up [¹⁸F]FDG (7, 8). Radiolabeled α-MSH peptide analogs have been shown to specifically bind to MC1R that is overexpressed on human and mouse melanoma cells (4, 5, 7, 9, 10). N-(2-Aminoethyl)-trans-1,2-diaminocyclohexane-N,N”,N”’-pentaacetic acid (CHX-A”) has been successfully coupled to α-MSH peptide analogs for radiolabeling with a variety of radionuclides (7, 11, 12). A rhenium-cyclized α-MSH analog, Re-[Cys^3,4,10,D-Phe⁷,Arg¹¹]α-MSH_3-13 (ReCCMSH(Arg¹¹)), was conjugated with CHX-A” (CHX-A”-ReCCMSH(Arg¹¹)) and radiolabeled with ¹¹¹In (¹¹¹In-CHX-A”-ReCCMSH(Arg¹¹)) as a molecular imaging agent for single-photon emission computed tomography (SPECT) to target melanoma (13). Rhenium-mediated cyclization exhibits significantly reduced nonspecific renal radioactivity accumulation, high tumor uptake and retention coupled with rapid clearance kinetics, compared with its free sulfhydryl and disulfide bond–containing counterparts (10). ¹¹¹In is a gamma emitter with a physical half-life of 2.8 days.

Synthesis

[PubMed]

Wei et al. (13) reported the synthesis of ¹¹¹In-CHX-A”-ReCCMSH(Arg¹¹). The CCMSH(Arg¹¹) peptide was synthesized using standard Fmoc chemistry on an amide resin with a peptide synthesizer. CCMSH(Arg¹¹) was then reacted with 2 M excess of the glutaric acid succinimidyl ester derivative of CHX-A” to the N-terminus of CCMSH(Arg¹¹) to form CHX-A”-CCMSH(Arg¹¹). A mixture of CHX-A”-CCMSH(Arg¹¹) and ReOCl₃ (1:1.5 molar ratio) was incubated for 30 min at 85°C. The cyclized peptide, CHX-A”-ReCCMSH(Arg¹¹), was purified with high-performance liquid chromatography (HPLC). For ¹¹¹In labeling, a solution of 44.4 MBq (1.2 mCi) ¹¹¹InCl₃ and 10 nmol CHX-A”-ReCCMSH(Arg¹¹) was heated for 40 min at 40°C. Radiochemical efficiency was reported to be >95% with a specific activity of 10.6 GBq/µmol (287 mCi/µmol).

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Chen et al. (10) determined the 50% inhibition concentration (IC₅₀) value of DOTA-ReCCMSH(Arg¹¹) to be 1.2 ± 0.3 nM using B16/F1 murine melanoma cells with ¹²⁵I-(Tyr²)-[Nle⁴, d-Phe]α-MSH (¹²⁵I-NDP). In comparison, the IC₅₀ value of ReCCMSH(Arg¹¹) was 2.9 ± 0.3 nM. Wei et al. (13) found that the IC₅₀ value for CHX-A”-ReCCMSH(Arg¹¹) was 3.8 nM.

Animal Studies

Human Studies

[PubMed]

No publication is currently available.

NIH Support

Intramural Research Program, R24 CA86307, R24 CA86060, P30 CA91842

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