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. However, 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 pituitary gland, is a tridecapeptide (13 amino acids) and is the most potent melanotropic peptide (6) in the regulation of skin pigmentation via the MC1R.

Although positron emission tomography (PET) imaging with [¹⁸F]fluoro-2-deoxy-2-d-glucose ([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). 1,4,7,10-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) has been successfully coupled to the α-MSH peptide analogs for radiolabeling with a variety of radionuclides (7). To improve the tumor/kidney uptake ratio and metabolic stability, a rhenium-cyclized α-MSH analog, Re-[Cys^3,4,10,D-Phe⁷,Arg¹¹]α-MSH_3-13 (Re-CCMSH(Arg¹¹)), was conjugated with DOTA. DOTA-Re-CCMSH(Arg¹¹) was radiolabeled with ⁶⁸Ga as a potential molecular imaging agent to target melanoma. ⁶⁸Ga is a positron emitter with a physical half-life of 68 min and is suitable for PET imaging.

Synthesis

[PubMed]

Wei et al. (11) reported the synthesis of ⁶⁸Ga-DOTA-ReCCMSH(Arg¹¹). The DOTA-CCMSH(Arg¹¹) peptide was synthesized using standard Fmoc/HBTU(2-[1H-benzotriazole-1-yl]-l,1,3,3,-tetramethyluronium hexafluorophosphate) chemistry on an amide resin with a peptide synthesizer as reported previously by Chen et al. (10). A mixture of DOTA-CCMSH(Arg¹¹) and ReOCl₃ (1:1.5 molar ratio) was incubated for 2 h at 75°C. The cyclized peptide, DOTA-ReCCMSH(Arg¹¹), was purified with high-performance liquid chromatography (HPLC). The overall synthetic yield was 10–20%. For ⁶⁸Ga labeling, ⁶⁸GaCl₃ in 0.1 M hydrochloric acid was added to DOTA-ReCCMSH(Arg¹¹) in 1.25 M ammonium acetate, and the mixture was heated for 30 min at 85ºC. Radiochemical purity (as confirmed with HPLC) was >95% with a specific activity of 3.85 TBq/mmol (104 Ci/mmol) and a labeling yield of <10%.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Chen et al. (10) conducted in vitro competitive receptor-binding studies of ReCCMSH and DOTA-ReCCMSH with B16/F1 murine melanoma cells (MC1R-positive). The inhibition concentrations were 2.9 ± 0.3 nM and 1.2 ± 0.3 nM for ReCCMSH and DOTA- ReCCMSH, respectively. The radioactive ligand was ¹²⁵I-Tyr²-[Nle⁴,D-Phe⁷]α-MSH.

Animal Studies

Human Studies

[PubMed]

No publication is currently available.

NIH Support

R24 CA86307, P50 CA103130, R24 CA86060, P30 CA91842, R41 CA85106

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Wei L., Miao Y., Gallazzi F., Quinn T.P., Welch M.J., Vavere A.L., Lewis J.S. Gallium-68-labeled DOTA-rhenium-cyclized alpha-melanocyte-stimulating hormone analog for imaging of malignant melanoma. Nucl Med Biol. 2007;34(8):945–53. [PMC free article: PMC2330268] [PubMed: 17998097]