Cu-1,4,7,10-Tetraazacyclododecane-,’,’’,’’’-1,4,7,10-tetraacetic acid-rhenium-cyclized-[Cys,D-Phe,Arg]α-MSH

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-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH), 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 the MC1R. Although positron emission tomography (PET) imaging with [F]fluoro-2-deoxy-2-d-glucose ([F]FDG) is effective in the detection of melanoma, it is not melanoma-specific and some melanoma cells do not take up [F]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-,,,-tetraacetic acid (DOTA) has been successfully coupled to the α-MSH peptide analogs for radiolabeling with a variety of radionuclides (7). In- and Tc-DOTA-Re(Arg)CCMSH showed favorable tumor imaging properties in mice bearing murine melanoma (11). To improve the tumor/kidney uptake ratio and stability, a rhenium-cyclized α-MSH analog, Re-[Cys,D-Phe,Arg]α-MSH (Re-CCMSH(Arg)), was conjugated with DOTA. DOTA-Re-CCMSH(Arg) was radiolabeled with Cu as a potential molecular imaging agent to target melanoma (12). Cu is a positron emitter with a physical half-life of 12.7 h and is suitable for PET imaging.