Background

[PubMed]

Malignant melanoma is the deadliest 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, proopiomelanocortin (POMC), and prohormone convertases, and they also release MCs. However, these receptors have been found to be overexpressed in melanoma cells. There are five MC receptors (MC1R to MC5R), which belong to the G-protein−coupled receptor superfamily. Melanotropin-stimulating hormones (α-, β-, and γ-MSH) are derived from POMC by the proteolytic action of prohormone convertases. 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 (4) in the regulation of skin pigmentation via 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 (5, 6). [¹⁸F]FDG has been approved for cancer imaging by the United States Food and Drug Administration. Radiolabeled α-MSH peptide analogs have been shown to specifically bind to MC1R that is overexpressed on human and mouse melanoma cells (5, 7-10). 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 (5). A lactam bridge-cyclized α-MSH analog, GlyGlu-c[Lys-Nlc-Glu-His-d-Phe-Arg-Trp-Gly-Arg-Pro-Val-Asp] (GlyGlu-CycMSH), was conjugated with DOTA (11). DOTA-GlyGlu-CycMSH was radiolabeled with ⁶⁷Ga as a potential molecular imaging agent to target melanoma (12). ⁶⁷Ga is a positron emitter with a physical half-life of 3.3 d and is suitable for single-photon emission computed tomography (SPECT) imaging.

Synthesis

[PubMed]

Guo et al. (12) reported the synthesis of ⁶⁷Ga-DOTA-GlyGlu-CycMSH. The DOTA-GlyGlu-CycMSH peptide was synthesized using standard Fmoc chemistry on an amide resin with a peptide synthesizer. A solution of 10 µg DOTA-GlyGlu-CycMSH and 37 MBq (1 mCi) ⁶⁷GaCl₃ was incubated for 20 min at 90°C. ⁶⁷Ga-DOTA-GlyGlu-CycMSH was purified with high-performance liquid chromatography (HPLC). Radiochemical purity (as confirmed with HPLC) was >95% with a labeling yield of >95%. The specific activity was not reported.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Guo et al. (11) conducted in vitro competitive receptor-binding studies of DOTA-GlyGlu-CycMSH with B16/F1 murine melanoma cells that express the MC1R (~3,000 sites/cell). The radioactive ligand was ¹²⁵I-Tyr²-[Nle⁴,d-Phe⁷]α-MSH. The inhibition concentration (IC₅₀) was 2.4 nM.

Guo et al. (12) performed in vitro cellular internalization and efflux studies of ⁶⁷Ga-DOTA-GlyGlu-CycMSH in B16/F1 melanoma cells. ⁶⁷Ga-DOTA-GlyGlu-CycMSH exhibited 54% and 70% uptake of incubation dose inside the cells at 20 min and 90 min after incubation at 25°C, respectively. More than 80% of the internalized radioactivity remained inside the cells after 2 h of incubation in fresh medium.

Animal Studies

Human Studies

[PubMed]

No publication is currently available.

NIH Support

P30 CA118100, P20 RR016480

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