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Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.

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68Ga-1,4,7,10-Tetraazacyclododecane-N,N’,N’’,N’’’-1,4,7,10-tetraacetic acid-rhenium-cyclized-[Cys3,4,10,D-Phe7,Arg11]α-MSH3-13

, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD

Created: ; Last Update: May 11, 2009.

Chemical name:68Ga-1,4,7,10-Tetraazacyclododecane-N,N’,N’’,N’’’-1,4,7,10-tetraacetic acid-rhenium-cyclized-[Cys3,4,10,d-Phe7,Arg11]α-MSH3-13
Abbreviated name:68Ga-DOTA-ReCCMSH(Arg11)
Agent category:Peptide
Target:Melanocortin-1 (MC-1) receptor, MC1R
Target category:Receptor
Method of detection:Positron emission tomography (PET)
Source of signal:68Ga
  • Checkbox In vitro
  • Checkbox Rodents
Click on protein, nucleotide (RefSeq), and gene for more information about the Melanocortin-1 receptor.



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-[Cys3,4,10,D-Phe7,Arg11]α-MSH3-13 (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.



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


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



Wei et al. (11) performed biodistribution studies in female C57BL/6 mice (n = 5/group) bearing 10-day-old B16/F1 murine melanoma tumors. Each mouse received 0.444 MBq (0.012 mCi (~0.1 nmol)) 68Ga-DOTA-ReCCMSH(Arg11). The radioactivity levels in percent injected dose per gram (% ID/g) were obtained at 30 min and 2 h after injection. The tumor uptake of 68Ga-DOTA-ReCCMSH(Arg11) was 4.31 ± 1.94% ID/g at 30 min and 4.25 ± 1.41% ID/g at 2 h, indicating that the tumor retention is high. Pre-administration of 10 nmol DOTA-ReCCMSH(Arg11) significantly reduced the tumor uptake to 0.42 ± 0.05% ID/g (P <.01) at 2 h after injection. No other tissues showed significant inhibition by DOTA-ReCCMSH(Arg11). The nontarget tissue uptake of 68Ga-DOTA-ReCCMSH(Arg11) was high at 30 min. However, the radioactivity was quickly cleared from all tissues at 2 h after injection (e.g., kidney: 16.50 ± 4.30% ID/g at 30 min and 6.80 ± 1.72% ID/g at 2 h, P < 0.01; blood: 4.65 ± 0.84% ID/g at 30 min and 0.40 ± 0.13% ID/g at 2 h, P < 0.001; liver: 1.34 ± 0.09% ID/g at 30 min and 0.50 ± 0.11% ID/g at 2 h, P < 0.00001). The fast clearance from normal tissues and high tumor retention resulted in good tumor/nontarget tissue ratios at 2 h (e.g., tumor/muscle ratio of 42). When 15 mg l-lysine was coinjected with 68Ga-DOTA-ReCCMSH(Arg11), the kidney and tumor radioactivity levels were decreased by 53% and 19% at 2 h after injection, respectively. In contrast, the radioactivity levels in other major tissues were not affected. PET imaging of mice bearing the B16/F1 melanomas in the neck was conducted with intravenous injection of 3.7 MBq (0.1 mCi (1 nmol)) 68Ga-DOTA-ReCCMSH(Arg11) at 0.5, 1, and 2 h. At 0.5 h, the tumor, kidney, blood, lung, and heart were visible. As the background radioactivity decreased, only the tumor, kidney, and bladder were clearly visible by 2 h. Pre-injection of 10 nmol DOTA-ReCCMSH(Arg11) inhibited the tumor accumulation of radioactivity by ~50% at all time points, whereas there was little effect on the kidney and liver radioactivity levels.

Other Non-Primate Mammals


No publication is currently available.

Non-Human Primates


No publication is currently available.

Human Studies


No publication is currently available.

NIH Support

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


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