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4-[18F]Fluorobenzoyl-rhenium-cyclized-Ac-D-Lys-[Cys3,4,10, D-Phe7, Arg11]α-MSH3-13

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

Created: ; Last Update: April 8, 2010.

Chemical name:4-[18F]Fluorobenzoyl-rhenium-cyclized-Ac-D-Lys-[ Cys3,4,10, D-Phe7, Arg11]α-MSH
Abbreviated name:[18F]FB-RMSH
Agent category:Peptide
Target:Melanocortin-1 (MC-1) receptor, MC1R
Target category:Receptor
Method of detection:Positron emission tomography (PET)
Source of signal:18F
  • 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 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). Rhenium-cyclized α-MSH analogs have demonstrated high in vivo accumulation in tumors because of their high resistance to proteolysis (10, 11). A rhenium-cyclized α-MSH analog, Re-cyclized-Ac-D-Lys-[Cys3,4,10,D-Phe7,Arg11]α-MSH3-13 (RMSH), was radiolabeled with N-succinimidyl-4-[18F]fluorobenzoate ([18F]SFB) to form [18F]FB-RMSH as a potential positron emission tomography (PET) imaging agent to target melanoma (12).



Ren et al. (12) reported the synthesis of [18F]FB-RMSH. The Ac-D-Lys-[Arg11]α-MSH peptide was synthesized using standard Fmoc chemistry on an amide resin with a peptide synthesizer. Ac-D-Lys-[Arg11]α-MSH was then reacted with rhenium-glucoheptonate (1:1.5 molar ratio) for 30 min at 85°C. The cyclized peptide, RMSH, was purified with high-performance liquid chromatography (HPLC). HPLC analysis revealed two rhenium-cyclized isomers as RMSH-1 and RMSH-2, which were purified with HPLC and identified with mass spectroscopy. For 18F labeling, a solution of [18F]SFB and RMSH-1 or RMSH-2 peptide (100 ug) was heated for 60 min at 60°C. The maximum radiochemical yield was ~35% with a specific activity of 132-166 GBq/µmol (3.57-4.49 Ci/µmol) at the end of synthesis (decay-corrected). The radiochemical purities of [18F]FB-RMSH-1 and [18F]FB-RMSH-2 were >95% after HPLC purification. The total radiosynthesis time was ~ 3 h.

In Vitro Studies: Testing in Cells and Tissues


Ren et al. (12) determined the 50% inhibition concentration (IC50) value of RMSH-1 and RMSH-2 to be 5.4 ± 0.7 and 13.9 ± 1.4 nM using B16/F1 murine melanoma cells with 125I-(Tyr2)-[Nle4, D-Phe]α-MSH (125I-NDP), respectively. In comparison, the IC50 values of FB-RMSH-1 and FB-RMSH-2 were 5.7 ± 0.7 and 9.0 ± 1.0 nM, respectively.

Animal Studies



Ren et al. (12) performed biodistribution studies in male C57BL/6 mice (n = 3/group) bearing B16/F1 murine melanoma tumors. Each mouse received 1.11 MBq (0.03 mCi) [18F]FB-RMSH-1. The tumor uptake radioactivity levels were obtained at 1 h, 2 h, and 4 h, respectively: 1.97 ± 0.39% injected dose per gram (% ID/g), 2.11 ± 0.12% ID/g, and 0.83 ± 0.05% ID/g. The tumor/blood and tumor/muscle ratios were 2.6 and 7.4 at 2 h after injection, respectively. Co-treatment with 9 nmol NDP reduced these ratios to 1.5 and 3.1 at 2 h after injection, respectively. The [18F]FB-RMSH-1 uptake in nontarget tissue (except the kidneys (5.4% ID/g), lung (2.4% ID/g) and liver (2.5% ID/g)) was low at 2 h. The radioactivity levels were 0.76% and 0.83% ID/g in the blood and bone at 2 h, respectively. The blood and bone radioactivity decreased to 0.39% and 0.30% ID/g at 4 h, respectively. [18F]FB-RMSH-2 exhibited similar biodistribution pattern except with higher kidney accumulation (16.9-17.8% ID/g) at 2 and 4 after injection.

PET imaging of mice bearing the B16F1 melanoma was conducted with intravenous injection of 13 MBq (0.35 mCi) [18F]FB-RMSH-1 or [18F]FB-RMSH-2 at 1 and 2 h after injection. The tumor, liver and kidneys were clearly visible. [18F]FB-RMSH-1 exhibited higher tumor accumulation but lower kidney accumulation than [18F]FB-RMSH-2.

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 CA93862, P50 CA114747


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