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

[18F]FB-RMSH
, 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
Synonym:
Agent category:Peptide
Target:Melanocortin-1 (MC-1) receptor, MC1R
Target category:Receptor
Method of detection:Positron emission tomography (PET)
Source of signal:18F
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
Click on protein, nucleotide (RefSeq), and gene for more information about the Melanocortin-1 receptor.

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 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).

Synthesis

[PubMed]

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

[PubMed]

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

Rodents

[PubMed]

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

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

No publication is currently available.

Human Studies

[PubMed]

No publication is currently available.

NIH Support

R24 CA93862, P50 CA114747

References

1.
Jemal A., Siegel R., Ward E., Murray T., Xu J., Thun M.J. Cancer statistics, 2007. CA Cancer J Clin. 2007;57(1):43–66. [PubMed: 17237035]
2.
Miao Y., Hylarides M., Fisher D.R., Shelton T., Moore H., Wester D.W., Fritzberg A.R., Winkelmann C.T., Hoffman T., Quinn T.P. Melanoma therapy via peptide-targeted {alpha}-radiation. Clin Cancer Res. 2005;11(15):5616–21. [PubMed: 16061880]
3.
Bohm M., Luger T.A., Tobin D.J., Garcia-Borron J.C. Melanocortin receptor ligands: new horizons for skin biology and clinical dermatology. J Invest Dermatol. 2006;126(9):1966–75. [PubMed: 16912693]
4.
Miao Y., Whitener D., Feng W., Owen N.K., Chen J., Quinn T.P. Evaluation of the human melanoma targeting properties of radiolabeled alpha-melanocyte stimulating hormone peptide analogues. Bioconjug Chem. 2003;14(6):1177–84. [PubMed: 14624632]
5.
Siegrist W., Solca F., Stutz S., Giuffre L., Carrel S., Girard J., Eberle A.N. Characterization of receptors for alpha-melanocyte-stimulating hormone on human melanoma cells. Cancer Res. 1989;49(22):6352–8. [PubMed: 2804981]
6.
Catania A., Airaghi L., Garofalo L., Cutuli M., Lipton J.M. The neuropeptide alpha-MSH in HIV infection and other disorders in humans. Ann N Y Acad Sci. 1998;840:848–56. [PubMed: 9629310]
7.
Weiner R.E., Thakur M.L. Radiolabeled peptides in oncology: role in diagnosis and treatment. BioDrugs. 2005;19(3):145–63. [PubMed: 15984900]
8.
Dimitrakopoulou-Strauss A., Strauss L.G., Burger C. Quantitative PET studies in pretreated melanoma patients: a comparison of 6-[18F]fluoro-L-dopa with 18F-FDG and (15)O-water using compartment and noncompartment analysis. J Nucl Med. 2001;42(2):248–56. [PubMed: 11216523]
9.
Tatro J.B., Reichlin S. Specific receptors for alpha-melanocyte-stimulating hormone are widely distributed in tissues of rodents. Endocrinology. 1987;121(5):1900–7. [PubMed: 2822378]
10.
Chen J., Cheng Z., Owen N.K., Hoffman T.J., Miao Y., Jurisson S.S., Quinn T.P. Evaluation of an (111)In-DOTA-rhenium cyclized alpha-MSH analog: a novel cyclic-peptide analog with improved tumor-targeting properties. J Nucl Med. 2001;42(12):1847–55. [PubMed: 11752084]
11.
Giblin M.F., Wang N., Hoffman T.J., Jurisson S.S., Quinn T.P. Design and characterization of alpha-melanotropin peptide analogs cyclized through rhenium and technetium metal coordination. Proc Natl Acad Sci U S A. 1998;95(22):12814–8. [PMC free article: PMC23606] [PubMed: 9788997]
12.
Ren G., Liu Z., Miao Z., Liu H., Subbarayan M., Chin F.T., Zhang L., Gambhir S.S., Cheng Z. PET of malignant melanoma using 18F-labeled metallopeptides. J Nucl Med. 2009;50(11):1865–72. [PMC free article: PMC4136965] [PubMed: 19837749]
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