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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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Molecular Imaging and Contrast Agent Database (MICAD) [Internet].

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86Y-CHX-A”-Rhenium-cyclized-[Cys3,4,10,D-Phe7,Arg11]α-MSH3-13

86Y-CHX-A”-ReCCMSH(Arg11)
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD
Corresponding author.

Created: ; Last Update: September 8, 2010.

Chemical name:86Y-CHX-Rhenium-cyclized-[Cys3,4,10,d-Phe7,Arg11]α-MSH3-13
Abbreviated name:86Y-CHX-A”-ReCCMSH(Arg11)
Synonym:
Agent category:Peptide
Target:Melanocortin-1 (MC-1) receptor (MC1R)
Target category:Receptor
Method of detection:Positron emission tomography (PET)
Source of signal:86Y
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, and 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 the pituitary gland, is a tridecapeptide (13 amino acids) and is the most potent melanotropic peptide (6) in the regulation of skin pigmentation via MC1R.

Positron emission tomography (PET) imaging with [18F]fluoro-2-deoxy-2-d-glucose ([18F]FDG) in cancer has been approved by United States Food and Drug Administration with many on-going clinical trials. Although [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). N-(2-Aminoethyl)-trans-1,2-diaminocyclohexane-N,N”,N”’-pentaacetic acid (CHX-A”) has been successfully coupled to α-MSH peptide analogs for radiolabeling with a variety of radionuclides (7, 11, 12). A rhenium-cyclized α-MSH analog, Re-[Cys3,4,10,D-Phe7,Arg11]α-MSH3-13 (ReCCMSH(Arg11)), was conjugated with CHX-A” (CHX-A”-ReCCMSH(Arg11)) and radiolabeled with 86Y (86Y-CHX-A”-ReCCMSH(Arg11)) as a potential molecular imaging agent to target melanoma (13). Rhenium-mediated cyclization exhibits significantly reduced nonspecific renal radioactivity accumulation high tumor uptake and retention coupled with rapid clearance kinetics, compared with its free sulfhydryl and disulfide bond–containing counterparts (10). 86Y is a positron emitter with a physical half-life of 14.7 h and is suitable for PET imaging.

Synthesis

[PubMed]

Wei et al. (13) reported the synthesis of 86Y-CHX-A”-ReCCMSH(Arg11). The CCMSH(Arg11) peptide was synthesized using standard Fmoc chemistry on an amide resin with a peptide synthesizer. CCMSH(Arg11) was then reacted with 2 M excess of the glutaric acid succinimidyl ester derivative of CHX-A” to the N-terminus of CCMSH(Arg11) to form CHX-A”-CCMSH(Arg11). A mixture of CHX-A”-CCMSH(Arg11) and ReOCl3 (1:1.5 molar ratio) was incubated for 30 min at 85°C. The cyclized peptide, CHX-A”-ReCCMSH(Arg11), was purified with high-performance liquid chromatography. For 86Y labeling, a solution of 86Y and CHX-A”-ReCCMSH(Arg11) was heated for 30 min at 75°C. Radiochemical efficiency was reported to be >95% with a specific activity of 8.77 GBq/µmol (237 mCi/µmol) at the end of purification.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Chen et al. (10) determined the 50% inhibition concentration (IC50) value of DOTA-ReCCMSH(Arg11) to be 1.2 ± 0.3 nM using B16/F1 murine melanoma cells with 125I-(Tyr2)-[Nle4, d-Phe]α-MSH (125I-NDP). In comparison, the IC50 value of ReCCMSH(Arg11) was 2.9 ± 0.3 nM. Wei et al. (13) found that the IC50 value for CHX-A”-ReCCMSH(Arg11) was 3.8 nM.

Animal Studies

Rodents

[PubMed]

Wei et al. (13) performed biodistribution studies in female C57BL/6 mice (n = 5/group) bearing 10-day-old B16/F1 murine melanoma tumors. Each mouse received 0.3 MBq (0.008 mCi, 35 pmol) 86Y-CHX-A”-ReCCMSH(Arg11). The tumor uptake radioactivity levels were obtained at 30 min, 2 h, 4 h, and 24 h, respectively: 3.99 ± 0.54% injected dose per gram (% ID/g), 4.68 ± 1.02% ID/g, 4.18 ± 0.45% ID/g, and 2.79 ± 0.44% ID/g. The tumor retention was high up to 4 h after injection. Pretreatment with 9 nmol unlabeled NDP significantly reduced the tumor uptake to 2.1 ± 0.46% ID/g (P < 0.02) at 2 h after injection. No other tissues showed significant inhibition by NDP. The 86Y-CHX-A”-ReCCMSH(Arg11) uptake in nontarget tissue (except the kidneys and liver) was low at 2 h. Furthermore, the radioactivity was quickly cleared from most of the tissues (except the kidneys and liver) at 2 h after injection (e.g., kidney: 10.95 ± 3.01% ID/g at 30 min and 8.1 ± 3.62% ID/g at 2 h; liver: 4.23 ± 0.36% ID/g at 30 min and 3.30 ± 0.54% ID/g at 2 h; blood: 4.65 ± 0.98% ID/g at 30 min and 1.09 ± 0.24% ID/g at 2 h; lung: 3.44 ± 0.43% ID/g at 30 min and 1.24 ± 0.18% ID/g at 2 h). The tumor/muscle and tumor/blood ratios at 2 h were 20 and 4, respectively. PET imaging of mice bearing the B16/F1 melanoma tumors was conducted at 2 h after intravenous injection of 13 MBq (0.35 mCi) 86Y-CHX-A”-ReCCMSH(Arg11). The tumor, urinary bladder, and kidneys were clearly visible. Preinjection of 9 nmol unlabeled NDP inhibited the tumor accumulation, whereas there was little inhibition of radioactivity in the kidneys. In comparison with 111In- and 68Ga-CHX-A”-ReCCMSH(Arg11), 86Y-CHX-A”-ReCCMSH(Arg11) exhibited higher liver accumulation. 111In- and 86Y-CHX-A”-ReCCMSH(Arg11) showed higher tumor accumulation than 68Ga-CHX-A”-ReCCMSH(Arg11), which has a lower specific activity.

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

Intramural Research Program, R24 CA86307, R24 CA86060, P30 CA91842

References

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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]
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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.
Wei L., Butcher C., Miao Y., Gallazzi F., Quinn T.P., Welch M.J., Lewis J.S. Synthesis and biologic evaluation of 64Cu-labeled rhenium-cyclized alpha-MSH peptide analog using a cross-bridged cyclam chelator. J Nucl Med. 2007;48(1):64–72. [PubMed: 17204700]
12.
Wei L., Miao Y., Gallazzi F., Quinn T.P., Welch M.J., Vavere A.L., Lewis J.S. Gallium-68-labeled DOTA-rhenium-cyclized alpha-melanocyte-stimulating hormone analog for imaging of malignant melanoma. Nucl Med Biol. 2007;34(8):945–53. [PMC free article: PMC2330268] [PubMed: 17998097]
13.
Wei L., Zhang X., Gallazzi F., Miao Y., Jin X., Brechbiel M.W., Xu H., Clifford T., Welch M.J., Lewis J.S., Quinn T.P. Melanoma imaging using 111In-, 86Y- and 68Ga-labeled CHX-A''-Re(Arg11)CCMSH. Nucl Med Biol. 2009;36(4):345–54. [PMC free article: PMC2752876] [PubMed: 19423001]

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