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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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64Cu-1,4,7,10-4,11-Bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-rhenium-cyclized-[Cys3,4,10,D-Phe7,Arg11]α-MSH3-13

64Cu-CBTE2A-ReCCMSH(Arg11)
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD

Created: ; Last Update: May 11, 2009.

Chemical name:64Cu-1,4,7,10-4,11-Bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-rhenium-cyclized-[Cys3,4,10,d-Phe7,Arg11]α-MSH3-13
Abbreviated name:64Cu-CBTE2A-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:64Cu
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, thesereceptors 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 bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CBTE2A). CBTE2A-Re-CCMSH(Arg11) was radiolabeled with 64Cu as a potential molecular imaging agent to target melanoma (11). 64Cu is a positron emitter with a physical half-life of 12.7 h and is suitable for PET imaging.

Synthesis

[PubMed]

Wei et al. (11) reported the synthesis of 64Cu-CBTE2A-ReCCMSH(Arg11).The CBTE2A-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 CBTE2A-CCMSH(Arg11) and trichlorooxobis-(triphenylphosphine)-rhenium (1:1 molar ratio) was incubated for 3 h at 25°C. The cyclized peptide, CBTE2A-ReCCMSH(Arg11), was purified with high-performance liquid chromatography (HPLC). For 64Cu labeling, 64CuCl3 in 0.1 M ammonium acetate was added to CBTE2A-ReCCMSH(Arg11) in 0.1 M ammonium acetate, and the mixture was heated for 60 min at 95ºC. Radiochemical purity (as confirmed with HPLC) was >98% with specific activities of 22–185 GBq/µmol (0.6–5 Ci/µmol).

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Wei et al. (11) conducted in vitro competitive receptor-binding studies of Cu-CBTE2A-ReCCMSH and Cu-DOTA-ReCCMSH with B16/F1 murine melanoma cells that express the MC1R. The radioactive ligand was 125I-Tyr2-[Nle4,D-Phe7]α-MSH. The inhibition concentrations (IC50) were 5.4 nM and 6.9 nM for Cu-CBTE2A-ReCCMSH and Cu-DOTA-ReCCMSH, respectively.

Animal Studies

Rodents

[PubMed]

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 0.2 MBq (0.005 mCi (~0.01 nmol)) 64Cu-CBTE2A-ReCCMSH(Arg11). The radioactivity levels in percent injected dose per gram (% ID/g) were obtained at 30 min, 2 h, 4 h, and 24 h after injection, with tumor uptake values of 8.45 ± 1.42, 7.09 ± 3.20, 7.37 ± 1.26, and 4.01 ± 0.77, respectively. Tumor retention is high. Pre-administration of 10 nmol CBTE2A-ReCCMSH(Arg11) significantly reduced the tumor uptake to 0.99 ± 0.15% ID/g (P < 0.005) at 2 h after injection. No other tissues showed significant inhibition by CBTE2A-ReCCMSH(Arg11). The nontarget tissue uptake of 64Cu-CBTE2A-ReCCMSH(Arg11) was high at 30 min. However, the radioactivity was quickly cleared from all tissues at 2 h after injection (except kidney: 12.71 ± 1.50% ID/g at 30 min and 8.57 ± 2.51% ID/g at 2 h; e.g.,lung: 3.29 ± 1.16% ID/g at 30 min and 0.53 ± 0.06% ID/g at 2 h; blood: 2.95 ± 1.11% ID/g at 30 min and 0.19 ± 0.04% ID/g at 2 h; liver: 2.37 ± 0.28% ID/g at 30 min and 1.57 ± 0.42% ID/g at 2 h]. 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 44). When 15 mg d-lysine was coinjected with 64Cu-CBTE2A-ReCCMSH(Arg11), the kidney and tumor radioactivity levels were decreased by >60% at 2 h after injection. 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 5.55 MBq (0.15 mCi (0.25 nmol)) 64Cu-CBTE2A-ReCCMSH(Arg11) at 0.5, 2, 4, and 24 h. At 0.5 h, the tumor, kidney, blood, lung, and heart were visible. As the background radioactivity decreased, only the tumor, kidney, liver, and bladder were clearly visible by 2 h. Pre-injection of 10 nmol CBTE2A-ReCCMSH(Arg11) inhibited the tumor accumulation of radioactivity by ~80% at all time points, whereas there was little effect on the kidney and liver radioactivity levels.

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 CA86307, P50 CA103130, R24 CA86060, P30 CA91842

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.
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]
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