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PET of Malignant Melanoma Using ¹⁸F-Labeled Metallopeptides

¹ Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bio-X Program, Stanford University, Stanford, California; and ² Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai, China

Correspondence: For correspondence or reprints contact: Zhen Cheng, Molecular Imaging Program at Stanford, Department of Radiology and Bio-X Program, 1201 Welch Rd., Lucas Expansion, P020A, Stanford University, Stanford, CA 94305-5484. E-mail: zcheng{at}stanford.edu

Melanocortin type 1 receptor (MC1R), also known as -melanocyte–stimulating hormone (-MSH) receptor, is an attractive molecular target for melanoma imaging and therapy. An ¹⁸F-labeled linear -MSH peptide (¹⁸F-FB-Ac-Nle-Asp-His-D-Phe-Arg-Trp-Gly-Lys-NH₂ [NAPamide]) shows promising melanoma imaging properties but with only moderate tumor uptake and retention. A transition metal rhenium-cyclized -MSH peptide, ReO[Cys^3,4,10,D-Phe⁷,Arg¹¹]-MSH_3–13 (ReCCMSH(Arg¹¹)), has shown high in vitro binding affinity to MC1R and excellent in vivo melanoma-targeting profiles when labeled with radiometals. Therefore, we hypothesized that ReCCMSH(Arg¹¹) could be a good platform for the further development of an ¹⁸F-labeled probe for PET of MC1R-positive malignant melanoma. Methods: In this study, the metallopeptide Ac-D-Lys-ReCCMSH(Arg¹¹) was synthesized using conventional solid-phase peptide synthesis chemistry and a rhenium cyclization reaction. The resulting peptides were then labeled with N-succinimidyl-4-¹⁸F-fluorobenzoate (¹⁸F-SFB). The ¹⁸F-labeled metallopeptides were further tested for their in vitro receptor binding affinities, in vivo biodistribution, and PET imaging properties. Results: Both isomers of Ac-D-Lys-ReCCMSH(Arg¹¹), named as RMSH-1 and RMSH-2, were purified and identified by high-performance liquid chromatography. The binding affinities of RMSH-1 and RMSH-2 and their respective ¹⁹F-SFB–conjugated peptides (¹⁹F-FB-RMSH-1 and ¹⁹F-FB-RMSH-2) were all determined to be within nanomolar range. Both ¹⁸F-labeled metallopeptides showed good tumor uptake in the B16F10 murine model, with high MC1R expression, but much lower uptake in the A375M human melanoma xenografted in mice, indicating low MC1R expression. ¹⁸F-FB-RMSH-1, when compared with ¹⁸F-FB-RMSH-2, displayed more favorable in vivo performance in terms of slightly higher tumor uptakes and much lower accumulations in the kidney and liver at 2 h after injection. Small-animal PET of ¹⁸F-FB-RMSH-1 and -2 in mice bearing B16F10 tumors at 1 and 2 h showed good tumor imaging quality. As expected, much lower tumor uptakes and poorer tumor–to–normal organ contrasts were observed for the A375M model than for the B16F10 model. ¹⁸F-FB-RMSH-1 and -2 showed higher tumor uptake and better tumor retention than did ¹⁸F-FB-NAPamide. Conclusion: Specific in vivo targeting of ¹⁸F-FB-RMSH-1 to malignant melanoma was successfully achieved in preclinical models with high MC1R expression. Thus, the radiofluorinated metallopeptide ¹⁸F-FB-RMSH-1 is a promising molecular probe for PET of MC1R-positive tumors.

Key Words: malignant melanoma • -MSH • PET • imaging • ¹⁸F

^* Contributed equally to this work.

COPYRIGHT © 2009 by the Society of Nuclear Medicine, Inc.

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