PET of malignant melanoma using 18F-labeled metallopeptides

Abstract

Melanocortin type 1 receptor (MC1R), also known as α-melanocyte- stimulating hormone (α-MSH) receptor, is an attractivemolecular target for melanoma imaging and therapy. An 18F-labeled linear α-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 rheniumcyclized α-MSH peptide, ReO[Cys3,4,10,D-Phe7,Arg11] α-MSH3-13 (ReCCMSH(Arg11)), has shown high in vitro binding affinity toMC1R and excellent in vivo melanoma-targeting profiles when labeled with radiometals. Therefore, we hypothesized that ReCCMSH(Arg 11) 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 (18FSFB). The 18F-labeledmetallopeptides 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-FBRMSH-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. Copyright © 2009 by the Society of Nuclear Medicine, Inc.