Small-animal PET of melanocortin 1 receptor expression using a ¹⁸F-labeled α-melanocyte-stimulating hormone analog

¹⁸F-Labeled small synthetic peptides have emerged as attractive probes for imaging various molecular targets with PET. The α-melanocyte- stimulating hormone (α-MSH) receptor (melanocortin type 1 receptor [MC1R]) is overexpressed in most murine and human melanomas. It is a promising molecular target for diagnosis and therapy of melanomas. However, ¹⁸F compounds have not been successfully developed for imaging the MC1R. Methods: In this study, an α-MSH analog, Ac-Nle-Asp-His-D-Phe-Arg-Trp-Gly-Lys- NH₂ (NAPamide), was radiolabeled with N-succinimidyl-4- ¹⁸F-fluorobenzoate (¹⁸F-SFB). The resulting radiopeptide was evaluated as a potential molecular probe for small-animal PET of melanoma and MC1R expression in melanoma xenografted mouse models. Results: The binding affinity of ¹⁹F-SFB-conjugated NAPamide, ¹⁹F-FB-NAPamide, was determined to be 7.2 ± 1.2 nM (mean ± SD) using B16/F10 cells and ¹²⁵l-(Tyr²)-[Nle⁴,D-Phe⁷]- α-MSH [¹²⁵l-(Tyr²)-NDP] as a radioligand. The biodistribution of ¹⁸F-FB-NAPamide was then investigated in C57BL76 mice bearing subcutaneous murine B16/F10 melanoma tumors with high expression of MC1Rs and Fox Chase Scid mice bearing human A375M melanoma with a relatively low number of MC1R receptors. Biodistribution experiments showed that tumor uptake values (percentage injected dose per gram of tumor [%ID/g]) of ¹⁸F-FB-NAPamide were 1.19 ± 0.11 %ID/g and 0.46 ± 0.11 %ID/g, in B16/F10 and A375M xenografted melanoma at 1 h after injection, respectively. Furthermore, the B16/F10 tumor uptake was significantly inhibited by coinjection with excess α-MSH peptide (P < 0.05), indicating that ¹⁸F-FB-NAPamide specifically recognizes the MC1R in living mice. Small-animal PET of ¹⁸F-FB-NAPamide in mice bearing B16/F10 and A375M tumors at 1 h after tail vein injection revealed good B16/F10 tumor-to-background contrast and low A375M tumor-to-background ratios. Conclusion: ¹⁸F-FB-NAPamide is a promising molecular probe for α-MSH receptor-positive melanoma PET and warrants further study.