Selective Cyclized α‑Melanocyte-Stimulating Hormone Derivative with Multiple N‑Methylations for Melanoma Imaging with Positron Emission Tomography

In this study, we designed and evaluated a novel α-melanocyte-stimulating hormone derivative with four N-methylations for melanocortin 1 receptor-targeted melanoma imaging with positron emission tomography (PET). The resulting peptide, DOTA-Pip-Nle4-Cyclo­[Asp5-N-Me-His6-d-Phe7-N-Me-Arg8-N-Me-Trp9-N-Me-Lys10]­αMSH4‑10-NH2 (CCZ01099), showed high receptor selectivity, greatly improved stability, and rapid internalization. [68Ga]­Ga-CCZ01099 showed clear tumor visualization and excellent tumor-to-normal tissue contrast with PET imaging in a preclinical melanoma model. Therefore, CCZ01099 is a promising compound for imaging and potentially radioligand therapy for melanoma.