Preclinical evaluation of MC1R targeted radiopharmaceuticals using the ^203/212Pb theranostic pair

Melanomas are the deadliest form of skin cancer owing to a lack of effective treatment options available for metastatic disease. Melanocortin 1 receptor (MC1R) is found overexpressed in the vast majority of melanomas, making this receptor a suitable target for a radiopharmaceutical to specifically deliver diagnostic and therapeutic radionuclides to tumours. We report here the synthesis and preclinical evaluation of a series of such compounds derived from α-melanocyte stimulating hormone for use with the diagnostic nuclide ²⁰³Pb and its therapeutic counterpart ²¹²Pb. Competition binding assays identified compound 9, a derivative of the potent MC1R agonist NDP-MSH, as possessing sub-nanomolar binding affinity for MC1R and a high selectivity against the closely related melanocortin 4 receptor. A subsequent biodistribution study in B16 melanoma bearing mice revealed a high tumour uptake of [²⁰³Pb]Pb-9 relative to the other tested compounds, whilst simultaneously possessing the lowest hepatic and splenic uptakes of the series. Organ uptake of [²⁰³Pb]Pb-9 was accordingly by far the most specific for the tumour, and its low accumulation in normal organs confirmed in a subsequent biodistribution study in healthy mice. Compound 9 therefore represents a promising candidate for further development towards an MC1R targeted melanoma therapy.