Synthesis and Evaluation of a Macrocyclic Actinium‐225 Chelator, Quality Control and In Vivo Evaluation of 225 Ac‐crown‐αMSH Peptide

Targeted alpha‐therapy (TAT) has great potential for treating a broad range of late‐stage cancers by delivering a focused and lethal radiation dose to tumors. Actinium‐225 ( 225 Ac) is an emerging alpha emitter suitable for TAT; however, the availability of chelators for Ac remains limited to a small number of examples (DOTA and macropa). Herein, we report a new Ac macrocyclic chelator named ‘ crown’ , which binds quantitatively and rapidly (<10 min) to Ac at ambient temperature. We synthesized 225 Ac‐ crown ‐αMSH, a peptide targeting the melanocortin 1 receptor (MC1R), specifically expressed in primary and metastatic melanoma. Biodistribution of 225 Ac‐ crown ‐αMSH showed favorable tumor‐to‐background ratios at 2 h post injection in a preclinical model. In addition, we demonstrated dramatically different biodistrubution patterns of 225 Ac‐ crown ‐αMSH when subjected to different latency times before injection. A combined quality control methodology involving HPLC, gamma spectroscopy and radioTLC is recommended.