Synthesis and Evaluation of a Macrocyclic Actinium‐225 Chelator, Quality Control and In Vivo Evaluation of <sup>225</sup>Ac‐crown‐αMSH Peptide
Hua Yang, Chengcheng Zhang, Zheliang Yuan, Cristina Rodríguez‐Rodríguez, Andrew K. H. Robertson, Valery Radchenko, Randy Perron, Denise Gendron, Patrick Causey, Feng Gao, François Bénard, Paul Schaffer
Abstract
Abstract 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.