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Synthesis and Evaluation of a Macrocyclic Actinium‐225 Chelator, Quality Control and In Vivo Evaluation of 225 Ac‐crown‐αMSH Peptide
Author(s) -
Yang Hua,
Zhang Chengcheng,
Yuan Zheliang,
RodriguezRodriguez Cristina,
Robertson Andrew,
Radchenko Valery,
Perron Randy,
Gendron Denise,
Causey Patrick,
Gao Feng,
Bénard François,
Schaffer Paul
Publication year - 2020
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202002999
Subject(s) - dota , biodistribution , chemistry , in vivo , radiochemistry , peptide , melanocortin 1 receptor , chelation , in vitro , biochemistry , biology , organic chemistry , allele , microbiology and biotechnology , gene
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.