Synthesis of Two Versions of Carbon-14-Labeled ARV-110: An Androgen Receptor PROTAC Degrader for Prostate Cancer.

N-((1R,4R)-4-(3-Chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide (ARV-110) is a proteolysis-targeting chimera (PROTAC) designed against the androgen receptor (AR), which shows great potential for treating AR-dependent diseases, such as prostate cancer. To support preclinical safety evaluations as well as studies of drug metabolism and pharmacokinetics, two versions of carbon-14-labeled ARV-110 were synthesized: N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-[1,3-C2]dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide (C-ARV-110-a) and N-((1R,4R)-4-(3-chloro-4-[cyano-C]cyanophenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide (C-ARV-110-b). The synthesis of C-ARV-110-a was initiated from 1,2-dibromo-4,5-difluorobenzene and zinc cyanide-C (Zn(CN)₂), while C-ARV-110-b was prepared from 2-chloro-4-fluoro[cyano-C]benzonitrile.