Radiosynthesis of microtubule‐targeted theranostic methyl N N ‐5‐(3’‐radiohalobenzoyl)‐1 H H ‐benzimidazol‐2‐ylcarbamates

摘要

Microtubules are a target for a broad spectrum of drugs used as chemotherapeutics to treat hematological malignancies and solid tumors. Most of these drugs have significant dose‐limiting toxicities including peripheral neuropathies that can be debilitating and permanent. In an ongoing effort to develop safer and more effective drugs, benzimidazole‐based compounds are being developed as replacement for vincristine and similar agents. In this report, we describe radiosyntheses of novel microtubule‐targeting methyl N ‐5‐(3’‐radiohalobenzoyl)‐1 H ‐benzimidazol‐2‐ylcarbamates 4 that are intended as potential imaging agents and molecular radiotherapeutics. 125 I‐ and 131 I‐radiolabeled derivatives were prepared either by direct radioiodination of methyl N ‐(6‐benzoyl‐1 H ‐benzimidazol‐2‐yl)carbamate 1 or radioiododestannylation of the corresponding stannane precursor 3 . The direct radioiodination was conducted in a solution of 1 in triflic acid and produced after ~1?hour at elevated temperatures and HPLC purification on average 62 of the no‐carrier added products 125 I‐ 4 and 131 I‐ 4 . Radioiododestannylation of 3’‐trimethylstannane 3 proceeded with ease at room temperature in the presence of H 2 O 2 as the oxidant and produced no‐carrier‐added 125 I‐ 4 and 131 I‐ 4 in high isolated yields, on average 85. The radiohalodestannylation protocol is universal and can be applied to other radiohalides including 124 I to produce 124 I‐ 4 , a positron emission tomography agent, and 211 At to produce 211 At‐ 4 , an α‐particle emitting radiotherapeutic.