Radiosynthesis of microtubule-targeted theranostic methyl N-[5-(3'-radiohalobenzoyl)-1H-benzimidazol-2-yl]carbamates.

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)-1H-benzimidazol-2-yl]carbamates 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-1H-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 H2 O2 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.