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

Abstract

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. I- and 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 I-4 and I-4. Radioiododestannylation of 3'-trimethylstannane 3 proceeded with ease at room temperature in the presence of H O as the oxidant and produced no-carrier-added I-4 and I-4 in high isolated yields, on average 85%. The radiohalodestannylation protocol is universal and can be applied to other radiohalides including I to produce I-4, a positron emission tomography agent, and At to produce At-4, an α-particle emitting radiotherapeutic.

Norepinephrine-Transporter-Targeted and DNA-Co-Targeted Theranostic Guanidines

“…The processes shown in Schemes and involve three consecutive steps: the initial preparation of nonradioactive iodo analogs followed by the stannylation of iodides to the corresponding stannanes and the subsequent non-carrier-added electrophilic 125 I-iododestannylation of organotin precursors to the target 125 I-iodinated products. This well-proven radioiodination sequence based on the modified Stille coupling and originally applied in our laboratories to produce no-carrier-added 5-[ 125 I]­iodo-2′-deoxyuridine and other radiolabeled compounds − served just as effectively in this project.…”

Biological Evaluation of a Potential Anticancer Agent MethylN-[5-(3′-Iodobenzoyl)-1H-Benzimidazol-2-yl]Carbamate

“…Chemical structures of compounds evaluated in this study are shown in Figure 1 and they were synthesized as described previously. 22 Mebendazole 3 was purchased from Sigma-Aldrich. Physicochemical parameters of evaluated compounds are listed in Supplementary Table S1.…”

In vitro and in vivo evaluation of radiolabeled methyl N‐[5‐(3′‐halobenzoyl)‐1H‐benzimidazol‐2‐yl]carbamate for cancer radiotherapy

“…Chemical structures of compounds evaluated in this study are shown in Figure 1. Methyl N-[5-(3 0 -radiohalobenzoyl)-1H-benzimidazol-2-yl] carbamates 1 and 2 were synthesized as previously described (Kortylewicz & Baranowska-Kortylewicz, 2018). All agents used in the biological evaluation studies were purified on an HPLC system.…”

“…When radiolabeled with αor β-particle emitting radiohalides, these new BCars can be developed into an effective and safe treatment modality across a wide spectrum of cancers. They can function as theranostics, that is, can be also radiolabeled without reshaping their chemical structure with either PET-and SPECT-compatible radionuclides for imaging (Kortylewicz & Baranowska-Kortylewicz, 2018). To date, only a few attempts have been made to develop microtubule-targeted imaging agents, which can measure the drug concentration in tumors and facilitate rational treatment choices (Korde et al, 2006;van der Veldt et al, 2010;van der Veldt et al, 2011;Zareneyrizi et al, 1999).…”