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

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The role of theranostics in cancer management is growing so is the selection of vectors used to deliver these modalities to cancer cells. We describe biological evaluation of a novel theranostic agent targeted to microtubules. Methyl N-[5-(3′-[131I]iodobenzoyl)-1H-benzimidazol-2-yl]carbamate (1) and methyl N-[5-(3′-[125I]iodobenzoyl)-1H-benzimidazol-2-yl]carbamate (2) were synthesized from a common precursor 3′-stannylated derivative (4). Antiproliferative effects and radiotoxicity of 131I-labeled β-particle emitting 1 were examined in vitro in human neuroblastoma and glioblastoma cells lines. The therapeutic potential of 1 was also examined in a subcutaneous mouse model of human glioblastoma U-87 MG. Compound 1 at the extracellular radioactive concentration of 0.35 MBq/mL, easily achievable in vivo, kills >90% of neuroblastoma cells and >60% glioblastoma cells as measured in a clonogenic assay. D10 doses established for 1 indicate that as few as 3,000 decays are sufficient to kill 90% of BE(2)-C cells. Even U-87 MG cells, the least sensitive of the tested cell lines, require <20,000 decays of intracellular 131I to reduce number of clonogenic cells by 90%. Biodistribution studies of 2 delivered either intratumorally or intraperitoneally show a similar tissue distribution for both routes of the drug administration. The whole body clearance half-lives were on average 6 hr. Intratumor administration of 1 produces significant tumor growth delay. After a single dose of 8.4 ± 0.3 MBq of compound 1, the tumor doubling times were 3.2 ± 0.1 and 7.9 ± 0.6 days in control and treated mice, respectively. Methyl N-[5-(3′-radiohalobenzoyl)-1H-benzimidazol-2-yl]carbamates have properties compatible with a theranostic approach to cancer management.

Original languageEnglish (US)
Pages (from-to)62-69
Number of pages8
JournalDrug Development Research
Issue number1
StatePublished - Feb 1 2020



  • benzimidazole carbamates
  • cancer therapy
  • microtubules
  • theranostics
  • β-particles

ASJC Scopus subject areas

  • Drug Discovery

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