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

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′‐[ 131 I]iodobenzoyl)‐1 H ‐benzimidazol‐2‐yl]carbamate ( 1 ) and methyl N ‐[5‐(3′‐[ 125 I]iodobenzoyl)‐1 H ‐benzimidazol‐2‐yl]carbamate ( 2 ) were synthesized from a common precursor 3′‐stannylated derivative ( 4 ). Antiproliferative effects and radiotoxicity of 131 I‐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. D 10 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 131 I 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.