Synthesis and evaluation of a boronated nitroimidazole for boron neutron capture therapy

We postulated that nitroimidazoles, previously used for radiosensitizing solid tumors, may be interesting templates as carriers of ¹⁰B for boron neutron capture therapy. To test this hypothesis, we synthesized a ¹⁰B- enriched nitroimidazole, 1-[2-[(undecahydro-closo-dodecaborato)thio]ethyl]- 2-methyl-5-nitroimidazole (imidocaptate), by coupling the Cs salt of BSH (Cs₂¹⁰B₁₂H₁₁SH) with 1-(2-bromoethyl)-2-methyl-5-nitroimidazole followed by purification of the adduct. Imidocaptate was taken up by V-79 cells in culture and showed no inherent toxicity under euoxic conditions up to 1.05 mM (126 μg of ¹⁰B/mL of culture medium). Imidocaptate showed a dose-dependent decrease in D(o) when the treated cells were irradiated with a thermal neutron beam. At the highest dose tested (126 μg of ¹⁰B/mL of culture medium), the ratio of control to sample D(o) values was 2.6 for both linear quadratic and single-hit multitarget models. At 33 μg of ¹⁰B/mL, imidocaptate showed a control/treated Do ratio (1.5) equal to that observed with the disulfide form of BSH at 28 μg of ¹⁰B/mL. Compared to BSH and its disulfide, the reduced toxicity and equipotency of imidocaptate suggest that this agent may be useful for boron neutron capture therapy of cancer.