Bromomisonidazole: Synthesis and characterization of a new radiosensitizer

4-Bromomisonidazole has been synthesized by direct bromination of misonidazole and has been characterized chemically and in animals. The compound is highly stable in vitro and in vivo and, relative to misonidazole, has an increased partition coefficient of 2.9 in octanol-water. In EMT-6/UW tumor-bearing mice, misonidazole and 4-bromomisonidazole (1 mmole/kg) sensitize tumors equally well to ¹³⁷Cs γ rays; sensitizer enhancement ratios of 1.9 (D₀ (- sensitizer)/[D₀ (+ sensitizer)] were obtained for both drugs. Toxicity studies (LD₅₀/₂(days)) showed that 4-bromomisonidazole is more toxic (LD₅₀ <6.5 mmole/kg) than misonidazole (LD₅₀ = 9.05 mmole/kg = 1.82 mg/g) in C3H/HeJ mice. Biodistribution studies of 4-[⁸²Br]bromomisonidazole in mice reveal that iv and ip routes of administration are equally effective in delivering the drug to tissue. The tumor:blood ratio reaches a maximum at 40 min postinjection. Tumor:blood ratios are similar to those for misonidazole; tumor:brain ratios are generally higher. Biodistributions of 4-[⁸²Br]bromomisonidazole and [⁸²Br]bromide ion are significantly different, suggesting that the label remains on the imidazole ring. Bromomisonidazole is stable, appears to retain its label in vivo, and has biodistribution and toxicity characteristics consistent with its high partition coefficient. It is at least as good a sensitizer as misonidazole. It may retain other properties of misonidazole, which may make it directly cytotoxic to hypoxic cells or capable of binding in such cells. These properties suggest that it may be useful for imaging hypoxic cells in tumors as well as other tissues.