Pharmacokinetic studies of amino acid analogues of 2-nitroimidazole, new hypoxic cell radiosensitizers.

A series of new analogues of 2-nitroimidazole has been synthesized by inserting various amino acids at 1-position through an amide bond. The ethyl esters of N-alpha-[(2-nitro-1-imidazolyl)acetyl]-L-phenylalanine and N-alpha-[2-nitro-1-imidazolyl)acetyl]-L-tyrosine were found to be the most effective radiosensitizers in vitro against hypoxic Chinese hamster (V-79) cells. The sensitizer enhancement ratios (SER) of these derivatives were 2.2 and 2.3 respectively at 1 mM concentration after 2 hr exposure under hypoxia. However, the free acid of phenylalanine analogue was less active as a radiosensitizer and required 5 mM concentration to produce SER of 1.9. In contrast, the free acid of tyrosine analogue was inactive in this test system. The pharmacokinetic studies with the esters revealed their rapid hydrolysis in serum to the corresponding acids within 5 minutes as detected by HPLC. The pharmacokinetic parameters were therefore determined by employing the free acid analogues and solubilizing them as their sodium salts. The drugs were administered intraperitoneally at 0.5 mg/g dose level to C-57 mice bearing B16 melanoma. These agents were cleared from the plasma rapidly with an apparent t 1/2 of 18.8 and 15.6 min respectively. Peak tumor concentration of approximately 217 micrograms/g was achieved within 15 min with phenylalanine analogue. The tumor to brain ratio was 10:1 suggesting that this agent is excluded from CNS and that the phenylalanine analogue should be considered a potentially less neurotoxic radiosensitizer than misonidazole.