Pharmacokinetics of Fluorinated 2-nitroimidazole Hypoxic Cell Radiosensitizers in Murine Peripheral Nervous Tissue

Abstract

We have previously reported that KU-2285, a 2-nitroimidazole with a fluorinated N1-substituent (-CH₂-CF₂CONH(CH₂)_nOH, n = 2), was a promising hypoxic cell radiosensitizer. In this study the pharmacokinetics of KU-2285 and its related compounds (n = 3 and n = 4) were compared with those of entanidazole (a 2-nitroimidazole with an N1-substituent of -CH₂CONH(CH₂)_nOH, n = 2) and its related compounds (n = 3 and n = 4) to assess the effects of incorporation of a CF₂ group. The lipophilicity of the fluorinated compounds was higher than that of etanidazole, as measured by the octanol/water partition coefficient. As the number of CH₂ groups increased, the lipophilicity of the compounds in both the KU-2285 and etanidazole series increased. The brain tissue levels of the fluorinated compounds were as low as those of the etanidazole derivatives, while the biological half-lives of the fluorinated compounds in peripheral nervous tissues were shorter than those of related non-fluorinated compounds.