Synthesis and Characterization of Lipophilic 1-[¹⁸F]Fluoroalkyl-2-nitroimidazoles for Imaging Hypoxia

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In order to develop new imaging markers for brain hypoxia, two lipophilic nitroimidazoles, 1-(3-fluoropropyl)-2-nitroimidazole (FPN) and 1-(8-fluorooctyl)-2-nitroimidazole (FON) were synthesized and labeled with fluorine-18. The octanol/water partition coefficients were measured as an indication of lipophilicity, giving values of log P=0.28 for FPN and log P=2.72 for FON, respectively, which are in the range thought to be optimal for the diffusion of molecules across the blood-brain barrier. It was suggested from a comparative study of in vitro radiosensitization in V79 cells that these lipophilic analogs may have reduction potentials close to those of fluoromisonidazole (FMISO) and misonidazole (MISO), known hypoxic cell radiosensitizers. The preparation of ¹⁸F-labeled FON (¹⁸FON) and FPN (¹⁸FPN) was achieved via two-steps through [¹⁸F]fluoride ion displacement of tosylate precursors. in reasonable radiochemical yields. Tissue distribution of ¹⁸FPN and ¹⁸FON in normal rats and tumor-bearing mice after intravenous injection was investigated and compared to the behavior of ¹⁸F-labeled FMISO (¹⁸FMISO), a proven hypoxic imaging agent. The high lipophilicity of ¹⁸FON and ¹⁸FPN resulted in increased initial uptake into normal rat brain, relative to ¹⁸FMISO, followed by a rapid washout from brain. Both of these lipophilic analogs had significantly lower tumor uptake and lower tumor-to-blood rations than ¹⁸FMISO, suggestive of a poor trapping mechanism within the tumor tissue. Neither ¹⁸FON or ¹⁸FPN offers improved biological properties over ¹⁸FMISO as a potential agent for use in brain hypoxic imaging.