Synthesis and characterization of lipophilic 1-[18F]fluoroalkyl-2-nitroimidazoles for imaging hypoxia.

Abstract

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 logP=0.28 for FPN and logP=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 ratios 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.

• Authors: F Yamamoto, H Oka, S Antoku, Y Ichiya, K Masuda, M Maeda
• Journal: Biological & pharmaceutical bulletin (Biol Pharm Bull) Vol. 22 Issue 6 Pg. 590-7 (Jun 1999) ISSN: 0918-6158 [Print] Japan
• PMID: 10408232 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1-(3-fluoropropyl)-2-nitroimidazole
• 1-(8-fluorooctyl)-2-nitroimidazole
• Fluorine Radioisotopes
• Imidazoles
• Nitro Compounds
• Nitroimidazoles

Topics

• Animals
• Brain (metabolism)
• Female
• Fluorine Radioisotopes
• Hypoxia (diagnostic imaging)
• Imidazoles (chemical synthesis, chemistry, pharmacokinetics)
• Male
• Mice
• Mice, Inbred C3H
• Neoplasms, Experimental (metabolism)
• Nitro Compounds (chemical synthesis, chemistry, pharmacokinetics)
• Nitroimidazoles (chemical synthesis, pharmacokinetics)
• Radionuclide Imaging
• Rats
• Rats, Wistar
• Solubility
• Tissue Distribution