Radiosynthesis and Biodistribution in Mice of a ^<18>F-Labeled Analog of O-1302 for Use in Cerebral CB1 Cannabinoid Receptor Imaging(Medicinal Chemistry)

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The suitability of an ^<18>F-labeled form of N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-{4'-(5-fluoropentyl)-phenyl}-4-methyl-1H-pyrazole-3-carboxamide (1), a CB1 cannabinoid ligand with high binding affinity (K_i=0.91 nM) and moderate lipophilicity (log P_<7.4>=2.9), as a radiotracer for positron emission tomography imaging was evaluated in mice. Ligand 1 was labeled with ^<18>F (T_<1/2>=109.7 min) by treatment of the corresponding tosyl derivative with [^<18>F]fluoride ion in acetonitrile. Tissue distribution studies of the ^<18>F-labeled form ([^<18>F]1) in mice demonstrated low brain uptake with minimal specific binding in brain regions. Cyclosporin A ( a modulator of P-glycoprotein) treatment significantly increased both the brain uptake and the brain-to-blood ratio of [^<18>F]1, indicating the possibility that P-glycoprotein regulates the ability of [^<18>F]1 to cross the blood brain barrier. Radioligand [^<18>F]1 does not have the required properties for imaging the cerebral cannabinoid CB1 receptor in vivo.
社団法人日本薬学会の論文
2008-06-01