Radiosynthesis and Biodistribution in Mice of a ¹⁸F-Labeled Analog of O-1302 for Use in Cerebral CB1 Cannabinoid Receptor Imaging

Abstract

The suitability of an ¹⁸F-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 ¹⁸F (T_1/2=109.7 min) by treatment of the corresponding tosyl derivative with [¹⁸F]fluoride ion in acetonitrile. Tissue distribution studies of the ¹⁸F-labeled form ([¹⁸F]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 [¹⁸F]1, indicating the possibility that P-glycoprotein regulates the ability of [¹⁸F]1 to cross the blood brain barrier. Radioligand [¹⁸F]1 does not have the required properties for imaging the cerebral cannabinoid CB1 receptor in vivo.