Radiosynthesis and biodistribution in mice of a 18F-labeled analog of O-1302 for use in cerebral CB1 cannabinoid receptor imaging.
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 (Ki=0.91 nM) and moderate lipophilicity (log P7.4=2.9), as a radiotracer for positron emission tomography imaging was evaluated in mice. Ligand 1 was labeled with 18F (T1/2=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.
Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Yumiko
Y
Nojiri
Kiichi
K
Ishiwata
Qinggeletu
Shintaro
S
Tobiishi
Toru
T
Sasada
Fumihiko
F
Yamamoto
Takahiro
T
Mukai
Minoru
M
Maeda
D000818:Animals; D001711:Biotransformation; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D002855:Chromatography, Thin Layer; D016572:Cyclosporine / Q000494:pharmacology; D005462:Fluorine Radioisotopes; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007202:Indicators and Reagents; D007275:Injections, Intravenous; D007553:Isotope Labeling; D008297:Male; D051379:Mice; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects*; D014018:Tissue Distribution
D005462:Fluorine Radioisotopes; D007166:Immunosuppressive Agents; D007202:Indicators and Reagents; C522675:N-(piperidinyl)-1-(2,4-dichlorophenyl)-4-methyl-5-(4-pentylphenyl)-1H-pyrazole-3-carboxamide; D010880:Piperidines; D011720:Pyrazoles; D019275:Radiopharmaceuticals; D043884:Receptor, Cannabinoid, CB1; D016572:Cyclosporine