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J Med Chem. 2008 Sep 25;51(18):5608-16. doi: 10.1021/jm800329z.

Discovery and labeling of high-affinity 3,4-diarylpyrazolines as candidate radioligands for in vivo imaging of cannabinoid subtype-1 (CB1) receptors.

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Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA.


Imaging of cannabinoid subtype-1 (CB1) receptors in vivo with positron emission tomography (PET) is likely to be important for understanding their role in neuropsychiatric disorders and for drug development. Radioligands for imaging with PET are required for this purpose. We synthesized new ligands from a 3,4- diarylpyrazoline platform of which (-)-12a ((-)-3-(4-chlorophenyl)-N'-[(4-cyanophenyl)sulfonyl]-4-phenyl- 4,5-dihydro-1H-pyrazole-1-carboxamidine) was found to have high-affinity and selectivity for binding to CB1 receptors. (-)-12a and its lower affinity enantiomer ((+)-12a) were labeled with carbon-11 (t1/2 ) 20.4 min) using [11C]cyanide ion as labeling agent and evaluated as PET radioligands in cynomolgus monkeys. After injection of [11C](-)-12a, there was high uptake and retention of radioactivity across brain according to the rank order of CB1 receptor densities. The distomer, [11C](+)-12a, failed to give a sustained CB1 receptor-specific distribution. Polar radiometabolites of [11C](-)-12a appeared moderately slowly in plasma. Radioligand [11C](-)-12a is promising for the study of brain CB1 receptors and merits further investigation in human subjects.

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