Journal Article Radiosynthesis and evaluation of new PET ligands for peripheral cannabinoid receptor type 1 imaging

Yamasaki, Tomoteru  ,  Fujinaga, Masayuki  ,  Shimoda, Yoko  ,  Mori, Wakana  ,  Zhang, Yiding  ,  Wakizaka, Hidekatsu  ,  Ogawa, Masanao  ,  Ming-Rong, Zhang

27 ( 17 )  , pp.4114 - 4117 , 2017-07 , Elsevier
Cannabinoid receptor type 1 (CB1) is mainly expressed in the brain, as well as being expressed in functional relevant concentrations in various peripheral tissues. 1-(4-Chlorophenyl)-3-(3-(6-(pyrrolidin-1-yl)pyridin-2-yl)phenyl)urea (PSNCBAM-1, 1) was developed as a potent allosteric antagonist for CB1 and its oral administration led to reductions in the appetite and body weight of rats. Several analogs of 1 (compounds 2 and 3) were recently identified through a series of structure-activity relationship studies. Herein, we report the synthesis of radiolabeled analogs of these compounds using [11C]COCl2, and an evaluation of their potential as PET ligands for CB1 imaging using in vitro and in vivo techniques. [11C]2 and [11C]3 were successfully synthesized in two steps using [11C]COCl2. The radiochemical yields of [11C]2 and [11C]3 were 17 ± 8% and 20 ± 9% (decay-corrected to the end of bombardment, based on [11C]CO2). The specific activities of [11C]2 and [11C]3 were 42 ± 36 and 37 ± 13 GBq/μmol, respectively. The results of an in vitro binding assay using brown adipose tissue (BAT) homogenate showed that the binding affinity of 2 for CB1 (KD = 15.3 µM) was much higher than that of 3 (KD = 26.0 µM). PET studies with [11C]2 showed a high uptake of radioactivity in BAT, which decreased considerably in animals pretreated with AM281 (a selective allosteric antagonist for CB1). In conclusion, [11C]2 may be a useful PET ligand for imaging peripheral CB1 in BAT.2009 Elsevier Ltd. All rights reserved.

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