Presentation Development of new PET ligands for cannabinoid receptor type 1 in the brown adipose tissue

Yamasaki, Tomoteru  ,  Fujinaga, Masayuki  ,  Shimoda, Yoko  ,  Mori, Wakana  ,  Zhang, Yiding  ,  Wakizaka, Hidekatsu  ,  Kurihara, Yusuke  ,  Kawamura, Kazunori  ,  Ming-Rong, Zhang

2017-05-15
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Objectives: The endocannabinoid system regulates multiple physiological functions and identified two types G-protein coupled receptors (CB1 and CB2). Among, CB1 is mainly expressed in the brain but also in various peripheral tissues with functionally relevant concentration. Recently, CB1 was confirmed the existence of significant deposits of the brown adipose tissue (BAT) in human adults and concerned with metabolic disorders. Therefore, several compounds targeting CB1 were developed for treatment of obesity. Of these, 1-(4-chlorophenyl)-3-(3-(6-(pyrrolidin-1-yl)pyridin-2-yl)phenyl)urea (PSNCBAM-1) was developed as a potent allosteric antagonist for CB1 and exhibited reductions of feeding and body weight in rats. More recently, PSNDM and PSNP were synthesized as analogs of PSNCBAM-1 via structure-activity relationship studies [1]. Herein, we synthesized [11C]PSNDM and [11C]PSNP using [11C]COCl2 and evaluated their potentials by in vitro assay and in vivo PET imaging.Methods: [11C]PSNDM and [11C]PSNP were synthesized from [11C]COCl2 via [11C]CH4 and then [11C]CCl4 by two steps reaction, respectively. To evaluate binding affinity for peripheral CB1, in vitro binding assays of PSNDM and PSNP were conducted using BAT homogenate of rats. Small-animal PET studies were performed in mice.Results: [11C]PSNDM and [11C]PSNP were successfully synthesized with appropriate radioactivity for animal studies. The radiochemical yields of [11C]PSNDM and [11C]PSNP from [11C]CO2 were 13±8% (n = 5) and 21±7% (n = 5) at EOS, respectively. The molar radioactivity of [11C]PSNDM and [11C]PSNP at EOS were 24±10 GBq/μmol (n = 5) and 32±16 GBq/μmol (n = 5), respectively. Radiochemical purity of both radioligands was >99%. Their synthesis time was approximately 35 min. In vitro binding assay using BAT homogenates indicated higher affinity of PSNDM (Ki = 3.9 µM) than that of PSNP (Ki > 100 µM). In PET studies of mice, the high uptake of radioactivity was shown in the BAT. By Pretreatment with AM281 (a selective allosteric antagonist for CB1), the radioactivity level in the BAT was significantly decreased.Conclusions: [11C]PSNDM and [11C]PSNP were successfully synthesized using [11C]COCl2. [11C]PSNDM showed high specific binding in the BAT of mice. [11C]PSNDM may be a useful PET ligand for imaging of CB1 in the BAT. Acknowledgements:References: [1] German N, et al., J. Med. Chem. 2014, 57, 7758–7769.
22nd International symposium on radiopharmaceutical science (ISRS)

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