
Journal of Medicinal Chemistry p. 7840 - 7855 (2016)
Update date:2022-08-15
Topics:
Moldovan, Rare?-Petru
Teodoro, Rodrigo
Gao, Yongjun
Deuther-Conrad, Winnie
Kranz, Mathias
Wang, Yuchuan
Kuwabara, Hiroto
Nakano, Masayoshi
Valentine, Heather
Fischer, Steffen
Pomper, Martin G.
Wong, Dean F.
Dannals, Robert F.
Brust, Peter
Horti, Andrew G.
Cannabinoid receptors type 2 (CB2) represent a target with increasing importance for neuroimaging due to its upregulation under various pathological conditions. Encouraged by preliminary results obtained with [11C](Z)-N-(3-(2-methoxyethyl)-4,5-dimethylthiazol-2(3H)-ylidene)-2,2,3,3-tetramethyl-cyclopropanecarboxamide ([11C]A-836339, [11C]1) in a mouse model of acute neuroinflammation (induced by lipopolysaccharide, LPS), we designed a library of fluorinated analogues aiming for an [18F]-labeled radiotracer with improved CB2 binding affinity and selectivity. Compound (Z)-N-(3-(4-fluorobutyl)-4,5-dimethylthiazol-2(3H)-ylidene)-2,2,3,3-tetramethyl-cyclopropanecarboxamide (29) was selected as the ligand with the highest CB2 affinity (Ki = 0.39 nM) and selectivity over those of CB1 (factor of 1000). [18F]29 was prepared starting from the bromo precursor (53). Specific binding was shown in vitro, whereas fast metabolism was observed in vivo in CD-1 mice. Animal PET revealed a brain uptake comparable to that of [11C]1. In the LPS-treated mice, a 20-30% higher uptake in brain was found in comparison to that in nontreated mice (n = 3, P < 0.05).
View More
Contact:+86-21-38228826
Address:Room 505 Building 2, No 3377 Kangxin Highway, Shanghai, Republic China
Contact:027-87677569
Address:Room 2203, yujingmingmen Buidling One, xiongchu Road, wuhan city, hubei province, China
Contact:86-371-63655023
Address:No.85,jinshui road,zhengzhou,China
Contact:86-898-65311214
Address:Room 102, BLDG. 68 Jiangnan City, No. 66 Heping Road,Haikou, Hainan, China
Hangzhou Bayee Chemical Co.,Ltd.
Contact:+86-571-86990109
Address:No.380, Jiangnan Auenue, Binjiang District, Hangzhou, China
Doi:10.1560/IJC.49.1.1
(2009)Doi:10.1016/j.tetlet.2009.05.033
(2009)Doi:10.1021/ja01192a045
(1948)Doi:10.1248/cpb.59.579
(2011)Doi:10.1002/adsc.200900112
(2009)Doi:10.1002/zaac.201100211
(2011)