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Development of a High-Affinity PET Radioligand for Imaging Cannabinoid Subtype 2 Receptor

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journal contribution
posted on 08.08.2016, 00:00 authored by Rareş-Petru Moldovan, Rodrigo Teodoro, Yongjun Gao, Winnie Deuther-Conrad, Mathias Kranz, Yuchuan Wang, Hiroto Kuwabara, Masayoshi Nakano, Heather Valentine, Steffen Fischer, Martin G. Pomper, Dean F. Wong, Robert F. Dannals, Peter Brust, Andrew G. Horti
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).

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