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

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).