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 (K_i = 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).