¹⁸F-JHU94620, a high affinity PET radioligand for imaging of cannabinoid subtype 2 receptors (CB2R)

Objectives CB2R represents a target with increasing importance for neuroimaging due to its upregulation in various pathological conditions. Encouraged by preliminary results obtained with ¹¹C‑A-836339 (Ki = 1.2 nM) in a mouse model of acute neuroinflammation (induced by lipopolysaccharide, LPS), we designed a library of fluorinated analogs to develop a radioligand with improved CB2R binding affinity and selectivity.

Methods A series of fifteen analogs of A836339 was synthesized and JHU94620, selected as ligand with the highest CB2R affinity (Ki = 0.38 nM) and selectivity over CB1R (factor 1000). It was labelled from the bromo precursor by standard nucleophilic radiofluorination. For in vivo experiments, control and LPS-treated CD1 mice have been used. Metabolic stability was investigated in plasma samples (30 min p.i) by radio‑HPLC. In vitro autoradiography was performed on rat spleen and pig brain using CB1, CB2, and CB1/CB2 specific ligands as competitors.

Results ¹⁸F-JHU94620 was prepared in ~10% radiochemical yield, >98% radiochemical purity and specific activity of >150 GBq/µmol. Animal PET revealed a brain uptake comparable to ¹¹C‑A-836339. 20-30% higher uptake in LPS-treated mice was found (n=3, p<0.05). In plasma, ~10% of total radioactivity accounted for intact tracer at 30 min p.i. Binding of ¹⁸F-JHU94620 on spleen could be displaced by CB2- and CB1/CB2-specific but not by CB1-specific compounds (61%, 44%, and 107% of total binding, respectively, at 1 µM). As expected, in brain slices from healthy pig no specific binding was observed.

Conclusions ¹⁸F-JHU94620 is a potential candidate for further studies with PET in neuroinflamation and related disorders.

Research Support DFG fellowship to RPM