Synthesis andPreclinical Evaluation of Fluorinated5-Azaindoles as CB2 PET Radioligands

Severalclasses of cannabinoid receptor type 2 radioligandshavebeen evaluated for imaging of neuroinflammation, with successful clinicaltranslation yet to take place. Here we describe the synthesis of fluorinated5-azaindoles and pharmacological characterization and in vivo evaluation of 18F-radiolabeled analogues. [18F]2 (hCB2 Ki = 96.5 nM)and [18F]9 (hCB2 Ki = 7.7 nM) were prepared using Cu-mediated 18F-fluorinationwith non-decay-corrected radiochemical yields of 15 ± 6% and18 ± 2% over 85 and 80 min, respectively, with high radiochemicalpurities (>97%) and molar activities (140-416 GBq/μmol).In PET imaging studies in rats, both [18F]2 and [18F]9 demonstrated specific bindingin CB2-rich spleen after pretreatment with CB2-specific GW405833.Moreover, [18F]9 exhibited higher brain uptakeat later time points in a murine model of neuroinflammation comparedwith a healthy control group. The results suggest further evaluationof azaindole based CB2 radioligands is warranted in other neuroinflammationmodels.