Synthesis and Preclinical Evaluation of Fluorinated 5-Azaindoles as CB2 PET Radioligands

Several classes of cannabinoid receptor type 2 radioligands have been evaluated for imaging of neuroinflammation, with successful clinical translation yet to take place. Here we describe the synthesis of fluorinated 5-azaindoles and pharmacological characterization and in vivo evaluation of ¹⁸F-radiolabeled analogues. [¹⁸F]2 (hCB2 K_i = 96.5 nM) and [¹⁸F]9 (hCB2 K_i = 7.7 nM) were prepared using Cu-mediated ¹⁸F-fluorination with non-decay-corrected radiochemical yields of 15 ± 6% and 18 ± 2% over 85 and 80 min, respectively, with high radiochemical purities (>97%) and molar activities (140-416 GBq/μmol). In PET imaging studies in rats, both [¹⁸F]2 and [¹⁸F]9 demonstrated specific binding in CB2-rich spleen after pretreatment with CB2-specific GW405833. Moreover, [¹⁸F]9 exhibited higher brain uptake at later time points in a murine model of neuroinflammation compared with a healthy control group. The results suggest further evaluation of azaindole based CB2 radioligands is warranted in other neuroinflammation models.