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

• Published in: ACS chemical neuroscience 2023-08, Vol.14 (16), p.2902-2921
• Main Authors: Kallinen, Annukka, Mardon, Karine, Lane, Samuel, Montgomery, Andrew P., Bhalla, Rajiv, Stimson, Damion H. R., Ahamed, Muneer, Cowin, Gary J., Hibbs, David, Werry, Eryn L., Fulton, Roger, Connor, Mark, Kassiou, Michael
• Format: Article
• Language: English
• ISSN: 1948-7193; 1948-7193
• DOI: 10.1021/acschemneuro.3c00345

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.