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

  • ACS Chem Neurosci. 2023 Aug 16;14(16):2902-2921. doi: 10.1021/acschemneuro.3c00345.
Annukka Kallinen  1 ,  Karine Mardon  2 ,  Samuel Lane  1 ,  Andrew P Montgomery  1 ,  Rajiv Bhalla ,  Damion H R Stimson ,  Muneer Ahamed  2 ,  Gary J Cowin  2 ,  David Hibbs  3 ,  Eryn L Werry  1 ,  Roger Fulton  4 ,  Mark Connor  5 ,  Michael Kassiou  1
Affiliations
  • 1. School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
  • 2. ARC Centre for Innovation in Biomedical Imaging Technology, The University of Queensland, Brisbane, QLD 4072, Australia.
  • 3. Sydney Pharmacy School, The University of Sydney, Sydney, NSW 2006, Australia.
  • 4. Faculty of Health Sciences, The University of Sydney, Sydney, NSW 2050, Australia.
  • 5. Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia.
PMID: 37499194 DOI: 10.1021/acschemneuro.3c00345
Abstract

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 Ki = 96.5 nM) and [18F]9 (hCB2 Ki = 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.

Keywords
CB2 radioligand; Cu-mediated fluorination; LPS; aryl boronate; fluorine-18; neuroinflammation.
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