Synthesis and Preclinical Evaluation of Fluorinated 5-Azaindoles as CB2 PET Radioligands.
Annukka KallinenKarine MardonSamuel LaneAndrew P MontgomeryRajiv BhallaDamion H R StimsonMuneer AhamedGary J CowinDavid E HibbsEryn L WerryRoger R FultonMark ConnorMichael KassiouPublished in: ACS chemical neuroscience (2023)
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 18 F-radiolabeled analogues. [ 18 F] 2 (hCB2 K i = 96.5 nM) and [ 18 F] 9 (hCB2 K i = 7.7 nM) were prepared using Cu-mediated 18 F-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 [ 18 F] 2 and [ 18 F] 9 demonstrated specific binding in CB2-rich spleen after pretreatment with CB2-specific GW405833. Moreover, [ 18 F] 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.
Keyphrases
- pet imaging
- lipopolysaccharide induced
- cerebral ischemia
- traumatic brain injury
- lps induced
- cognitive impairment
- photodynamic therapy
- positron emission tomography
- high resolution
- computed tomography
- inflammatory response
- white matter
- pet ct
- blood brain barrier
- cell therapy
- binding protein
- multiple sclerosis
- fluorescence imaging
- transcription factor
- mass spectrometry