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Synthesis and in vitro evaluation of fluorine-18 benzimidazole sulfones as CB2 PET-radioligands

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Abstract

Cannabinoid type 2 receptor (CB2) is up-regulated on activated microglial cells and can potentially be used as a biomarker for PET-imaging of neuroinflammation. In this study the synthesis and pharmacological evaluation of novel fluorinated pyridyl and ethyl sulfone analogues of 2-(tert-butyl)-5-((2-fluoropyridin-4-yl)sulfonyl)-1-(2-methylpentyl)-1H-benzo[d]imidazole (rac-1a) are described. In general, the ligands showed low nanomolar potency (CB2 EC50 < 10 nM) and excellent selectivity over the CB1 subtype (>10 000×). Selected ligands 1d, 1e, 1g and 3l showing high CB2 binding affinity (Ki < 10 nM) were radiolabelled with fluorine-18 from chloropyridyl and alkyl tosylate precursors with good to high isolated radioactive yields (25–44%, non-decay corrected, at the end of synthesis). CB2-specific binding of the radioligand candidates [18F]-1d and [18F]-3l was assessed on rat spleen cryosections using in vitro autoradiography. The results warrant further in vivo evaluation of the tracer candidates as prospective CB2 PET-imaging agents.

Graphical abstract: Synthesis and in vitro evaluation of fluorine-18 benzimidazole sulfones as CB2 PET-radioligands

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Publication details

The article was received on 21 Mar 2019, accepted on 01 May 2019 and first published on 01 May 2019


Article type: Paper
DOI: 10.1039/C9OB00656G
Org. Biomol. Chem., 2019, Advance Article

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    Synthesis and in vitro evaluation of fluorine-18 benzimidazole sulfones as CB2 PET-radioligands

    A. Kallinen, R. Boyd, S. Lane, R. Bhalla, K. Mardon, D. H. R. Stimson, E. L. Werry, R. Fulton, M. Connor and M. Kassiou, Org. Biomol. Chem., 2019, Advance Article , DOI: 10.1039/C9OB00656G

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