Synthesis and biodistribution of [¹¹C]A-836339, a new potential radioligand for PET imaging of cannabinoid type 2 receptors (CB₂)

Recently, A-836339 [2,2,3,3-tetramethylcyclopropanecarboxylic acid [3-(2-methoxyethyl)-4,5-dimethyl-3H-thiazol-(2Z)-ylidene]amide] (1) was reported to be a selective CB₂ agonist with high binding affinity. Here we describe the radiosynthesis of [¹¹C]A-836339 ([¹¹C]1) via its desmethyl precursor as a candidate radioligand for imaging CB₂ receptors with positron-emission tomography (PET). Whole body and the regional brain distribution of [¹¹C]1 in control CD1 mice demonstrated that this radioligand exhibits specific uptake in the CB₂-rich spleen and little specific in vivo binding in the control mouse brain. However, [ ¹¹C]1 shows specific cerebral uptake in the lipopolysaccharide (LPS)-induced mouse model of neuroinflammation and in the brain areas with Aβ amyloid plaque deposition in a mouse model of Alzheimer's disease (APPswe/PS1dE9 mice). These data establish a proof of principle that CB ₂ receptors binding in the neuroinflammation and related disorders can be measured in vivo.