From Structure-Activity Relationships on Thiazole Derivatives to the In Vivo Evaluation of a New Radiotracer for Cannabinoid Subtype 2 PET Imaging.

Upregulation of the cannabinoid type 2 receptors (CBR) unveils inflammation processes of pathological disorders, such as cancer, pain, or neurodegenerative diseases. Among others, CBR agonist A-836339 has been labeled with carbon-11 for PET imaging of the CBR and displayed promising results in a mouse model of Alzheimer's disease. The aim of the present work was to develop fluorinated analogs of A-836339 for labeling with fluorine-18 to design a new PET tracer for CBR imaging. Seven fluorinated analogs of A-836339 were synthesized in two to three steps and their binding affinities and selectivities for both the human and the mouse CBR were measured as well as their early ADME profiles. Among them, compound 2f (K = 0.1 nM, K/K = 300) displayed high affinity and selectivity for CBR but also promising lipophilicity, kinetic solubility, and membrane permeation properties and was further selected for in vitro metabolism studies. Incubation of 2f with human or rat liver microsomes followed by LC/MS analysis revealed the presence of six different metabolites mainly resulting from oxidation reactions. A tosylated precursor of 2f was synthesized in two steps and radiolabeled with fluorine-18 to afford [F]2f in 15 ± 5% radiochemical yield and a molar activity of 110 ± 30 GBq/μmol. Autoradiographies of rat spleen and biodistribution studies in healthy rats including pretreatments with either CBR or CBR-specific compounds suggested that [F]2f is a specific tracer for the CBR in vivo. We have therefore demonstrated here that [F]2f is a promising novel tracer for imaging CBR in vivo using PET. Further investigation in animal models of inflammation will follow.