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We have previously developed seven fluorinated analogues of A-836339 as new PET tracers for cannabinoid type 2 receptor (CB 2 R) imaging, among which ( Z )- N -(3-(2-(2-[ 18 F]fluoroethoxy)ethyl)-4,5-dimethylthiazol-2(3 H )-ylidene)-2,2,3,3-tetramethylcyclopropane-1-carboxamide ([ 18 F]FC0324) displayed high affinity and selectivity for CB 2 R in healthy rats. In the present study, we have further evaluated the imaging and metabolic properties of [ 18 F]FC0324 in a rat model of human CB 2 R overexpression in the brain (AAV- h CB 2 ) and in non-human primates (NHPs). Autoradiography with AAV- h CB 2 rat brain sections exhibited a signal of [ 18 F]FC0324 8-fold higher in the ipsilateral region than in the contralateral region. Blocking with NE40, a CB 2 R-specific agonist, resulted in a 91% decrease in the radioactivity. PET experiments showed a signal 7-fold higher in the ipsilateral region, and the specificity of [ 18 F]FC0324 for h CB 2 R in vivo was confirmed by the 80% decrease after blocking with NE40. In NHPs, brain time-activity curves displayed a fast and homogeneous distribution followed by a rapid washout, in accordance with the low amount of CB 2 Rs in healthy brain. Whole-body PET-CT suggested a high and specific uptake of the radiotracer in the spleen, a CB 2 R-rich organ, and in the organs involved in metabolism and excretion, with a low bone uptake. In vitro metabolism with monkey liver microsomes (MLMs) led to the formation of six main hydroxylated metabolites of FC0324. Five of them were produced by human liver microsomes, being much less active than MLMs. In vivo, in NHPs, the main radiometabolite was likely to result from further oxidation of hydroxylated compounds, and parent [ 18 F]FC0324 accounted for 8 ± 3% of plasma radioactivity (at 120 min p.i.) with a low level of potential interfering radiometabolites. Furthermore, this metabolism should be significantly reduced in humans due to species differences. In conclusion, [ 18 F]FC0324 appears to be a promising candidate for further human studies with suitable kinetics, selectivity, and metabolic profile for CB 2 R PET imaging., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)