Numerous studies have indicated the upregulation of the cannabinoid type 2 receptors (CB2 receptors) in neuroinflammation and cancer, and that their visualization with PET (Positron emission tomography) could provide a valuable diagnostic and/or therapy-monitoring tool in such disorders. However, the availability of reliable CB2-selective imaging probes is still lacking in clinical practice. Encouraged by promising CB2 affinity results obtained for a benzothiazole lead compound, 6a, further structural optimizations led to the development of a series of fluorinated and methoxylated benzothiazole derivatives, endowed with extremely high CB2 binding affinity and an exclusive selectivity to the CB2 receptor, along with structural sites suitable for radiolabeling. Compounds 20, 21, 24, 25, 29, 32 and 33 displayed subnanomolar CB2 Ki values (ranging from 0.16 nM to 0.68 nM) while lacked affinity to the CB1 receptor subtype. The fluorinated analogs, 21 and 29, were evaluated for their in vitro metabolic stability in mouse and human liver microsomes (MLM and HLM). Both 21 and 29 displayed an exceptionally high stability (98% and 91% intact compounds, respectively) after 60 min incubation with MLM. Contrastingly, compound 29 revealed an almost 2-fold greater metabolic stability after incubation with HLM for 60 min. Taken together, our data represent remarkably potent and selective CB2 ligands as credible leads that can be further exploited for 18F- or 11C-radiolabeling and utilization as PET tracers.