Synthesis, Structure–Activity Relationships, Radiofluorination, and Biological Evaluation of [(18)F]RM365, a Novel Radioligand for Imaging the Human Cannabinoid Receptor Type 2 (CB2R) in the Brain with PET

[Image: see text] The development of cannabinoid receptor type 2 (CB2R) PET radioligands has been intensively explored due to the pronounced CB2R upregulation under various pathological conditions. Herein, we report on the synthesis of a series of CB2R affine fluorinated indole-2-carboxamide ligands. Compound RM365 was selected for PET radiotracer development due to its high CB2R affinity (K(i) = 2.1 nM) and selectivity over CB1R (factor > 300). Preliminary in vitro evaluation of [(18)F]RM365 indicated species differences in the binding to CB2R (K(D) of 2.32 nM for the hCB2R vs K(D) > 10,000 nM for the rCB2R). Metabolism studies in mice revealed a high in vivo stability of [(18)F]RM365. PET imaging in a rat model of local hCB2R(D80N) overexpression in the brain demonstrates the ability of [(18)F]RM365 to reach and selectively label the hCB2R(D80N) with a high signal-to-background ratio. Thus, [(18)F]RM365 is a very promising PET radioligand for the imaging of upregulated hCB2R expression under pathological conditions.