Despite its essential role in the (patho)physiology of several diseases, CB2R tissue
expression profiles and signaling mechanisms are not yet fully understood. We report
the development of a highly potent, fluorescent CB2R agonist probe employing structure-based
reverse design. It commences with a highly potent, preclinically validated ligand,
which is conjugated to a silicon-rhodamine fluorophore, enabling cell permeability.
The probe is the first to preserve interspecies affinity and selectivity for both
mouse and human CB2R. Extensive cross-validation (FACS, TR-FRET and confocal microscopy)
set the stage for CB2R detection in endogenously expressing living cells along with
zebrafish larvae. Together, these findings will benefit clinical translatability of
CB2R based drugs.
