Detection of cannabinoid receptor type 2 in native cells and zebrafish with a highly potent, cell-permeable fluorescent probe.

Despite its essential role in the (patho)physiology of several diseases, CBR tissue expression profiles and signaling mechanisms are not yet fully understood. We report the development of a highly potent, fluorescent CBR 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 CBR. Extensive cross-validation (FACS, TR-FRET and confocal microscopy) set the stage for CBR detection in endogenously expressing living cells along with zebrafish larvae. Together, these findings will benefit clinical translatability of CBR based drugs.