Chromenopyrazole-based High Affinity, Selective Fluorescent Ligands for Cannabinoid Type 2 Receptor.

Cannabinoid type 2 receptor (CBR) is an attractive target for the treatment of pain and inflammatory disorders. Availability of a selective CBR fluorescent ligand to study CBR expression and localization in healthy and disease conditions would greatly contribute to improving our understanding of this receptor. Herein, we report a series of chromenopyrazole-based CBR fluorescent ligands. The highest affinity fluorescent ligand was Cy5-containing (hCBR p = 7.38 ± 0.05), which had 131-fold selectivity over CBR. In a cAMP BRET assay, behaved as a potent CBR inverse agonist. Widefield imaging experiments showed that binds to CBR in live cells with good selectivity and low levels of nonspecific fluorescence. The high affinity, selectivity, and suitable imaging properties of fluorescent ligand make it a valuable tool for studying CBR.