Synthesis and pharmacological validation of a novel radioligand for the orphan GPR88 receptor

GPR88 is an orphan G protein-coupled receptor which has been implicated in a number of striatal-associated disorders. Herein we describe the synthesis and pharmacological characterization of the first GPR88 radioligand, [³H]RTI-33, derived from a synthetic agonist RTI-13951-33. [³H]RTI-33 has a specific activity of 83.4 Ci/mmol and showed one-site, saturable binding (K_D of 85 nM) in membranes prepared from stable PPLS-HA-hGPR88-CHO cells. A competition binding assay was developed to determine binding affinities of several known GPR88 agonists. This radioligand represents a powerful tool for future mechanistic and cell-based ligand-receptor interaction studies of GPR88.