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

[Display omitted] •[3H]RTI-33 is the first radioligand for the GPR88 receptor.•[3H]RTI-33 has high affinity for GPR88 in PPLS-HA-hGPR88-CHO membranes.•GPR88 functional agonists competitively displace [3H]RTI-33. 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 (KD 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.