Preparation and characterization of radioligands for the orphan receptor GPR88

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Project Summary This application is in response to RFA-RM-19-011, which aims to support pilot projects for the Common Fund Program "Illuminating the Druggable Genome" (IDG) to study IDG-eligible understudied GPCRs, protein kinases, and ion channels. The orphan receptor GPR88 is an IDG-eligible GPCR with robust expression in the striatum throughout the dorsal and ventral areas. Multiple lines of evidence suggest that GPR88 plays an important role in the regulation of striatal functions and is implicated in a number of disorders such as Parkinson’s disease, schizophrenia, anxiety, and drug addiction. To date, the endogenous ligand for GPR88 has not been discovered. In order to characterize GPR88 signaling mechanisms and biological functions, our group has carried out a medicinal chemistry campaign to develop GPR88 small-molecule agonist probes. We have recently developed the first highly potent, selective, and brain-penetrant GPR88 agonist RTI-33 that has GPR88 on-target in vivo activity in reducing alcohol drinking and seeking behaviors in rats and mice. However, the pharmacology of the receptor and its mechanism of action are still largely unknown, thus limiting exploration of its potential for therapeutic applications. In this regard, a suitable radioligand, that is currently unavailable, will be a powerful tool for ligand-receptor interactions studies and for autoradiography to map the receptor binding sites in the brain, which can be used to predict the potential functions of the receptor and guide in vivo studies. In Aim 1, we will optimize and synthesize tritium-labeled RTI-33 radioligands with suitable radiochemical purity and specific radioactivity for receptor binding studies. In Aim 2, we will characterize the receptor binding properties using saturation, kinetic, and competition binding experiments. Overall, completion of this grant will provide GPR88 radioligands to serve IDG and the research community in an effort to further characterize the GPR88 system.