Development and Preclinical Evaluation of a Novel PET Probe for Phosphodiesterase 7B Imaging in Brain.

Abstract

Phosphodiesterase 7B (PDE7B) is involved in the cAMP-PKA signaling pathway and has been implicated in neurodegenerative disorders. Accordingly, PDE7B represents a promising target for the development of therapeutics to treat such diseases. Recent efforts have led to the discovery of pyrimidinone-based compounds with high affinity and selectivity for PDE7B. In this study, we developed a novel pyrimidinone-based positron emission tomography (PET) probe, [11C]5. In vitro autoradiography using rat brain sections revealed specific binding of [11C]5 in the striatum and thalamus, consistent with the known distribution of PDE7B. Baseline PET scans showed relatively low brain uptake of [11C]5, except in the olfactory bulb. Pretreatment with elacridar, a potent dual inhibitor of drug efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), enhanced the brain uptake of [11C]5, resulting in further specific in vivo binding in the olfactory bulb and striatum. In conclusion, although the brain permeability of [11C]5 was limited by P-gp and BCRP, [11C]5 demonstrated specific binding to PDE7B, both in vitro and in vivo, supporting its potential utility for imaging PDE7B in the central nervous system.