Development and Preclinical Evaluation of a Novel PET Probe for Phosphodiesterase 7B Imaging in Brain
Tomoteru Yamasaki, Zhiwei Xiao, Masayuki Fujinaga, Wakana Mori, Yiding Zhang, Jian Rong, Katsushi Kumata, Zhendong Song, Yusuke Kurihara, Haofeng Shi, Masanao Ogawa, Jiyun Sun, Nobuki Nengaki, Taoqian Zhao, Tomomi Kokufuta, Kazui Nakamoto, Lin Xie, Yinlong Li, Steven H Liang, Ming-Rong ZhangAbstract
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.