Biomaterial Database

Development of Novel 11C-Labeled Selective Orexin-2 Receptor Radioligands for Positron Emission Tomography Imaging. 2023

Jian Rong, and Tomoteru Yamasaki, and Yinlong Li, and Katsushi Kumata, and Chunyu Zhao, and Ahmed Haider, and Jiahui Chen, and Zhiwei Xiao, and Masayuki Fujinaga, and Kuan Hu, and Wakana Mori, and Yiding Zhang, and Lin Xie, and Xin Zhou, and Thomas L Collier, and Ming-Rong Zhang, and Steven Liang

Department of Radiology and Imaging Sciences, Emory University, Atlanta, Georgia 30322, United States.

Orexin 2 receptors (OX2R) represent a vital subtype of orexin receptors intricately involved in the regulation of wakefulness, arousal, and sleep-wake cycles. Despite their importance, there are currently no positron emission tomography (PET) tracers available for imaging the OX2R in vivo. Herein, we report [11C]1 ([11C]OX2-2201) and [11C]2 ([11C]OX2-2202) as novel PET ligands. Both compounds 1 (Ki = 3.6 nM) and 2 (Ki = 2.2 nM) have excellent binding affinity activities toward OX2R and target selectivity (OX2/OX1 > 600 folds). In vitro autoradiography in the rat brain suggested good to excellent in vitro binding specificity for [11C]1 and [11C]2. PET imaging in rat brains indicated that the low brain uptake of [11C]2 may be due to P-glycoprotein and/or breast cancer resistance protein efflux interaction and/or low passive permeability. Continuous effort in medicinal chemistry optimization is necessary to improve the brain permeability of this scaffold.