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

• Type of Material: Article
• Authors: Jian Rong, Emory University; Tomoteru Yamasaki, National Institutes for Quantum Science and Technology; yinlong Li, Emory University; Katsushi Kumata, National Institutes for Quantum Science and Technology; Chunyu Zhao, Emory University; Ahmed Haider Wahauib, Emory University; Jiahui Chen, Emory University; Zhiwei Xiao, Emory University; Masayuki Fujinaga, National Institutes for Quantum Science and Technology; Kuan Hu, National Institutes for Quantum Science and Technology; Wakana Mori, National Institutes for Quantum Science and Technology; Yiding Zhang, National Institutes for Quantum Science and Technology; Lin Xie, National Institutes for Quantum Science and Technology; Xin Zhou, Emory University; Thomas L. Collier, Emory University; Ming-Rong Zhang, National Institutes for Quantum Science and Technology; Steven Liang, Emory University
• Language: English
• Date: 2023-09-26
• Publisher: American Chemical Society
• Publication Version: Final Published Version
• Copyright Statement: © 2023 The Authors. Published by American Chemical Society
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): https://doi.org/10.1021/acsmedchemlett.3c00320
• Title of Journal or Parent Work: ACS Medicinal Chemistry Letters
• Volume: 14
• Issue: 10
• Start Page: 1419
• End Page: 1426
• Grant/Funding Information: A.H. was supported by the Swiss National Science Foundation (SNSF). S.H.L. gratefully acknowledges the support provided, in part, by Emory Radiology Chair Fund and Emory School of Medicine Endowed Directorship. M.R.Z gratefully acknowledges the support provided, in part, by JSPS KAKENHI (grant number 23H02867) and the AMED Moonshot Research and Development Program (grant number 21zf0127003h001).
• Keywords: antagonist; C-11; PET; Orexin-2
• Research Categories: Biology, Neuroscience; Health Sciences, Pharmacology; Chemistry, Organic

Abstract

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.