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

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

doi:10.1021/acsmedchemlett.3c00320

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

ACS Med Chem Lett. 2023 Sep 26;14(10):1419-1426. doi: 10.1021/acsmedchemlett.3c00320. eCollection 2023 Oct 12.

Authors

Jian Rong^{1

2}, Tomoteru Yamasaki³, Yinlong Li^{1

2}, Katsushi Kumata³, Chunyu Zhao^{1

2}, Ahmed Haider^{1

2}, Jiahui Chen^{1

2}, Zhiwei Xiao^{1

2}, Masayuki Fujinaga³, Kuan Hu³, Wakana Mori³, Yiding Zhang³, Lin Xie³, Xin Zhou¹, Thomas L Collier^{1

2}, Ming-Rong Zhang³, Steven Liang^{1

2}

Affiliations

¹ Department of Radiology and Imaging Sciences, Emory University, Atlanta, Georgia 30322, United States.
² Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital and Department of Radiology, Harvard Medical School, Boston, Massachusetts 02114, United States.
³ Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Sciences, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan.

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 (K_i = 3.6 nM) and 2 (K_i = 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.