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

Autor: Rong J; Department of Radiology and Imaging Sciences, Emory University, Atlanta, Georgia 30322, United States.; Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital and Department of Radiology, Harvard Medical School, Boston, Massachusetts 02114, United States., Yamasaki T; Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Sciences, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan., Li Y; Department of Radiology and Imaging Sciences, Emory University, Atlanta, Georgia 30322, United States.; Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital and Department of Radiology, Harvard Medical School, Boston, Massachusetts 02114, United States., Kumata K; Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Sciences, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan., Zhao C; Department of Radiology and Imaging Sciences, Emory University, Atlanta, Georgia 30322, United States.; Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital and Department of Radiology, Harvard Medical School, Boston, Massachusetts 02114, United States., Haider A; Department of Radiology and Imaging Sciences, Emory University, Atlanta, Georgia 30322, United States.; Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital and Department of Radiology, Harvard Medical School, Boston, Massachusetts 02114, United States., Chen J; Department of Radiology and Imaging Sciences, Emory University, Atlanta, Georgia 30322, United States.; Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital and Department of Radiology, Harvard Medical School, Boston, Massachusetts 02114, United States., Xiao Z; Department of Radiology and Imaging Sciences, Emory University, Atlanta, Georgia 30322, United States.; Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital and Department of Radiology, Harvard Medical School, Boston, Massachusetts 02114, United States., Fujinaga M; Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Sciences, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan., Hu K; Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Sciences, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan., Mori W; Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Sciences, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan., Zhang Y; Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Sciences, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan., Xie L; Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Sciences, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan., Zhou X; Department of Radiology and Imaging Sciences, Emory University, Atlanta, Georgia 30322, United States., Collier TL; Department of Radiology and Imaging Sciences, Emory University, Atlanta, Georgia 30322, United States.; Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital and Department of Radiology, Harvard Medical School, Boston, Massachusetts 02114, United States., Zhang MR; Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Sciences, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan., Liang S; Department of Radiology and Imaging Sciences, Emory University, Atlanta, Georgia 30322, United States.; Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital and Department of Radiology, Harvard Medical School, Boston, Massachusetts 02114, United States.
Jazyk: angličtina
Zdroj: ACS medicinal chemistry letters [ACS Med Chem Lett] 2023 Sep 26; Vol. 14 (10), pp. 1419-1426. Date of Electronic Publication: 2023 Sep 26 (Print Publication: 2023).
DOI: 10.1021/acsmedchemlett.3c00320
Abstrakt: Orexin 2 receptors (OX 2 R) 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 OX 2 R in vivo. Herein, we report [ 11 C] 1 ([ 11 C]OX 2 -2201) and [ 11 C] 2 ([ 11 C]OX 2 -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 OX 2 R and target selectivity (OX 2 /OX 1 > 600 folds). In vitro autoradiography in the rat brain suggested good to excellent in vitro binding specificity for [ 11 C] 1 and [ 11 C] 2 . PET imaging in rat brains indicated that the low brain uptake of [ 11 C] 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.
Competing Interests: The authors declare no competing financial interest.
(© 2023 The Authors. Published by American Chemical Society.)
Databáze: MEDLINE
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