Discovery and development of brain-penetrant 18F-labeled radioligands for neuroimaging of the sigma-2 receptors.
10.1016/j.apsb.2021.08.029
- Author:
Ying ZHANG
1
;
Tao WANG
1
;
Xiaojun ZHANG
2
;
Winnie DEUTHER-CONRAD
3
;
Hualong FU
1
;
Mengchao CUI
1
;
Jinming ZHANG
2
;
Peter BRUST
3
;
Yiyun HUANG
4
;
Hongmei JIA
1
Author Information
1. Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China.
2. Nuclear Medicine Department, Chinese PLA General Hospital, Beijing 100853, China.
3. Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Leipzig 04318, Germany.
4. PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT 06520-8048, USA.
- Publication Type:Journal Article
- Keywords:
Fluorine-18;
Indole-based derivatives;
Neuroimaging;
Positron emission tomography;
σ2 receptor
- From:
Acta Pharmaceutica Sinica B
2022;12(3):1406-1415
- CountryChina
- Language:English
-
Abstract:
We have discovered and synthesized a series of indole-based derivatives as novel sigma-2 (σ 2) receptor ligands. Two ligands with high σ 2 receptor affinity and subtype selectivity were then radiolabeled with F-18 in good radiochemical yields and purities, and evaluated in rodents. In biodistribution studies in male ICR mice, radioligand [18F]9, or 1-(4-(5,6-dimethoxyisoindolin-2-yl)butyl)-4-(2-[18F]fluoroethoxy)-1H-indole, was found to display high brain uptake and high brain-to-blood ratio. Pretreatment of animals with the selective σ 2 receptor ligand CM398 led to significant reductions in both brain uptake (29%-54%) and brain-to-blood ratio (60%-88%) of the radioligand in a dose-dependent manner, indicating high and saturable specific binding of [18F]9 to σ 2 receptors in the brain. Further, ex vivo autoradiography in male ICR mice demonstrated regionally heterogeneous specific binding of [18F]9 in the brain that is consistent with the distribution pattern of σ 2 receptors. Dynamic positron emission tomography imaging confirmed regionally distinct distribution and high levels of specific binding for [18F]9 in the rat brain, along with appropriate tissue kinetics. Taken together, results from our current study indicated the novel radioligand [18F]9 as the first highly specific and promising imaging agent for σ 2 receptors in the brain.
