Original articles
Ying Zhang, Tao Wang, Xiaojun Zhang, Winnie Deuther-Conrad, Hualong Fu, Mengchao Cui, Jinming Zhang, Peter Brust, Yiyun Huang, Hongmei Jia. Discovery and development of brain-penetrant 18F-labeled radioligands for neuroimaging of the sigma-2 receptors[J]. Acta Pharmaceutica Sinica B, 2022, 12(3): 1406-1415

Discovery and development of brain-penetrant 18F-labeled radioligands for neuroimaging of the sigma-2 receptors
Ying Zhanga, Tao Wanga, Xiaojun Zhangb, Winnie Deuther-Conradc, Hualong Fua, Mengchao Cuia, Jinming Zhangb, Peter Brustc,e, Yiyun Huangd, Hongmei Jiaa
a. Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China;
b. Nuclear Medicine Department, Chinese PLA General Hospital, Beijing 100853, China;
c. Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Leipzig 04318, Germany;
d. PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT 06520-8048, USA;
e. The L�beck Institute of Experimental Dermatology, University Medical Center Schleswig-Holstein, L�beck 23538, Germany
Abstract:
We have discovered and synthesized a series of indole-based derivatives as novel sigma-2 (σ2) receptor ligands. Two ligands with high σ2 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 σ2 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 σ2 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 σ2 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 σ2 receptors in the brain.
Key words:    Indole-based derivatives    σ2 receptor    Fluorine-18    Positron emission tomography    Neuroimaging   
Received: 2021-05-28     Revised: 2021-08-19
DOI: 10.1016/j.apsb.2021.08.029
Funds: This work was supported by the National Natural Science Foundation of China (No. 21876013) and Beijing Natural Science Foundation (7212203, China).
Corresponding author: Jinming Zhang,E-mai:zhangjm301@163.com;Yiyun Huang,E-mai:henry.huang@yale.edu;Hongmei Jia,E-mai:hmjia@bnu.edu.cn     Email:zhangjm301@163.com;henry.huang@yale.edu;hmjia@bnu.edu.cn
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Authors
Ying Zhang
Tao Wang
Xiaojun Zhang
Winnie Deuther-Conrad
Hualong Fu
Mengchao Cui
Jinming Zhang
Peter Brust
Yiyun Huang
Hongmei Jia

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