Original articles
Yu Lan, Ping Bai, Zude Chen, Ramesh Neelamegam, Michael S. Placzek, Hao Wang, Stephanie A. Fiedler, Jing Yang, Gengyang Yuan, Xiying Qu, Hayden R. Schmidt, Jinchun Song, Marc D. Normandin, Chongzhao Ran, Changning Wang. Novel radioligands for imaging sigma-1 receptor in brain using positron emission tomography (PET)[J]. Acta Pharmaceutica Sinica B, 2019, 9(6): 1204-1215

Novel radioligands for imaging sigma-1 receptor in brain using positron emission tomography (PET)
Yu Lana,d, Ping Baia, Zude Chena, Ramesh Neelamegamb, Michael S. Placzeka, Hao Wanga, Stephanie A. Fiedlera, Jing Yanga, Gengyang Yuanb, Xiying Qub, Hayden R. Schmidtc, Jinchun Songd, Marc D. Normandinb, Chongzhao Rana, Changning Wanga
a Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA;
b Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA;
c Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02129, USA;
d Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan 430060, China
The sigma-1 receptor (σ1R) is a unique intracellular protein. σ1R plays a major role in various pathological conditions in the central nervous system (CNS), implicated in several neuropsychiatric disorders. Imaging of σ1R in the brain using positron emission tomography (PET) could serve as a noninvasively tool for enhancing the understanding of the disease's pathophysiology. Moreover, σ1R PET tracers can be used for target validation and quantification in diagnosis. Herein, we describe the radiosynthesis, in vivo PET/CT imaging of novel σ1R 11C-labeled radioligands based on 6-hydroxypyridazinone,[11C]HCC0923 and[11C]HCC0929. Two radioligands have high affinities to σ1R, with good selectivity. In mice PET/CT imaging, both radioligands showed appropriate kinetics and distributions. Additionally, the specific interactions of two radioligands were reduced by compounds 13 and 15 (self-blocking). Of the two,[11C]HCC0929 was further investigated in positive ligands blocking studies, using classic σ1R agonist SA 4503 and σ1R antagonist PD 144418. Both σ1R ligands could extensively decreased the uptake of[11C]HCC0929 in mice brain. Besides, the biodistribution of major brain regions and organs of mice were determined in vivo. These studies demonstrated that two radioligands, especially[11C]HCC0929, possessed ideal imaging properties and might be valuable tools for non-invasive quantification of σ1R in brain.
Key words:    σ1R    PET    Brain imaging    6-Hydroxypyridazinone    11C-labeled radioligand   
Received: 2019-04-06     Revised: 2019-06-28
DOI: 10.1016/j.apsb.2019.07.002
Funds: This work was supported by a pilot funding from the Athinoula A. Martinos Center for Biomedical Imaging at the Massachusetts General Hospital (Changning Wang, USA), National Natural Science Foundation of China (Grant No.81602946, Yu Lan) and Natural Science Foundation of Hubei Province of China (Grant No. 2016CFB258, Yu Lan). The authors are grateful to Prof. Andrew C. Kruse in Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School for the constructive discussion and enthusiastic help in molecular docking, the Athinoula A. Martinos Center Radiopharmacy Lab staff for assistant in radiochemistry and Prof. Xudong Cao in Xuzhou Medical School for the discussion in chemistry and structure identification.
Corresponding author: Changning Wang     Email:cwang15@mgh.harvard.edu
Author description:
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Yu Lan
Ping Bai
Zude Chen
Ramesh Neelamegam
Michael S. Placzek
Hao Wang
Stephanie A. Fiedler
Jing Yang
Gengyang Yuan
Xiying Qu
Hayden R. Schmidt
Jinchun Song
Marc D. Normandin
Chongzhao Ran
Changning Wang

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