Novel radioligands for imaging sigma-1 receptor in brain using positron emission tomography (PET)

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

doi:10.1016/j.apsb.2019.07.002

Novel radioligands for imaging sigma-1 receptor in brain using positron emission tomography (PET)

Acta Pharm Sin B. 2019 Nov;9(6):1204-1215. doi: 10.1016/j.apsb.2019.07.002. Epub 2019 Jul 11.

Authors

Affiliations

¹ Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
² Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan 430060, China.
³ Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
⁴ Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02129, USA.

Abstract

The sigma-1 receptor (σ ₁R) is a unique intracellular protein. σ ₁R plays a major role in various pathological conditions in the central nervous system (CNS), implicated in several neuropsychiatric disorders. Imaging of σ ₁R in the brain using positron emission tomography (PET) could serve as a noninvasively tool for enhancing the understanding of the disease's pathophysiology. Moreover, σ ₁R PET tracers can be used for target validation and quantification in diagnosis. Herein, we describe the radiosynthesis, in vivo PET/CT imaging of novel σ ₁R ¹¹C-labeled radioligands based on 6-hydroxypyridazinone, [¹¹C]HCC0923 and [¹¹C]HCC0929. Two radioligands have high affinities to σ ₁R, 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 σ ₁R agonist SA 4503 and σ ₁R antagonist PD 144418. Both σ ₁R 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 σ ₁R in brain.

Keywords: 11C-labeled radioligand; 3D, three-dimensional; 6-Hydroxypyridazinone; AF, ammonium formate; BBB, brain blood barrier; BP, binding potential; Brain imaging; CNS, center nervous systems; CRPS, complex regional pain syndrome; DMF, dimethyl formamide; DMSO, dimethylsulfoxide; ER, endoplasmic reticulum; LCP, lipidic cubic phase; MAM, mitochondria-associated ER membrane; PCP, phencyclidine; PET; PET, positron emission tomography; TFA, trifluoroacetic acid; σ1R; σ1R, sigma-1 receptor; σ2R, sigma-2 receptor.