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.
Yu Lan  1  2 ,  Ping Bai  1 ,  Zude Chen  1 ,  Ramesh Neelamegam  3 ,  Michael S Placzek  1 ,  Hao Wang  1 ,  Stephanie A Fiedler  1 ,  Jing Yang  1 ,  Gengyang Yuan  3 ,  Xiying Qu  3 ,  Hayden R Schmidt  4 ,  Jinchun Song  2 ,  Marc D Normandin  3 ,  Chongzhao Ran  1 ,  Changning Wang  1
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.
PMID: 31867166 DOI: 10.1016/j.apsb.2019.07.002
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.