Abstract
The sigma-1 receptor (σ (1)R) is a unique intracellular protein. σ (1)R plays a major role in various pathological conditions in the central nervous system (CNS), implicated in several neuropsychiatric disorders. Imaging of σ (1)R 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 (1)R 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 (1)R (11)C-labeled radioligands based on 6-hydroxypyridazinone, [(11)C]HCC0923 and [(11)C]HCC0929. Two radioligands have high affinities to σ (1)R, 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, [(11)C]HCC0929 was further investigated in positive ligands blocking studies, using classic σ (1)R agonist SA 4503 and σ (1)R antagonist PD 144418. Both σ (1)R ligands could extensively decreased the uptake of [(11)C]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 [(11)C]HCC0929, possessed ideal imaging properties and might be valuable tools for non-invasive quantification of σ (1)R in brain.