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

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.