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

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.