RESUMO
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.
RESUMO
The sigma-1 receptor (R) is a unique intracellular protein. R plays a major role in various pathological conditions in the central nervous system (CNS), implicated in several neuropsychiatric disorders. Imaging of 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, R PET tracers can be used for target validation and quantification in diagnosis. Herein, we describe the radiosynthesis, PET/CT imaging of novel R C-labeled radioligands based on 6-hydroxypyridazinone, [C]HCC0923 and [C]HCC0929. Two radioligands have high affinities to 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 and (self-blocking). Of the two, [C]HCC0929 was further investigated in positive ligands blocking studies, using classic R agonist SA 4503 and R antagonist PD 144418. Both R ligands could extensively decreased the uptake of [C]HCC0929 in mice brain. Besides, the biodistribution of major brain regions and organs of mice were determined . These studies demonstrated that two radioligands, especially [C]HCC0929, possessed ideal imaging properties and might be valuable tools for non-invasive quantification of R in brain.
RESUMO
In recent years, multi-targeting directed ligands have attracted great interest as possible new atypical antipsychotics. Combinations of dopamine and serotonin receptor ligands within single molecules might afford new therapeutic opportunities. Herein, we describe the synthesis of a novel series of 6-hydroxypyridazinone benzisoxazoles and their binding behaviors to different receptors in terms of atypical antipsychotic behaviors. The most potent compound (46) exhibited excellent affinities for certain receptors (D2, Ki = 0.5 ± 0.07 nM; 5-HT1A, Ki = 5.9 ± 0.8 nM; 5-HT2A, Ki = 0.3 ± 0.01 nM; 5-HT6, Ki = 0.5 ± 0.04 nM) and combined with low affinities for the H1, 5-HT2C, and adrenergic α1 receptors. In contrast to risperidone, compound 46 exhibited a high cataleptic threshold; this may be useful in the development of a novel class of drugs treating schizophrenia.