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.

中文翻译：

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使用正电子发射断层扫描（PET）成像大脑中sigma-1受体的新型放射性配体。

sigma-1受体（σ1R）是一种独特的细胞内蛋白。σ1R在中枢神经系统（CNS）的各种病理状况中起主要作用，与多种神经精神疾病有关。使用正电子发射断层扫描（PET）在大脑中对σ1R进行成像可作为一种非侵入性工具，用于增强对该疾病的病理生理学的理解。此外，σ1R PET示踪剂可用于目标验证和诊断定量。在这里，我们描述了基于6-羟基哒嗪酮，[11C] HCC0923和[11C] HCC0929的新型σ1R 11C标记的放射性配体的放射合成，体内PET / CT成像。两个放射性配体对σ1R具有高亲和力，并且具有良好的选择性。在小鼠PET / CT成像中，两种放射性配体均显示出适当的动力学和分布。此外，化合物13和15降低了两个放射性配体的特异性相互作用（自封闭）。在这两种化合物中，[11C] HCC0929在经典的σ1R激动剂SA 4503和σ1R拮抗剂PD 144418的阳性配体阻断研究中作了进一步研究。这两个σ1R配体均可广泛降低小鼠脑中对[11C] HCC0929的吸收。此外，体内主要小鼠的大脑区域和器官的生物分布被确定。这些研究表明，两个放射性配体，特别是[11C] HCC0929，具有理想的成像特性，可能是对脑中σ1R进行无创定量的有价值的工具。两种σ1R配体均可广泛降低小鼠脑中对[11C] HCC0929的吸收。此外，体内主要小鼠的大脑区域和器官的生物分布被确定。这些研究表明，两个放射性配体，特别是[11C] HCC0929，具有理想的成像特性，可能是对脑中σ1R进行无创定量的有价值的工具。两种σ1R配体均可广泛降低小鼠脑中对[11C] HCC0929的吸收。此外，体内主要小鼠的大脑区域和器官的生物分布被确定。这些研究表明，两个放射性配体，特别是[11C] HCC0929，具有理想的成像特性，可能是对脑中σ1R进行无创定量的有价值的工具。