Synthesis and in vivo biological characterization of six carbon-11 sigma-1 receptor radiotracers in rodent and nonhuman primate

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry Pub Date : 2025-04-28 DOI:10.1016/j.bmc.2025.118218

Anil Kumar Soda , Tianyu Huang , Wenjuan Zhou , Hong Chen , Hao Jiang , Sandip B. Jadhav , Zhimin Xing , Yanbo Yu , Linlin Tian , Dean F. Wong , Joel S. Perlmutter , Ruiqing Ni , Tammie L.S. Benzinger , Zhude Tu

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Abstract

Six enantiomers of three racemic sigma-1 receptor (σ₁R) ligands were resolved, and absolute configuration was determined. Their high σ₁R potency and selectivity were determined through in vitro binding assays, further validated by molecular docking analysis. Central Nervous System Multiparameter Optimization algorithm (CNS MPO) predicts efficient brain penetration for these enantiomers. Six C-11 radiotracers were radiosynthesized successfully, ex vivo biodistribution in rats showed that (−)-[¹¹C]7 had high brain uptake of ∼4.8-fold for 5 min versus 60 min. Mouse brain PET imaging studies showed (−)-[¹¹C]7 and (−)-[¹¹C]16 have in vivo binding specificity for σ₁R. Macaque PET scans showed high brain uptake for all six radiotracers, with (−)-[¹¹C]7 peaked at ∼45 min (SUV 2.5), possessing the best washout kinetics and highest cerebellum-to-white matter ratio (∼3.1), in agreement with in vitro or ex vivo measures of σ₁R expression. Radiometabolite analysis showed that no newly formed radiometabolite was observed post-injection of (−)-[¹¹C]7. Our data suggest that further evaluation is warranted to determine that (−)-[¹¹C]7 is a suitable PET radiotracer for imaging σ₁R in the brain of animal and human.

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六种碳-11 sigma-1受体示踪剂在啮齿动物和非人灵长类动物体内的合成和生物学特性

对3种外消旋sigma-1受体（σ1R）配体的6个对映体进行了拆分，确定了绝对构型。通过体外结合实验确定了它们的高σ1R效价和选择性，并通过分子对接分析进一步验证了它们的有效性。中枢神经系统多参数优化算法（CNS MPO）预测这些对映体的有效脑穿透。6种C-11示踪剂在大鼠体内的生物分布表明，(−)-[11C]7在5分钟和60分钟内具有高的脑摄取约4.8倍。小鼠脑PET成像研究表明(−)-[11C]7和(−)-[11C]16对σ1R具有体内结合特异性。猕猴PET扫描显示，所有六种放射性示踪剂的大脑摄取都很高，(−)-[11C]7在~ 45分钟达到峰值（SUV 2.5），具有最佳的冲洗动力学和最高的小脑与白质比率（~ 3.1），与体外或离体测量的σ1R表达一致。放射性代谢物分析表明，注射(−)-[11C]7后未观察到新形成的放射性代谢物。我们的数据表明，有必要进一步评价(−)-[11C]7是一种合适的PET示踪剂，用于动物和人类大脑中的σ1R成像。

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来源期刊

Bioorganic & Medicinal Chemistry 医学-生化与分子生物学

CiteScore

6.80

自引率

2.90%

发文量

413

审稿时长

17 days

期刊介绍： Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides. The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.