暨南大学Lu Wang等研究人员合作完成[¹⁸F]D₂-LW223的临床前表征。该研究于2024年8月29日在线发表于国际一流学术期刊《中国药理学报》。

研究人员表示，正电子发射断层扫描（PET）靶向跨位点蛋白18 kDa（TSPO）可用于神经炎症的无创检测。改进的TSPO示踪剂在体内的稳定性有助于减少放射性代谢物可能引起的混淆效应。氘代是一种重要策略，可改善现有药物分子在血浆中的药代动力学和稳定性。

研究人员通过对[¹⁸F]LW223进行氘代开发了一种新型示踪剂，并评估了其在神经炎症啮齿动物模型和非人灵长类动物（NHP）大脑中的体内稳定性和特异性结合性。与LW223相比，D₂-LW223对TSPO表现出更高的结合亲和力。

与[¹⁸F]LW223相比，[¹⁸F]D₂-LW223具有更优越的物理化学性质和良好的大脑动力学，表现出增强的代谢稳定性和减少的去氟化作用。

在脂多糖（LPS）诱导的神经炎症和脑缺血的啮齿动物模型中进行的临床前研究表明，[¹⁸F]D₂-LW223在受神经炎症影响的区域特异性结合TSPO。

双组织隔室模型分析提供了出色的模型拟合，并允许对NHP大脑中的TSPO进行定量映射。研究结果表明，[¹⁸F]D₂-LW223在神经炎症病理学中TSPO表达的精确定量方面具有重要的应用潜力。

附：英文原文

Title: Preclinical characterization of [18F]D2-LW223: an improved metabolically stable PET tracer for imaging the translocator protein 18kDa (TSPO) in neuroinflammatory rodent models and non-human primates

Author: Liao, Kai, Chen, Jia-hui, Ma, Jie, Dong, Chen-chen, Bi, Chun-yang, Gao, Ya-biao, Jiang, Yuan-fang, Wang, Tao, Wei, Hui-yi, Hou, Lu, Hu, Jun-qi, Wei, Jun-jie, Zeng, Chun-yuan, Li, Yin-long, Yan, Sen, Xu, Hao, Liang, Steven H., Wang, Lu

Issue&Volume: 2024-08-29

Abstract: Positron emission tomography (PET) targeting translocator protein 18kDa (TSPO) can be used for the noninvasive detection of neuroinflammation. Improved in vivo stability of a TSPO tracer is beneficial for minimizing the potential confounding effects of radiometabolites. Deuteration represents an important strategy for improving the pharmacokinetics and stability of existing drug molecules in the plasma. This study developed a novel tracer via the deuteration of [18F]LW223 and evaluated its in vivo stability and specific binding in neuroinflammatory rodent models and nonhuman primate (NHP) brains. Compared with LW223, D2-LW223 exhibited improved binding affinity to TSPO. Compared with [18F]LW223, [18F]D2-LW223 has superior physicochemical properties and favorable brain kinetics, with enhanced metabolic stability and reduced defluorination. Preclinical investigations in rodent models of LPS-induced neuroinflammation and cerebral ischemia revealed specific [18F]D2-LW223 binding to TSPO in regions affected by neuroinflammation. Two-tissue compartment model analyses provided excellent model fits and allowed the quantitative mapping of TSPO across the NHP brain. These results indicate that [18F]D2-LW223 holds significant promise for the precise quantification of TSPO expression in neuroinflammatory pathologies of the brain.

DOI: 10.1038/s41401-024-01375-9

Source: https://www.nature.com/articles/s41401-024-01375-9