Harada Ryuichi, Okamura Nobuyuki, Furumoto Shozo, Yanai Kazuhiko
Department of Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Division of Pharmacology, Tohoku Medical and Pharmaceutical University, Sendai, Japan.
Front Neurosci. 2018 Aug 21;12:585. doi: 10.3389/fnins.2018.00585. eCollection 2018.
Neurodegenerative diseases characterized by pathological protein accumulation in cells are termed "proteinopathies." Although various protein aggregates share cross-β-sheet structures, actual conformations vary among each type of protein deposit. Recent progress in the development of radiotracers for positron emission tomography (PET) has enabled the visualization of protein aggregates in living brains. Amyloid PET tracers have been developed, and are widely used for the diagnosis of Alzheimer's disease and non-invasive assessment of amyloid burden in clinical trials of anti-dementia drugs. Furthermore, several tau PET tracers have been successfully developed and used in the clinical studies. However, recent studies have identified the presence of off-target binding of radiotracers in areas of tau deposition, suggesting that concomitant neuroinflammatory changes might affect tracer binding. In contrast to amyloid and tau PET, there are no established tracers for imaging Lewy bodies in the human brain. In this review, we describe lessons learned from the development of PET tracers and discuss the future direction of tracer development for protein misfolding diseases.
以细胞内病理性蛋白质积聚为特征的神经退行性疾病被称为“蛋白病”。尽管各种蛋白质聚集体都具有交叉β-折叠结构，但每种类型的蛋白质沉积物的实际构象各不相同。正电子发射断层扫描（PET）放射性示踪剂开发方面的最新进展使得在活体大脑中可视化蛋白质聚集体成为可能。淀粉样蛋白PET示踪剂已经研发出来，并广泛用于阿尔茨海默病的诊断以及抗痴呆药物临床试验中淀粉样蛋白负荷的无创评估。此外，几种tau蛋白PET示踪剂已成功研发并用于临床研究。然而，最近的研究发现放射性示踪剂在tau蛋白沉积区域存在脱靶结合，这表明伴随的神经炎症变化可能会影响示踪剂的结合。与淀粉样蛋白和tau蛋白PET不同，目前还没有用于成像人脑中路易小体的成熟示踪剂。在这篇综述中，我们描述了从PET示踪剂开发中吸取的经验教训，并讨论了蛋白质错误折叠疾病示踪剂开发的未来方向。
