18F-THK5351: A Novel PET Radiotracer for Imaging Neurofibrillary Pathology in Alzheimer Disease
18F-THK5351: A Novel PET Radiotracer for Imaging Neurofibrillary Pathology in Alzheimer Disease
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DOI：
10.2967/jnumed.115.164848
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发表时间：
2016-02-01
影响因子：
9.3
通讯作者：
Kudo, Yukitsuka
中科院分区：
文献类型：
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作者：
Harada, Ryuichi;Okamura, Nobuyuki;Kudo, Yukitsuka
脑内神经原纤维病理成像有助于诊断痴呆，跟踪疾病进展，并评估抗痴呆药物的治疗效果。在这种成像中使用的放射性示踪剂必须对人脑中的tau蛋白原纤维高度敏感和特异性。通过对芳基喹啉衍生物的化合物优化，研制出新型tau型PET示踪剂F-18-THK5351。方法：研究F-18-THK5351的体外结合特性、药代动力学和安全性，并对阿尔茨海默病（AD）患者进行临床研究。结果：与F-18-THK5117相比，F-18-THK5351对AD大脑海马匀浆的结合亲和力更高，与白质组织的分离速度更快。THK5351结合量与人脑样品中tau沉积量相关。脑切片放射自显影显示THK5351选择性地结合神经原纤维缠结，并且具有比THK5117更高的信本比。THK5351在小鼠体内表现出良好的药代动力学，且无去氟作用。在AD患者的首次人体PET研究中，F-18-THK5351表现出比F-18-THK5117更快的动力学，更高的对比度和更低的皮层下白质滞留。结论：F-18-THK5351是一种有用的PET示踪剂，可早期发现AD患者的神经原纤维病变。
Imaging of neurofibrillary pathology in the brain helps in diagnosing dementia, tracking disease progression, and evaluating the therapeutic efficacy of antidementia drugs. The radiotracers used in this imaging must be highly sensitive and specific for tau protein fibrils in the human brain. We developed a novel-tau PET tracer, F-18-THK5351, through compound optimization of arylquinoline derivatives. Methods: The in vitro binding properties, pharmacokinetics, and safety of F-18-THK5351 were investigated, and a clinical study on Alzheimer disease (AD) patients was performed. Results: F-18-THK5351 demonstrated higher binding affinity for hippocampal homogenates from AD brains and faster dissociation from white matter tissue than did F-18-THK5117. The THK5351 binding amount correlated with the amount of tau deposits in human brain samples. Autoradiography of brain sections revealed that THK5351 bound to neurofibrillary tangles selectively and with a higher signal-to background ratio than did THK5117. THK5351 exhibited favorable pharmacokinetics and no defluorination in mice. In first-in-human PET studies in AD patients, F-18-THK5351 demonstrated faster kinetics, higher contrast, and lower retention in subcortical white matter than F-18-THK5117. Conclusion: F-18-THK5351 is a useful PET tracer for the early detection of neurofibrillary pathology in AD patients.