18F-THK5351：一种用于阿尔茨海默病神经纤维病理成像的新型正电子发射断层显像剂。
18F-THK5351: A Novel PET Radiotracer for Imaging Neurofibrillary Pathology in Alzheimer Disease.
作者信息
Harada Ryuichi, Okamura Nobuyuki, Furumoto Shozo, Furukawa Katsutoshi, Ishiki Aiko, Tomita Naoki, Tago Tetsuro, Hiraoka Kotaro, Watanuki Shoichi, Shidahara Miho, Miyake Masayasu, Ishikawa Yoichi, Matsuda Rin, Inami Akie, Yoshikawa Takeo, Funaki Yoshihito, Iwata Ren, Tashiro Manabu, Yanai Kazuhiko, Arai Hiroyuki, Kudo Yukitsuka
机构信息
Division of Neuro-imaging, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
Division of Neuro-imaging, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan Department of Pharmacology, Tohoku University School of Medicine, Sendai, Japan Division of Cyclotron Nuclear Medicine, Cyclotron and Radioisotope Center, Tohoku University, Sendai, Japan
出版信息
J Nucl Med. 2016 Feb;57(2):208-14. doi: 10.2967/jnumed.115.164848. Epub 2015 Nov 5.
UNLABELLED
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, (18)F-THK5351, through compound optimization of arylquinoline derivatives.
METHODS
The in vitro binding properties, pharmacokinetics, and safety of (18)F-THK5351 were investigated, and a clinical study on Alzheimer disease (AD) patients was performed.
RESULTS
(18)F-THK5351 demonstrated higher binding affinity for hippocampal homogenates from AD brains and faster dissociation from white-matter tissue than did (18)F-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, (18)F-THK5351 demonstrated faster kinetics, higher contrast, and lower retention in subcortical white matter than(18)F-THK5117.
CONCLUSION
(18)F-THK5351 is a useful PET tracer for the early detection of neurofibrillary pathology in AD patients.
未标注
脑部神经原纤维病理成像有助于诊断痴呆、追踪疾病进展以及评估抗痴呆药物的治疗效果。这种成像中使用的放射性示踪剂必须对人类大脑中的tau蛋白纤维具有高度敏感性和特异性。我们通过芳基喹啉衍生物的化合物优化开发了一种新型tau PET示踪剂，（18）F-THK5351。
方法
研究了（18）F-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）患者进行了临床研究。
结果
与（18）F-THK5117相比，（18）F-THK5351对AD脑的海马匀浆表现出更高的结合亲和力，并且从白质组织解离更快。THK5351的结合量与人类脑样本中tau沉积物的量相关。脑切片的放射自显影显示，THK5351与神经原纤维缠结选择性结合，且信号与背景比高于THK5117。THK5351在小鼠中表现出良好的药代动力学且无脱氟现象。在AD患者的首次人体PET研究中，（18）F-THK5351显示出比（18）F-THK5117更快的动力学、更高的对比度以及在皮质下白质中的更低滞留。
结论
（18）F-THK5351是用于早期检测AD患者神经原纤维病理的有用PET示踪剂。
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