Department of Pharmacology, Tohoku University School of Medicine, Sendai, Japan.
J Nucl Med. 2013 Aug;54(8):1420-7. doi: 10.2967/jnumed.112.117341. Epub 2013 Jul 15.
Neurofibrillary tangles in Alzheimer disease (AD) brains are composed of the microtubule-associated protein tau. Noninvasive monitoring of tau protein aggregates in the living brain will provide useful information regarding tau pathophysiology in AD. However, no PET probes are currently available for selective detection of tau pathology in AD. We have previously reported (18)F-labeled THK-523 ((18)F-6-(2-fluoroethoxy)-2-(4-aminophenyl)quinoline) as a tau imaging radiotracer candidate for PET. After compound optimization, we developed novel (18)F-labeled arylquinoline derivatives, (18)F-THK-5105 and (18)F-THK-5117, for use as tau imaging PET tracers.
(18)F-labeled compounds were prepared from the corresponding tosylated precursors. The binding affinity of compounds to synthetic tau aggregates and tau-rich AD brain homogenates was determined by saturation and competition binding assays. The binding selectivity of compounds to tau pathology was evaluated by autoradiography of AD brain sections. The pharmacokinetics of compounds were assessed in biodistribution studies in normal mice. A 14-d toxicity study with intravenous administration of compounds was performed using rats and mice.
In vitro binding assays demonstrated higher binding affinity of THK-5105 and THK-5117 than THK-523 to tau protein aggregates and tau-rich AD brain homogenates. Autoradiographic analyses of AD brain sections showed that these radiotracers preferentially bound to neurofibrillary tangles and neuropil threads, which colocalized with Gallyas-positive and immunoreactive tau protein deposits. The distribution of this radiotracer binding in AD brain sections was completely different from that of (11)C-Pittsburgh compound B, showing preferential binding to amyloid plaques. Furthermore, these derivatives demonstrated abundant initial brain uptake and faster clearance in normal mice than (18)F-THK-523 and other reported (18)F-labeled radiotracers. THK-5105 and THK-5117 showed no toxic effects related to the administration of these compounds in mice and rats and no significant binding for various neuroreceptors, ion channels, and transporters at 1-μM concentrations.
(18)F-labeled THK-5105 and THK-5117 are promising candidates as PET tau imaging radiotracers.
阿尔茨海默病（AD）大脑中的神经原纤维缠结由微管相关蛋白 tau 组成。在活脑中对 tau 蛋白聚集体进行非侵入性监测将为 AD 中的 tau 病理生理学提供有用信息。然而，目前尚无用于选择性检测 AD 中 tau 病理学的 PET 探针。我们之前曾报道过（18）F 标记的 THK-523（（18）F-6-（2-氟乙氧基）-2-（4-氨基苯基）喹啉）作为 PET 用 tau 成像放射性示踪剂候选物。在化合物优化后，我们开发了新型（18）F 标记的芳基喹啉衍生物（18）F-THK-5105 和（18）F-THK-5117，用作 tau 成像 PET 示踪剂。
从相应的 tosylated 前体制备（18）F 标记的化合物。通过饱和和竞争结合测定确定化合物与合成的 tau 聚集体和富含 tau 的 AD 脑匀浆的结合亲和力。通过 AD 脑切片的放射自显影评估化合物对 tau 病理学的结合选择性。在正常小鼠的生物分布研究中评估化合物的药代动力学。使用大鼠和小鼠进行了静脉内给药的化合物 14 天毒性研究。
体外结合测定表明，THK-5105 和 THK-5117 与 tau 蛋白聚集体和富含 tau 的 AD 脑匀浆的结合亲和力高于 THK-523。AD 脑切片的放射自显影分析表明，这些放射性示踪剂优先与神经原纤维缠结和神经原纤维缠结结合，与 Gallyas 阳性和免疫反应性 tau 蛋白沉积物共定位。这种放射性示踪剂在 AD 脑切片中的分布与（11）C-Pittsburgh 化合物 B 完全不同，显示出对淀粉样斑块的优先结合。此外，与（18）F-THK-523 和其他报道的（18）F 标记放射性示踪剂相比，这些衍生物在正常小鼠中表现出丰富的初始脑摄取和更快的清除。THK-5105 和 THK-5117 在小鼠和大鼠中未显示与这些化合物给药相关的毒性作用，并且在 1-μM 浓度下对各种神经受体、离子通道和转运体没有明显结合。
（18）F 标记的 THK-5105 和 THK-5117 是有前途的 PET tau 成像放射性示踪剂候选物。
