2-芳基喹啉类化合物作为阿尔茨海默病 tau 病理学 PET 成像示踪剂的构效关系。
Structure-Activity Relationship of 2-Arylquinolines as PET Imaging Tracers for Tau Pathology in Alzheimer Disease.
机构信息
Division of Radiopharmaceutical Chemistry, Cyclotron and Radioisotope Center, Tohoku University, Sendai, Japan Department of Radiopharmaceutical Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Division of Radiopharmaceutical Chemistry, Cyclotron and Radioisotope Center, Tohoku University, Sendai, Japan Department of Radiopharmaceutical Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
出版信息
J Nucl Med. 2016 Apr;57(4):608-14. doi: 10.2967/jnumed.115.166652. Epub 2015 Dec 23.
UNLABELLED
Abnormal deposition of amyloid-β and hyperphosphorylated tau protein in the brain are the pathologic hallmark of Alzheimer disease (AD). Noninvasive detection of the lesions is considered an effective tool for early diagnosis and staging of AD. In the past decade, we developed 2-arylquinoline (2-AQ) derivatives as PET tau tracers. In this study, we synthesized new derivatives and evaluated their properties.
METHODS
Fifteen 2-AQ derivatives were labeled with (18)F, and their binding to tau lesions was evaluated by autoradiography using AD brain sections. The binding affinity for the AD brain homogenates was assessed by an in vitro competitive binding assay with (18)F-THK-5105. (18)F-labeled derivatives were injected into mice via the tail vein, and their pharmacokinetics over the first 120 min after injection were evaluated by an ex vivo biodistribution study. Tracer metabolism analysis was also assessed in mice.
RESULTS
The average logP value was 2.80. This study revealed that 2-AQ derivatives having (18)F-labeled side chains on benzene or position 7 of the quinoline showed significantly lower binding affinity for tau than 6-substituted quinoline derivatives. The 2-AQ derivatives labeled with (18)F-fluoroethoxy, (18)F-fluoropropoxy, and (18)F-fluoro-polyethyleneglycol groups displayed slow clearance from blood or a high accumulation in bone, whereas derivatives labeled with the (18)F-(3-fluoro-2-hydroxy)propoxyl group did not. (18)F-THK-5151 had outstanding tau binding properties and pharmacokinetics. Furthermore, the properties of its optically pure (S)-enantiomer (THK-5351) were superior to those of the (R)-enantiomer (THK-5451), particularly in terms of its clearance from the brain and its resistance to defluorination in mice.
CONCLUSION
The structure-activity relationship study of 2-AQ derivatives revealed the optimal structural features for tau imaging agents. On the basis of these results, (18)F-THK-5351 ((S)-(18)F-THK-5151) was selected as a potential agent for tau imaging.
目的
异常淀粉样蛋白-β和过度磷酸化的 tau 蛋白在大脑中的沉积是阿尔茨海默病（AD）的病理标志。非侵入性检测病变被认为是 AD 早期诊断和分期的有效工具。在过去的十年中，我们开发了 2-芳基喹啉（2-AQ）衍生物作为 PET tau 示踪剂。在这项研究中，我们合成了新的衍生物，并评估了它们的性质。
方法
用（18）F 标记了 15 种 2-AQ 衍生物，并通过 AD 脑切片的放射自显影评估了它们与 tau 病变的结合。通过用（18）F-THK-5105 进行体外竞争性结合测定评估了它们对 AD 脑匀浆的结合亲和力。通过离体生物分布研究评估了（18）F 标记衍生物在注射后 120 分钟内的药代动力学。还在小鼠中评估了示踪剂代谢分析。
结果
平均 logP 值为 2.80。这项研究表明，苯或喹啉 7 位上带有（18）F 标记侧链的 2-AQ 衍生物对 tau 的结合亲和力明显低于 6-取代喹啉衍生物。用（18）F-氟乙氧基、（18）F-氟丙氧基和（18）F-氟聚乙二醇基团标记的 2-AQ 衍生物从血液中清除缓慢或在骨骼中高度积聚，而用（18）F-（3-氟-2-羟基）丙氧基标记的衍生物则没有。（18）F-THK-5151 具有出色的 tau 结合特性和药代动力学。此外，其光学纯（S）-对映体（THK-5351）的性质优于（R）-对映体（THK-5451）的性质，特别是在大脑中的清除率和在小鼠中的抗脱氟能力方面。
结论
2-AQ 衍生物的构效关系研究揭示了 tau 成像剂的最佳结构特征。基于这些结果，选择（18）F-THK-5351（（S）-（18）F-THK-5151）作为 tau 成像的潜在试剂。
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