Synthesis and evaluation of 2-pyrrolopyridinylquinoline derivatives as selective tau PET tracers for the diagnosis of Alzheimer's disease
Synthesis and evaluation of 2-pyrrolopyridinylquinoline derivatives as selective tau PET tracers for the diagnosis of Alzheimer's disease
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DOI：
10.1016/j.nucmedbio.2020.10.002
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发表时间：
2021-02-01
影响因子：
3.1
通讯作者：
Furumoto, Shozo
中科院分区：
文献类型：
--
作者：
Lerdsirisuk, Pradith;Harada, Ryuichi;Furumoto, Shozo
简介：[F-18]THK-5351最初是作为一种正电子发射断层扫描（PET）成像示踪剂开发的，用于检测积累的tau蛋白，这是阿尔茨海默病（AD）的病理标志。然而，[F-18]THK-5351的临床研究显示存在与单胺氧化酶-B（MAO-B）的脱靶结合。为了克服这种脱靶结合，在这项工作中，我们合成和评估2-吡咯并吡啶基喹啉（PPQ）衍生物作为选择性tau PET成像tracers.Methods：PPQ衍生物的核心结构主要使用Buchwald-Hartwig胺化偶联反应合成。通过体外竞争性结合测定评价所有衍生物对tau和MAO-B的结合亲和力。PPQ衍生物的放射合成是通过在二甲基亚砜中加热110 ℃ 10 min，用活化的[F-18]KF/Kryptofix 222复合物对其甲苯磺酸盐前体进行F-18放射性标记来进行的。这些[F-18]PPQ衍生物的生物学特性通过死后AD脑切片的体外放射自显影和小鼠体内离体生物分布测定来表征。合成了PPQ衍生物，产率为49- 84%。体外竞争结合试验表明，两种新型PPQ衍生物-PPQ 8和PPQ 9-表现出对tau的高结合亲和力（IC 50分别为4.9和6.9 nM）。[F-18] PPQ 8和[F-18] PPQ 9的放射合成分别产生1.4%和50.1%的分离的非衰变校正放射化学产率，放射化学纯度>99%。[F-18] PPQ 8和[F-18] PPQ 9的摩尔放射性分别为16.9和64.8 GBq/μ mol。[F-18] PPQ 8和[F-18] PPQ 9的体外和离体生物学特性表明，这些示踪剂在AD脑切片中对tau具有选择性，而没有脱靶结合，并且它们还证明了正常小鼠脑摄取。结论：F-18标记的PPQ衍生物提高了AD中tau聚集体的结合亲和力和选择性。需要进一步的结构优化以改善有效的tau PET成像示踪剂的药代动力学。(C)2020爱思唯尔公司All rights reserved.
Introduction: [F-18]THK-5351 was originally developed as a positron emission tomography (PET) imaging tracer for the detection of accumulated tau proteins, the pathological hallmark of Alzheimer's disease (AD). However, clinical studies of [F-18]THK-5351 revealed the existence of off-target binding to monoamine oxidase-B (MAO-B). To overcome this off-target binding, in this work, we synthesized and evaluated 2-pyrrolopyridinylquinoline (PPQ) derivatives as selective tau PET imaging tracers.Methods: The core structure of PPQ derivatives was synthesized mainly using the Buchwald-Hartwig amination coupling reaction. All derivatives were evaluated for binding affinity towards tau and MAO-B by in vitro competitive binding assay. Radiosynthesis of PPQ derivatives was performed by F-18-radiolabeling of their tosylate precursors with activated [F-18]KF/Kryptofix222 complex in dimethylsulfoxide by heating at 110 degrees C for 10 min. The biological properties of these [F-18]PPQ derivatives were characterized by in vitro autoradiography of postmortem AD brain sections and by assay of ex vivo biodistribution in mice.Results: The PPQ derivatives were synthesized, with yields of 49-84%. In vitro competitive binding assay revealed that two novel PPQ derivatives-PPQ8 and PPQ9-demonstrated high binding affinity for tau (IC50 = 4.9 and 6.9 nM, respectively). The radiosynthesis of [F-18]PPQ8 and [F-18]PPQ9 yielded 1.4% and 50.1% isolated non-decay corrected radiochemical yield, respectively, with >99% radiochemical purity. The molar radioactivities of [F-18] PPQ8 and [F-18]PPQ9 were 16.9 and 64.8 GBq/mu mol, respectively. The in vitro and ex vivo biological characterization of [F-18]PPQ8 and [F-18]PPQ9 revealed that these tracers were selective for tau in AD brain sections without off-target binding, and they furthermore demonstrated brain uptake in normal mice.Conclusions: F-18-labeled PPQ derivatives improved binding affinity and selectivity for tau aggregates in AD. Further structural optimization to improve pharmacokinetics for potent tau PET imaging tracers is required. (C) 2020 Elsevier Inc. All rights reserved.