Radiopharmaceutical Chemistry, Graduate School of Pharmaceutical Science, Tohoku University, Sendai 980-8578, Japan; Cyclotron and Radioisotope Center (CYRIC), Tohoku University, Sendai 980-8578, Japan.
Department of Pharmacology, Graduate School of Medicine, Tohoku University, Sendai 980-0872, Japan; Department of Gerontology and Geriatrics, Division of Brain Science, Institute of Development Aging and Cancer (IDAC), Tohoku University, Sendai 980-0872, Japan.
Nucl Med Biol. 2021 Feb;93:11-18. doi: 10.1016/j.nucmedbio.2020.10.002. Epub 2020 Oct 26.
[F]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]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.
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-radiolabeling of their tosylate precursors with activated [F]KF/Kryptofix222 complex in dimethylsulfoxide by heating at 110 °C for 10 min. The biological properties of these [F]PPQ derivatives were characterized by in vitro autoradiography of postmortem AD brain sections and by assay of ex vivo biodistribution in mice.
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 (IC = 4.9 and 6.9 nM, respectively). The radiosynthesis of [F]PPQ8 and [F]PPQ9 yielded 1.4% and 50.1% isolated non-decay corrected radiochemical yield, respectively, with >99% radiochemical purity. The molar radioactivities of [F]PPQ8 and [F]PPQ9 were 16.9 and 64.8 GBq/μmol, respectively. The in vitro and ex vivo biological characterization of [F]PPQ8 and [F]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.
F-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.
[F]THK-5351 最初被开发为正电子发射断层扫描（PET）成像示踪剂，用于检测阿尔茨海默病（AD）的病理标志——tau 蛋白的积累。然而，[F]THK-5351 的临床研究揭示了存在与单胺氧化酶-B（MAO-B）的非靶标结合。为了克服这种非靶标结合，在这项工作中，我们合成并评估了 2-吡咯吡啶并喹啉（PPQ）衍生物作为选择性 tau PET 成像示踪剂。
PPQ 衍生物的核心结构主要通过 Buchwald-Hartwig 胺化偶联反应合成。通过体外竞争结合测定评估所有衍生物与 tau 和 MAO-B 的结合亲和力。通过在二甲基亚砜中将其对甲苯磺酸盐前体与活化的[F]KF/Kryptofix222 络合物进行 F-放射性标记，在 110°C 下加热 10 分钟来进行 PPQ 衍生物的放射性合成。通过对 AD 尸检脑组织切片的体外放射自显影和在小鼠中的离体生物分布测定来表征这些[F]PPQ 衍生物的生物学特性。
PPQ 衍生物的合成收率为 49-84%。体外竞争结合测定显示，两种新型 PPQ 衍生物-PPQ8 和 PPQ9-对 tau 具有高结合亲和力（IC=4.9 和 6.9 nM，分别）。[F]PPQ8 和[F]PPQ9 的放射性合成分别得到 1.4%和 50.1%的非衰变校正放射性化学产率，放射性化学纯度均>99%。[F]PPQ8 和[F]PPQ9 的摩尔放射性活度分别为 16.9 和 64.8 GBq/μmol。[F]PPQ8 和[F]PPQ9 的体外和离体生物学特性表明，这些示踪剂在 AD 脑组织切片中对 tau 具有选择性，没有非靶标结合，并且在正常小鼠中具有脑摄取。
F 标记的 PPQ 衍生物提高了 AD 中 tau 聚集物的结合亲和力和选择性。需要进一步的结构优化，以提高用于有力 tau PET 成像示踪剂的药代动力学。
