Synthesis and evaluation of 2-pyrrolopyridinylquinoline derivatives as selective tau PET tracers for the diagnosis of Alzheimer's disease

Pradith Lerdsirisuk, Ryuichi Harada, Yoshimi Hayakawa, Yuki Shimizu, Yoichi Ishikawa, Ren Iwata, Yukitsuka Kudo, Nobuyuki Okamura, Shozo Furumoto

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9 Citations (Scopus)


Introduction: [18F]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 [18F]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 18F-radiolabeling of their tosylate precursors with activated [18F]KF/Kryptofix222 complex in dimethylsulfoxide by heating at 110 °C for 10 min. The biological properties of these [18F]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 [18F]PPQ8 and [18F]PPQ9 yielded 1.4% and 50.1% isolated non-decay corrected radiochemical yield, respectively, with >99% radiochemical purity. The molar radioactivities of [18F]PPQ8 and [18F]PPQ9 were 16.9 and 64.8 GBq/μmol, respectively. The in vitro and ex vivo biological characterization of [18F]PPQ8 and [18F]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: 18F-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.

Original languageEnglish
Pages (from-to)11-18
Number of pages8
JournalNuclear Medicine and Biology
Publication statusPublished - 2021 Feb


  • Alzheimer's disease
  • Imaging
  • Monoamine oxidase-B
  • PET tracer
  • Pyrrolopyridinylquinoline
  • Tau


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