Novel 18F-labeled arylquinoline derivatives for noninvasive imaging of Tau pathology in Alzheimer disease

Nobuyuki Okamura, Shozo Furumoto, Ryuichi Harada, Tetsuro Tago, Takeo Yoshikawa, Michelle Fodero-Tavoletti, Rachel S. Mulligan, Victor L. Villemagne, Hiroyasu Akatsu, Takayuki Yamamoto, Hiroyuki Arai, Ren Iwata, Kazuhiko Yanai, Yukitsuka Kudo

Research output: Contribution to journalArticlepeer-review

238 Citations (Scopus)


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 18F-labeled THK-523 (18F-6-(2-fluoroethoxy)-2-(4- aminophenyl)quinoline) as a tau imaging radiotracer candidate for PET. After compound optimization, we developed novel 18F-labeled arylquinoline derivatives, 18F-THK- 5105 and 18F-THK-5117, for use as tau imaging PET tracers. Methods: 18F-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. Results: 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 11C-Pittsburgh compound B, showing preferential binding to amyloid plaques. Furthermore, these derivatives demonstrated abundant initial brain uptake and faster clearance in normal mice than 18F-THK-523 and other reported 18F-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-mM concentrations. Conclusion: 18Flabeled THK-5105 and THK-5117 are promising candidates as PET tau imaging radiotracers. COPYRIGHT

Original languageEnglish
Pages (from-to)1420-1427
Number of pages8
JournalJournal of Nuclear Medicine
Issue number8
Publication statusPublished - 2013 Aug 1


  • Alzheimer disease
  • Molecular imaging
  • Neurofibrillary tangles
  • Positron emission tomography
  • Tau

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging


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