title: Novel 18F-labeled arylquinoline derivatives for noninvasive imaging of tau pathology in Alzheimer disease.
abstract: 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 (18)F-labeled THK-523 ((18)F-6-(2-fluoroethoxy)-2-(4-aminophenyl)quinoline) as a tau imaging radiotracer candidate for PET. After compound optimization, we developed novel (18)F-labeled arylquinoline derivatives, (18)F-THK-5105 and (18)F-THK-5117, for use as tau imaging PET tracers.
  
  
  METHODS
  (18)F-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 (11)C-Pittsburgh compound B, showing preferential binding to amyloid plaques. Furthermore, these derivatives demonstrated abundant initial brain uptake and faster clearance in normal mice than (18)F-THK-523 and other reported (18)F-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-μM concentrations.
  
  
  CONCLUSIONS
  (18)F-labeled THK-5105 and THK-5117 are promising candidates as PET tau imaging radiotracers.
authors.affiliation: Department of Pharmacology, Tohoku University School of Medicine, Sendai, Japan. nookamura@med.tohoku.ac.jp
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Okamura
authors.forename: Shozo
authors.initials: S
authors.lastname: Furumoto
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Harada
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Tago
authors.forename: Takeo
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: Michelle
authors.initials: M
authors.lastname: Fodero-Tavoletti
authors.forename: Rachel S
authors.initials: RS
authors.lastname: Mulligan
authors.forename: Victor L
authors.initials: VL
authors.lastname: Villemagne
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Akatsu
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Arai
authors.forename: Ren
authors.initials: R
authors.lastname: Iwata
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yanai
authors.forename: Yukitsuka
authors.initials: Y
authors.lastname: Kudo
mesh_terms: D000544:Alzheimer Disease / Q000000981:diagnostic imaging* / Q000378:metabolism*; D000814:Aniline Compounds / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D000818:Animals; D005260:Female; D005462:Fluorine Radioisotopes; D008297:Male; D051379:Mice; D049268:Positron-Emission Tomography; D011804:Quinolines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D011854:Radiochemistry; D051381:Rats; D017981:Receptors, Neurotransmitter / Q000378:metabolism; D016875:tau Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: C000604726:6-((3-fluoro-2-hydroxy)propoxy)-2-(4-methylaminophenyl)quinoline; D000814:Aniline Compounds; D005462:Fluorine Radioisotopes; D011804:Quinolines; D017981:Receptors, Neurotransmitter; D016875:tau Proteins
keywords: Alzheimer disease; molecular imaging; neurofibrillary tangles; positron emission tomography; tau