title: Characterization of the radiolabeled metabolite of tau PET tracer18F-THK5351.
abstract: 18F-THK5351 is a novel radiotracer developed for in vivo imaging of tau pathology in the brain. For the quantitative assessment of tau deposits in the brain, it is important that the radioactive metabolite does not enter the brain and that it does not bind to tau fibrils. The purpose of the study was to identify a radiolabeled metabolite of18F-THK5351 in blood samples from human subjects and to characterize its pharmacological properties.
  
  
  
  Venous blood samples were collected from three human subjects after injection of18F-THK5351 and the plasma metabolite was measured by high performance thin layer chromatography. In addition, mass spectrometry analysis and enzymatic assays were used to identify this metabolite. Mice were used to investigate the blood-brain barrier permeability of the radioactive metabolite. Furthermore, the binding ability of the metabolite to tau aggregates was evaluated using autoradiography and binding assays using human brain samples.
  
  
  
  About 13 % of the unmetabolized radiotracer was detectable in human plasma at 60 min following the injection of18F-THK5351. The isolated radiometabolite of18F-THK5351 was the sulphoconjugate of THK5351. This metabolite could be produced in vitro by incubating THK5351 with liver but not brain homogenates. The metabolite did not penetrate the blood-brain barrier in mice, and exhibited little binding to tau protein aggregates in post-mortem human brain samples.
  
  
  
  These results suggest that the sole metabolite detectable in plasma seems to be generated outside the brain and does not cross into the brain, which does not affect quantitative analysis of PET images.
authors.affiliation: Division of Neuro-imaging, Institute of Development, Aging and Cancer, Tohoku University, Sendai, 980-8575, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Harada
authors.affiliation: Cyclotron and Radioisotope Center, Tohoku University, Sendai, 980-8578, Japan.
authors.forename: Shozo
authors.initials: S
authors.lastname: Furumoto
authors.affiliation: Cyclotron and Radioisotope Center, Tohoku University, Sendai, 980-8578, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Tago
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Furukawa
authors.affiliation: Department of Geriatrics and Gerontology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, 980-8575, Japan.
authors.forename: Aiko
authors.initials: A
authors.lastname: Ishiki
authors.affiliation: Department of Geriatrics and Gerontology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, 980-8575, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Tomita
authors.affiliation: Cyclotron and Radioisotope Center, Tohoku University, Sendai, 980-8578, Japan.
authors.forename: Ren
authors.initials: R
authors.lastname: Iwata
authors.affiliation: Cyclotron and Radioisotope Center, Tohoku University, Sendai, 980-8578, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Tashiro
authors.affiliation: Department of Geriatrics and Gerontology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, 980-8575, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Arai
authors.affiliation: Cyclotron and Radioisotope Center, Tohoku University, Sendai, 980-8578, Japan.|Department of Pharmacology, Tohoku University School of Medicine, Sendai, 980-8575, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yanai
authors.affiliation: Division of Neuro-imaging, Institute of Development, Aging and Cancer, Tohoku University, Sendai, 980-8575, Japan.|Cyclotron and Radioisotope Center, Tohoku University, Sendai, 980-8578, Japan.
authors.forename: Yukitsuka
authors.initials: Y
authors.lastname: Kudo
authors.affiliation: Division of Neuro-imaging, Institute of Development, Aging and Cancer, Tohoku University, Sendai, 980-8575, Japan. nookamura@med.tohoku.ac.jp.|Cyclotron and Radioisotope Center, Tohoku University, Sendai, 980-8578, Japan. nookamura@med.tohoku.ac.jp.|Division of Pharmacology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, 981-8558, Japan. nookamura@med.tohoku.ac.jp.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Okamura
mesh_terms: D000368:Aged; D000631:Aminopyridines / Q000097:blood* / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D000818:Animals; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging / Q000378:metabolism*; D005260:Female; D006801:Humans; D007553:Isotope Labeling / Q000379:methods; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008813:Mice, Inbred ICR; D057054:Molecular Imaging / Q000379:methods*; D011804:Quinolines / Q000097:blood* / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics; D014018:Tissue Distribution; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D000631:Aminopyridines; C054369:MAPT protein, human; D011804:Quinolines; D019275:Radiopharmaceuticals; C000608225:THK5351; D016875:tau Proteins
keywords: Alzheimer’s disease; PET; Radiolabeled metabolite; Tau