title: Exploratory human PET study of the effectiveness of (11)C-ketoprofen methyl ester, a potential biomarker of neuroinflammatory processes in Alzheimer's disease.
abstract: Neuroinflammatory processes play an important role in the pathogenesis of Alzheimer's disease (AD). As a biomarker of neuroinflammatory processes, we designed (11)C-labeled ketoprofen methyl ester ([(11)C]KTP-Me) to increase the blood-brain barrier permeability of ketoprofen (KTP), a selective cyclooxygenase-1 (COX-1) inhibitor. Animal studies indicated that [(11)C]KTP-Me enters the brain and accumulates in activated microglia of inflammatory lesions. In a first-in-human study, we reported that [(11)C]KTP-Me is a safe positron emission tomography (PET) tracer and enters the brain; the radioactivity is washed out from normal cerebral tissue. Here we explored the efficacy of [(11)C]KTP-Me as a diagnostic biomarker of neuroinflammatory processes in AD.
  
  
  
  [(11)C]KTP-Me was synthesized by rapid C-[(11)C]methylation of [(11)C]CH3I and the corresponding arylacetate precursor. Nine subjects (four healthy subjects, two Pittsburgh compound-B (PiB)-positive patients with mild cognitive impairment (MCI), and three PiB-positive AD patients) underwent a dynamic brain PET scan for 70min after injection. We evaluated differences in cortical retention and washout rate in the brain between healthy subjects and MCI/AD patients.
  
  
  
  A brain distribution pattern reflecting blood flow in the early-phase image was seen in both healthy subjects and MCI/AD patients. Cortical activity gradually cleared in all groups. However, we observed no obvious difference in the washout rate between healthy subjects and MCI/AD patients or between MCI and AD patients.
  
  
  
  [(11)C]KTP-Me cannot be useful as a potential diagnostic biomarker for MCI/AD. Further improvements in binding affinity and specificity, etc., are needed to be a diagnostic biomarker of neuroinflammation in AD.
  
  
  
  [(11)C]KTP-Me is a new tracer that targets COX-1. [(11)C]KTP-Me is expected to be a diagnostic biomarker of neuroinflammation in AD in the future. The effectiveness was limited in a small number of AD patients. Therefore, further studies are needed to clarify the usefulness of [(11)C]KTP-Me.
authors.affiliation: Division of Molecular Imaging, Institute of Biomedical Research and Innovation, Kobe, Japan.
authors.forename: Akihito
authors.initials: A
authors.lastname: Ohnishi
authors.affiliation: Division of Molecular Imaging, Institute of Biomedical Research and Innovation, Kobe, Japan. Electronic address: senda@fbri.org.
authors.forename: Michio
authors.initials: M
authors.lastname: Senda
authors.affiliation: Division of Molecular Imaging, Institute of Biomedical Research and Innovation, Kobe, Japan; Department of Nuclear Medicine, Saitama Medical University International Medical Center, Hidaka, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Yamane
authors.affiliation: Division of Molecular Imaging, Institute of Biomedical Research and Innovation, Kobe, Japan; Department of Radiological Technology, Okayama Rosai Hospital, Okayama, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Mikami
authors.affiliation: Division of Molecular Imaging, Institute of Biomedical Research and Innovation, Kobe, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nishida
authors.affiliation: Division of Molecular Imaging, Institute of Biomedical Research and Innovation, Kobe, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Nishio
authors.affiliation: Division of Molecular Imaging, Institute of Biomedical Research and Innovation, Kobe, Japan.
authors.forename: Go
authors.initials: G
authors.lastname: Akamatsu
authors.affiliation: Division of Molecular Imaging, Institute of Biomedical Research and Innovation, Kobe, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Ikari
authors.affiliation: Division of Molecular Imaging, Institute of Biomedical Research and Innovation, Kobe, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Kimoto
authors.affiliation: Division of Molecular Imaging, Institute of Biomedical Research and Innovation, Kobe, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Aita
authors.affiliation: Division of Molecular Imaging, Institute of Biomedical Research and Innovation, Kobe, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sasaki
authors.affiliation: Department of Psychiatry, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Shinkawa
authors.affiliation: Department of Psychiatry, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Yasuji
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Division of Bio-Function Dynamics Imaging, Center for Life Science Technologies RIKEN, Kobe, Japan; Division of Pharmaceutical Chemistry, Center Showa Pharmaceutical University, Machida, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Shukuri
authors.affiliation: Division of Bio-Function Dynamics Imaging, Center for Life Science Technologies RIKEN, Kobe, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Mawatari
authors.affiliation: Division of Bio-Function Dynamics Imaging, Center for Life Science Technologies RIKEN, Kobe, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Doi
authors.affiliation: Division of Bio-Function Dynamics Imaging, Center for Life Science Technologies RIKEN, Kobe, Japan.
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Division of Bio-Function Dynamics Imaging, Center for Life Science Technologies RIKEN, Kobe, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Onoe
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000000981:diagnostic imaging* / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002250:Carbon Radioisotopes; D005260:Female; D006801:Humans; D007660:Ketoprofen / Q000031:analogs & derivatives* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography / Q000379:methods*
chemical_list: D015415:Biomarkers; D002250:Carbon Radioisotopes; C560799:ketoprofen methyl ester; D007660:Ketoprofen
keywords: Alzheimer's disease; Neuroinflammation; [(11)C]Ketoprofen methyl ester