title: In vivo PET imaging of beta-amyloid deposition in mouse models of Alzheimer's disease with a high specific activity PET imaging agent [(18)F]flutemetamol.
abstract: BACKGROUND
  The purpose of the study was to evaluate the applicability of (18) F-labelled amyloid imaging positron emission tomography (PET) agent [ (18) F]flutemetamol to detect changes in brain beta-amyloid (Aβ) deposition in vivo in APP23, Tg2576 and APPswe-PS1dE9 mouse models of Alzheimer's disease. We expected that the high specific activity of [ (18) F]flutemetamol would make it an attractive small animal Aβ imaging agent.
  
  
  METHODS
  [ (18) F]flutemetamol uptake in the mouse brain was evaluated in vivo at 9 to 22 months of age with an Inveon Multimodality PET/CT camera (Siemens Medical Solutions USA, Knoxville, TN, USA). Retention in the frontal cortex (FC) was evaluated by Logan distribution volume ratios (DVR) and FC/cerebellum (CB) ratios during the late washout phase (50 to 60 min). [ (18) F]flutemetamol binding to Aβ was also evaluated in brain slices by in vitro and ex vivo autoradiography. The amount of Aβ in the brain slices was determined with Thioflavin S and anti-Aβ1-40 immunohistochemistry.
  
  
  RESULTS
  In APP23 mice, [ (18) F]flutemetamol retention in the FC increased from 9 to 18 months. In younger mice, DVR and FC/CB50-60 were 0.88 (0.81) and 0.88 (0.89) at 9 months (N = 2), and 0.98 (0.93) at 12 months (N = 1), respectively. In older mice, DVR and FC/CB50-60 were 1.16 (1.15) at 15 months (N = 1), 1.13 (1.16) and 1.35 (1.35) at 18 months (N = 2), and 1.05 (1.31) at 21 months (N = 1). In Tg2576 mice, DVR and FC/CB50-60 showed modest increasing trends but also high variability. In APPswe-PS1dE9 mice, DVR and FC/CB50-60 did not increase with age. Thioflavin S and anti-Aβ1-40 positive Aβ deposits were present in all transgenic mice at 19 to 22 months, and they co-localized with [ (18) F]flutemetamol binding in the brain slices examined with in vitro and ex vivo autoradiography.
  
  
  CONCLUSIONS
  Increased [ (18) F]flutemetamol retention in the brain was detected in old APP23 mice in vivo. However, the high specific activity of [ (18) F]flutemetamol did not provide a notable advantage in Tg2576 and APPswe-PS1dE9 mice compared to the previously evaluated structural analogue [(11)C]PIB. For its practical benefits, [ (18) F]flutemetamol imaging with a suitable mouse model like APP23 is an attractive alternative.
authors.affiliation: Medicity/PET Preclinical Laboratory, Turku PET Centre, University of Turku, Tykistökatu 6 A, Turku 20520, Finland.
authors.forename: Anniina
authors.initials: A
authors.lastname: Snellman
authors.affiliation: Radiopharmaceutical Chemistry Laboratory, Turku PET Centre, University of Turku, Porthaninkatu 3, Turku 20500, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Rokka
authors.affiliation: Medicity/PET Preclinical Laboratory, Turku PET Centre, University of Turku, Tykistökatu 6 A, Turku 20520, Finland.
authors.forename: Francisco R
authors.initials: FR
authors.lastname: López-Picón
authors.affiliation: Radiopharmaceutical Chemistry Laboratory, Turku PET Centre, University of Turku, Porthaninkatu 3, Turku 20500, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Eskola
authors.affiliation: Mario Negri Institute for Pharmacological Research, Milan 20156, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Salmona
authors.affiliation: Mario Negri Institute for Pharmacological Research, Milan 20156, Italy.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Forloni
authors.affiliation: Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Kiinamyllynkatu 10, Turku 20520, Finland ; Unit of Clinical Pharmacology, TYKSLAB, Turku University Hospital, Kiinamyllynkatu 10, Turku 20520, Finland.
authors.forename: Mika
authors.initials: M
authors.lastname: Scheinin
authors.affiliation: Radiopharmaceutical Chemistry Laboratory, Turku PET Centre, University of Turku, Porthaninkatu 3, Turku 20500, Finland.
authors.forename: Olof
authors.initials: O
authors.lastname: Solin
authors.affiliation: Turku PET Centre, University of Turku, Turku 20521, Finland.
authors.forename: Juha O
authors.initials: JO
authors.lastname: Rinne
authors.affiliation: Medicity/PET Preclinical Laboratory, Turku PET Centre, University of Turku, Tykistökatu 6 A, Turku 20520, Finland.
authors.forename: Merja
authors.initials: M
authors.lastname: Haaparanta-Solin
keywords: APP23; APPswe-PS1dE9; Alzheimer's disease; Amyloid imaging; Beta-amyloid; High specific activity; Preclinical evaluation; Tg2576; Transgenic mouse model; [18F]flutemetamol