title: In Vivo Amyloid-β Imaging in the APPPS1-21 Transgenic Mouse Model with a (89)Zr-Labeled Monoclonal Antibody.
abstract: BACKGROUND
  The accumulation of amyloid-β is a pathological hallmark of Alzheimer's disease and is a target for molecular imaging probes to aid in diagnosis and disease monitoring. This study evaluated the feasibility of using a radiolabeled monoclonal anti-amyloid-β antibody (JRF/AβN/25) to non-invasively assess amyloid-β burden in aged transgenic mice (APPPS1-21) with μPET imaging.
  
  
  METHODS
  We investigated the antibody JRF/AβN/25 that binds to full-length Aβ. JRF/AβN/25 was radiolabeled with a [(89)Zr]-desferal chelate and intravenously injected into 12-13 month aged APPPS1-21 mice and their wild-type (WT) controls. Mice underwent in vivo μPET imaging at 2, 4, and 7 days post injection and were sacrificed at the end of each time point to assess brain penetrance, plaque labeling, biodistribution, and tracer stability. To confirm imaging specificity we also evaluated brain uptake of a non-amyloid targeting [(89)Zr]-labeled antibody (trastuzumab) as a negative control, additionally we performed a competitive blocking study with non-radiolabeled Df-Bz-JRF/AβN/25 and finally we assessed the possible confounding effects of blood retention.
  
  
  RESULTS
  Voxel-wise analysis of μPET data demonstrated significant [(89)Zr]-Df-Bz-JRF/AβN/25 retention in APPPS1-21 mice at all time points investigated. With ex vivo measures of radioactivity, significantly higher retention of [(89)Zr]-Df-Bz-JRF/AβN/25 was found at 4 and 7 days pi in APPPS1-21 mice. Despite the observed genotypic differences, comparisons with immunohistochemistry revealed that in vivo plaque labeling was low. Furthermore, pre-treatment with Df-Bz-JRF/AβN/25 only partially blocked [(89)Zr]-Df-Bz-JRF/AβN/25 uptake indicative of a high contribution of non-specific binding.
  
  
  CONCLUSIONS
  Amyloid plaques were detected in vivo with a radiolabeled monoclonal anti-amyloid antibody. The low brain penetrance of the antibody in addition to non-specific binding prevented an accurate estimation of plaque burden. However, it should be noted that [(89)Zr]-Df-Bz-JRF/AβN/25 nevertheless demonstrated in vivo binding and strategies to increase brain penetrance would likely achieve better results.
authors.affiliation: Faculty of Medicine and Health Sciences, Molecular Imaging Center Antwerp, University of AntwerpAntwerp, Belgium; Translational Neurosciences, University of AntwerpAntwerp, Belgium.
authors.forename: Ann-Marie
authors.initials: AM
authors.lastname: Waldron
authors.affiliation: Faculty of Medicine and Health Sciences, Molecular Imaging Center Antwerp, University of AntwerpAntwerp, Belgium; Laboratory of Medicinal Chemistry, University of AntwerpAntwerp, Belgium.
authors.forename: Jens
authors.initials: J
authors.lastname: Fissers
authors.affiliation: Translational Neurosciences, University of Antwerp Antwerp, Belgium.
authors.forename: Annemie
authors.initials: A
authors.lastname: Van Eetveldt
authors.affiliation: Department of Neuroscience, Janssen Research and Development, A Division of Janssen Pharmaceutica NV Beerse, Belgium.
authors.forename: Bianca
authors.initials: B
authors.lastname: Van Broeck
authors.affiliation: Department of Neuroscience, Janssen Research and Development, A Division of Janssen Pharmaceutica NV Beerse, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: Mercken
authors.affiliation: Department of Neuroscience, Janssen Research and Development, A Division of Janssen Pharmaceutica NV Beerse, Belgium.
authors.forename: Darrel J
authors.initials: DJ
authors.lastname: Pemberton
authors.affiliation: Laboratory of Medicinal Chemistry, University of Antwerp Antwerp, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Van Der Veken
authors.affiliation: Laboratory of Medicinal Chemistry, University of Antwerp Antwerp, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Augustyns
authors.affiliation: Laboratory of Medicinal Chemistry, University of Antwerp Antwerp, Belgium.
authors.forename: Jurgen
authors.initials: J
authors.lastname: Joossens
authors.affiliation: Nuclear Medicine, University Hospital Antwerp Antwerp, Belgium.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Stroobants
authors.affiliation: Translational Neurosciences, University of Antwerp Antwerp, Belgium.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dedeurwaerdere
authors.affiliation: Faculty of Medicine and Health Sciences, Molecular Imaging Center Antwerp, University of AntwerpAntwerp, Belgium; Nuclear Medicine, University Hospital AntwerpAntwerp, Belgium.
authors.forename: Leonie
authors.initials: L
authors.lastname: Wyffels
authors.affiliation: Faculty of Medicine and Health Sciences, Molecular Imaging Center Antwerp, University of Antwerp Antwerp, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Staelens
keywords: 89Zirconium; Alzheimer; amyloid imaging; monoclonal antibody; small animal imaging