title: Synthesis, characterization, and preclinical validation of a PET radiopharmaceutical for interrogating Aβ (β-amyloid) plaques in Alzheimer's disease.
abstract: BACKGROUND
  PET radiopharmaceuticals capable of imaging β-amyloid (Aβ) plaque burden in the brain could offer highly valuable diagnostic tools for clinical studies of Alzheimer's disease. To further supplement existing armamentarium of FDA-approved agents as well as those under development, and to correlate multiphoton-imaging data reported earlier, herein, we describe preclinical validation of a PET tracer.
  
  
  METHODS
  A novel PET radiopharmaceutical ((18)F-7B) was synthesized and characterized. To assess its affinity for Aβ, binding assays with Aβ1-42 fibrils, Alzheimer's disease (AD) homogenates, and autoradiography studies and their IHC correlations were performed. For assessing its overall pharmacokinetic profiles in general and its ability to cross the blood-brain barrier (BBB) in particular, biodistribution studies in normal mice were performed. Finally, for evaluating potential for (18)F-7B to serve as a targeted Aβ probe, the microPET/CT imaging was performed in age-matched amyloid precursor protein/presenilin-1 (APP/PS1) mice and wild-type (WT) counterparts.
  
  
  RESULTS
  The radiotracer (18)F-7B shows saturable binding to autopsy-confirmed AD homogenates (K d = 17.7 nM) and Aβ1-42 fibrils (K d = 61 nM). Preliminary autoradiography studies show binding of (18)F-7B to cortical Aβ plaques in autopsy-confirmed AD tissue sections, inhibition of that binding by unlabeled counterpart 7A-indicating specificity, and a good correlation of tracer binding with Aβ immunostaining. The agent indicates high initial penetration into brains (7.23 ± 0.47%ID/g; 5 min) of normal mice, thus indicating a 5-min/120-min brain uptake clearance ratio of 4.7, a benchmark value (>4) consistent with the ability of agents to traverse the BBB to enable PET brain imaging. Additionally, (18)F-7B demonstrates the presence of parental species in human serum. Preliminary microPET/CT imaging demonstrates significantly higher retention of (18)F-7B in brains of transgenic mice compared with their WT counterparts, consistent with expected binding of the radiotracer to Aβ plaques, present in APP/PS1 mice, compared with their age-matched WT counterparts lacking those Aβ aggregates.
  
  
  CONCLUSIONS
  These data offer a platform scaffold conducive to further optimization for developing new PET tracers to study Aβ pathophysiology in vitro and in vivo.
authors.affiliation: ICCE Institute, Molecular Imaging Center, Box 8225, 510 S. Kingshighway Blvd., St. Louis, MO, 63110, USA, guruswamis@wustl.edu.
authors.forename: Guruswami Sm
authors.initials: GS
authors.lastname: Sundaram
authors.forename: Dhruva
authors.initials: D
authors.lastname: Dhavale
authors.forename: Julie L
authors.initials: JL
authors.lastname: Prior
authors.forename: Jothilingam
authors.initials: J
authors.lastname: Sivapackiam
authors.forename: Richard
authors.initials: R
authors.lastname: Laforest
authors.forename: Paul
authors.initials: P
authors.lastname: Kotzbauer
authors.forename: Vijay
authors.initials: V
authors.lastname: Sharma