title: [18F]Fluoroazabenzoxazoles as potential amyloid plaque PET tracers: synthesis and in vivo evaluation in rhesus monkey.
abstract: BACKGROUND
  An (18)F-labeled positron emission tomography (PET) tracer for amyloid plaque is desirable for early diagnosis of Alzheimer's disease, particularly to enable preventative treatment once effective therapeutics are available. Similarly, such a tracer would be useful as a biomarker for enrollment of patients in clinical trials for evaluation of antiamyloid therapeutics. Furthermore, changes in the level of plaque burden as quantified by an amyloid plaque PET tracer may provide valuable insights into the effectiveness of amyloid-targeted therapeutics. This work describes our approach to evaluate and select a candidate PET tracer for in vivo quantification of human amyloid plaque.
  
  
  METHODS
  Ligands were evaluated for their in vitro binding to human amyloid plaques, lipophilicity and predicted blood-brain barrier permeability. Candidates with favorable in vitro properties were radiolabeled with (18)F and evaluated in vivo. Baseline PET scans in rhesus monkey were conducted to evaluate the regional distribution and kinetics of each tracer using tracer kinetic modeling methods. High binding potential in cerebral white matter and cortical grey matter was considered an unfavorable feature of the candidate tracers.
  
  
  RESULTS
  [(18)F]MK-3328 showed the most favorable combination of low in vivo binding potential in white matter and cortical grey matter in rhesus monkeys, low lipophilicity (Log D=2.91) and high affinity for human amyloid plaques (IC(50)=10.5±1.3 nM).
  
  
  CONCLUSIONS
  [(18)F]MK-3328 was identified as a promising PET tracer for in vivo quantification of amyloid plaques, and further evaluation in humans is warranted.
authors: Merck Research Laboratories, PA 19486, USA. eric_hostetler@merck.com
authors: Eric D
authors: ED
authors: Hostetler
authors: Sandra
authors: S
authors: Sanabria-Bohórquez
authors: Hong
authors: H
authors: Fan
authors: Zhizhen
authors: Z
authors: Zeng
authors: Linda
authors: L
authors: Gammage
authors: Patricia
authors: P
authors: Miller
authors: Stacey
authors: S
authors: O'Malley
authors: Brett
authors: B
authors: Connolly
authors: James
authors: J
authors: Mulhearn
authors: Scott T
authors: ST
authors: Harrison
authors: Scott E
authors: SE
authors: Wolkenberg
authors: James C
authors: JC
authors: Barrow
authors: David L
authors: DL
authors: Williams
authors: Richard J
authors: RJ
authors: Hargreaves
authors: Cyrille
authors: C
authors: Sur
authors: Jacquelynn J
authors: JJ
authors: Cook
mesh_terms: D000544:Alzheimer Disease / Q000000981:diagnostic imaging; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics*; D006801:Humans; D020128:Inhibitory Concentration 50; D008253:Macaca mulatta; D010080:Oxazoles / Q000493:pharmacokinetics*; D058225:Plaque, Amyloid / Q000000981:diagnostic imaging / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods; D011725:Pyridines / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D005462:Fluorine Radioisotopes; C571122:MK-3328; D010080:Oxazoles; D011725:Pyridines; D019275:Radiopharmaceuticals