Preliminary evaluation of fluoro-pegylated benzyloxybenzenes for quantification of β-amyloid plaques by positron emission tomography

Yanping Yang, Hualong Fu, Mengchao Cui, Cheng Peng, Zhigang Liang, Jiapei Dai, Zhiyong Zhang, Chunping Lin, Boli Liu

Research output: Contribution to journalArticlepeer-review

Abstract

A new series of fluoro-pegylated benzyloxybenzenes were designed, synthesized and evaluated as PET probes for early detection of Aβ plaques. Molecular docking revealed that all of the flexible benzyloxybenzenes inserted themselves into the hydrophobic Val18_Phe20 cleft on the flat spine of the Aβ fiber, in a manner similar to that of IMPY molecule. The most potent probe, [(18)F]9a, exhibited a combination of high binding affinity to Aβ aggregates (Ki = 21.0 ± 4.9 nM), high initial brain uptake (9.14% ID/g at 2 min), fast clearance from normal brain tissue (1.79% ID/g at 60 min), and satisfactory in vivo biostability in the brain (95% of intact form at 2 min). [(18)F]9a clearly labeled Aβ plaques in in vitro autoradiography of postmortem AD patients and Tg mice brain sections. Ex vivo autoradiography further demonstrated that [(18)F]9a did penetrate the intact BBB and specifically bind to Aβ plaques in vivo. Overall, [(18)F]9a may be a potential PET probe for imaging Aβ plaques in AD brains.

Original languageEnglish (US)
Pages (from-to)86-96
Number of pages11
JournalEuropean Journal of Medicinal Chemistry
Volume104
DOIs
StatePublished - Nov 2 2015

Keywords

  • Alzheimer Disease/diagnosis
  • Amyloid beta-Peptides/analysis
  • Animals
  • Autoradiography
  • Benzene Derivatives/chemical synthesis
  • Brain
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Mice, Transgenic
  • Molecular Docking Simulation
  • Molecular Probes/chemical synthesis
  • Molecular Structure
  • Plaque, Amyloid/chemistry
  • Positron-Emission Tomography

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