Radioiodinated benzyloxybenzene derivatives: a class of flexible ligands target to β-amyloid plaques in Alzheimer's brains

Yanping Yang, Mengchao Cui, Xiaoyang Zhang, Jiapei Dai, Zhiyong Zhang, Chunping Lin, Yuzhi Guo, Boli Liu

Research output: Contribution to journalArticlepeer-review


Benzyloxybenzene, as a novel flexible scaffold without rigid planarity, was synthesized and evaluated as ligand toward Aβ plaques. The binding site calculated for these flexible ligands was the hydrophobic Val18_Phe20 channel on the flat surface of Aβ fiber. Structure-activity relationship analysis generated a common trend that binding affinities declined significantly from para-substituted ligands to ortho-substituted ones, which was also quantitatively illustrated by 3D-QSAR modeling. Autoradiography in vitro further confirmed the high affinities of radioiodinated ligands [125I]4, [125I]24, and [125I]22 (Ki=24.3, 49.4, and 17.6 nM, respectively). In biodistribution, [125I]4 exhibited high initial uptake and rapid washout property in the brain with brain2 min/brain60 min ratio of 16.3. The excellent in vitro and in vivo biostability of [125I]4 enhanced its potential for clinical application in SPECT imaging of Aβ plaques. This approach could also allow the design of a new generation of Aβ targeting ligands without rigid and planar framework.

Original languageEnglish (US)
Pages (from-to)6030-42
Number of pages13
JournalJournal of Medicinal Chemistry
Issue number14
StatePublished - Jul 24 2014


  • Aged
  • Alzheimer Disease/diagnosis
  • Amyloid beta-Peptides/metabolism
  • Animals
  • Brain/metabolism
  • Female
  • Humans
  • Iodine Radioisotopes/chemistry
  • Ligands
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Middle Aged
  • Molecular Docking Simulation
  • Molecular Structure
  • Phenyl Ethers/chemistry
  • Plaque, Amyloid/diagnosis
  • Quantitative Structure-Activity Relationship
  • Tissue Distribution
  • Tomography, Emission-Computed, Single-Photon/methods


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