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

Abstract

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.

• Authors: Yanping Yang, Mengchao Cui, Xiaoyang Zhang, Jiapei Dai, Zhiyong Zhang, Chunping Lin, Yuzhi Guo, Boli Liu
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 57 Issue 14 Pg. 6030-42 (Jul 24 2014) ISSN: 1520-4804 [Electronic] United States
• PMID: 24936678 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Iodine Radioisotopes
• Ligands
• Phenyl Ethers

Topics

• Aged
• Alzheimer Disease (diagnosis, metabolism, pathology)
• Amyloid beta-Peptides (metabolism)
• Animals
• Brain (metabolism, pathology)
• 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, metabolism, pathology)
• Quantitative Structure-Activity Relationship
• Tissue Distribution
• Tomography, Emission-Computed, Single-Photon (methods)