title: 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.affiliation: Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University , Beijing 100875, P. R. China.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Yang
authors.forename: Mengchao
authors.initials: M
authors.lastname: Cui
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Zhang
authors.forename: Jiapei
authors.initials: J
authors.lastname: Dai
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Zhang
authors.forename: Chunping
authors.initials: C
authors.lastname: Lin
authors.forename: Yuzhi
authors.initials: Y
authors.lastname: Guo
authors.forename: Boli
authors.initials: B
authors.lastname: Liu
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes / Q000737:chemistry; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008875:Middle Aged; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D010647:Phenyl Ethers / Q000737:chemistry*; D058225:Plaque, Amyloid / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D021281:Quantitative Structure-Activity Relationship; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*
chemical_list: D016229:Amyloid beta-Peptides; D007457:Iodine Radioisotopes; D008024:Ligands; D010647:Phenyl Ethers