Radioiodinated Benzyloxybenzene Derivatives: A Class of Flexible Ligands Target to β-Amyloid Plaques in Alzheimer's Brains

Benzyloxybenzene, as a novel flexible scaffold without rigid planarity, was synthesized and evaluated as ligand toward A beta plaques. The binding site calculated for these flexible ligands was the hydrophobic Val18_Phe20 channel on the flat surface of A beta 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 [I-125]4, [I-125]24, and [I-125]22 (K-i = 24.3, 49.4, and 17.6 nM, respectively). In biodistribution, [I-125]4 exhibited high initial uptake and rapid washout property in the brain with brain(2 min)/brain(60 min) ratio of 16.3. The excellent in vitro and in vivo biostability of [I-125]4 enhanced its potential for clinical application in SPECT imaging of A beta plaques. This approach could also allow the design of a new generation of A beta targeting ligands without rigid and planar framework.