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.