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 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 (K_i = 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 brain _{2 min}/brain_{60 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.