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 (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.