Benzofuran derivatives as A-aggregate-specific imaging agents for Alzheimerfs
disease.
ABSTRACT
The purpose of this study is to develop potential I-123 labeled diagnostic
imaging agents targeting amyloid plaques in Alzheimerfs disease (AD). Formation
and accumulation of aggregates of beta-amyloid (A) peptides in the brain
are critical factors in the development and progression of AD. Small molecule-based
benzofuran derivatives were designed and synthesized. Both 5- and 6-iodobenzofuran
derivatives displayed excellent competition for I-125 TZDM binding to A40
aggregates with Ki values in the subnanomolar range. The radioiodinated ligands, with a high
specific activity, were successfully prepared through an iododestannylation
reaction from the corresponding tributyltin derivatives using hydrogen
peroxide as the oxidant in high yields (60-80%) and with high radiochemical
purities (greater than 95%). After an iv injection, all four radioiodinated
ligands displayed high brain uptakes ranging from 0.5 to 1.5% initial dose/organ
in normal mice. The radioactivity washed out from the mouse brain slowly
(less than 50% at 2 h post injection),suggesting high in vivo non-specific binding. In conclusion, the benzofuran ligands displayed
excellent binding affinity for A aggregates. The long retention of these
ligands in the normal mouse brain suggests that there may be high binding
for these probes in the brain not associated with A plaques. Additional
modifications are necessary to improve the in vivo imaging properties for plaque detection.