Benzofuran derivatives as A-aggregate-specific imaging agents for Alzheimerfs disease.


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.