Benzofuran derivatives as Aβ-aggregate-specific imaging agents for Alzheimer's disease

The purpose of this study is to develop potential I-123 labeled diagnostic imaging agents targeting amyloid plaques in Alzheimer's disease (AD). Formation and accumulation of aggregates of beta-amyloid (Abeta) 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 Abeta40 aggregates with K-i 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 Abeta 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 Abeta plaques. Additional modifications are necessary to improve the in vivo imaging properties for, plaque detection. (C) 2002 Elsevier Science Inc. All rights reserved.