Synthesis and characterization of styrylchromone derivatives as -amyloid imaging agents.

ABSTRACT

Several promising agents have been synthesized and evaluated for in vivo imaging probes of -amyloid plaques in Alzheimer's disease (AD) brain. Recently, we have developed flavone derivatives, which possess the basic structure of the 2-phenylchromone, as useful candidates for amyloid imaging agents. In an attempt to further develop novel tracers, we synthesized and evaluated a series of 2-styrylchromone derivatives, which replace the 2-phenyl substituent of flavone backbone with the 2-styryl. A series of radioiodinated styrylchromone derivatives were designed and synthesized. The binding affinities for amyloid plaques were assessed by in vitro binding assay using pre-formed synthetic A(1-40) aggregates. The new series of styrylchromone derivatives showed high binding affinity to A aggregates at the Kd values of 32.0, 17.5 and 8.7nM for [125I]6, [125I]9, and [125I]12, respectively. In biodistribution studies using normal mice, [125I]6 and [125I]9 examined in normal mice displayed high brain uptakes with 4.9 and 2.8%ID/g at 2min post injection. The radioactivity washed out from the brain rapidly (1.6 and 1.0%ID/g at 60min post injection for [125I]6 and [125I]9, respectively). But [125I]12 did not show marked brain uptake, and the washout rate from the brain was relatively slow throughout the time course (1.1 and 1.4%ID/g at 2 and 30min post injection, respectively). Although additional modifications are necessary to improve the brain uptake and rapid clearance of non-specifically bound radiotracer, the styrylchromone backbone may be useful as a backbone structure to develop novel -amyloid imaging agents.