Abstract
While Alzheimer’s Disease (AD) is the most common
neurodegenerative disease, there is still a dearth of efficient therapeutic and
diagnostic agents for this disorder. Reported herein are a series of new
multifunctional compounds (MFCs) with appreciable affinity for amyloid
aggregates that can be potentially used for both the modulation of Ab aggregation
and its toxicity, as well as positron emission tomography (PET) imaging of Ab
aggregates. Firstly, among the six compounds tested HYR-16 is shown to be capable to reroute the toxic Cu-mediated Ab
oligomerization into the formation of less toxic amyloid fibrils. In addition, HYR-16 can also alleviate the formation
of reactive oxygen species (ROS) caused by Cu2+ ions through
Fenton-like reactions. Secondly, these MFCs can be easily converted to PET imaging
agents by pre-chelation with the 64Cu radioisotope, and the Cu
complexes of HYR-4 and HYR-17 exhibit good fluorescent staining
and radiolabeling of amyloid plaques both in
vitro and ex vivo. Importantly,
the 64Cu-labeled HYR-17 is
shown to have a significant brain uptake of up to 0.99 ± 0.04 %ID/g. Overall, by
evaluating the various properties of these MFCs valuable structure-activity
relationships were obtained that should aid the design of improved therapeutic
and diagnostic agents for AD.
Supplementary materials
Title
SuppInfo050720
Description
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