Metal-chelating benzothiazole multifunctional compounds for the modulation and 64Cu PET imaging of Aβ aggregation |
| |
Authors: | Yiran Huang Hong-Jun Cho Nilantha Bandara Liang Sun Diana Tran Buck E Rogers Liviu M Mirica |
| |
Institution: | Department of Chemistry, University of Illinois at Urbana-Champaign, 600 S. Mathews Avenue, Urbana Illinois 61801 USA.; Department of Radiation Oncology, Washington University School of Medicine, St. Louis Missouri 63108 USA ; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis MO 63110 USA |
| |
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 Aβ aggregation and its toxicity, as well as positron emission tomography (PET) imaging of Aβ aggregates. Firstly, among the six compounds tested HYR-16 is shown to be capable to reroute the toxic Cu-mediated Aβ 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 per 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.A series of multifunctional compounds and their 64Cu complexes exhibit good affinity for Aβ aggregates and can also control Aβ toxicity. |
| |
Keywords: | |
|
|