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ACS Chem Neurosci. 2019 Apr 24. doi: 10.1021/acschemneuro.9b00093. [Epub ahead of print]

Fluorescent 1,4-Naphthoquinones To Visualize Diffuse and Dense-Core Amyloid Plaques in APP/PS1 Transgenic Mouse Brains.

Author information

1
Integrated Science and Engineering Division , Yonsei University , Incheon 21983 , Republic of Korea.
2
Department of Pharmacy and Yonsei Institute of Pharmaceutical Science , Yonsei University , Incheon 21983 , Republic of Korea.
3
Department of Biotechnology , Yonsei University , Seoul 03722 , Republic of Korea.
4
Natural Product Informatics Research Center , Korea Institute of Science and Technology , Gangneung 25451 , Republic of Korea.
5
Department of Medical Biotechnology, College of Life Science and Biotechnology , Dongguk University , Seoul 04620 , Republic of Korea.

Abstract

Recent clinical approvals of brain imaging radiotracers targeting amyloid-β provided clinicians the tools to detect and confirm Alzheimer's disease pathology without autopsy or biopsy. While current imaging agents are effective in postsymptomatic Alzheimer's patients, there is much room for improvement in earlier diagnosis, hence prompting a need for new and improved amyloid imaging agents. Here we synthesized 41 novel 1,4-naphthoquinone derivatives and initially discovered 14 antiamyloidogenic compounds via in vitro amyloid-β aggregation assay; however, qualitative analyses of these compounds produced conflicting results and required further investigation. Follow-up docking and biophysical studies revealed that four of these compounds penetrate the blood-brain barrier, directly bind to amyloid-β aggregates, and enhance fluorescence properties upon interaction. These compounds specifically stain both diffuse and dense-core amyloid-β plaques in brain sections of APP/PS1 double transgenic Alzheimer's mouse models. Our findings suggest 1,4-naphthoquinones as a new scaffold for amyloid-β imaging agents for early stage Alzheimer's.

KEYWORDS:

1,4-naphthoquinone; Alzheimer’s disease; Aβ; amyloid; diffuse plaques; imaging agent

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