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.
Bibliographical noteFunding Information:
*E-mail: firstname.lastname@example.org (I.K.), for medicinal chemistry. *E-mail: email@example.com (Y.K.), for amyloid investigation. ORCID Ikyon Kim: 0000-0002-0849-5517 YoungSoo Kim: 0000-0001-5029-7082 Author Contributions #N.N.S., H.J., and Y.J. contributed equally. N.N.S., H.J., Y.J., I.K., and Y.K. designed the experiments. N.N.S. and H.J. performed the in vitro and ex vivo experiments. Y.J., G.H.B., and I.K. designed and synthesized the YQ compounds. H.C.Y. and J.M.H. performed PAMPA assay. S.L. and S.B. prepared synthetic Aβ42. K.P. and S.H.Y. performed molecular docking model experiments. N.N.S., H.J., I.K., and Y.K. wrote the manuscript. All images were created by the authors for this manuscript. Funding This work was supported by Korea Health Industry Development Institute (KHIDI, HI18C0836010018), National Research Foundation (Basic Science Research Program NRF-2018R1A6A1A03023718, Original Technology Research Program for Brain Science NRF-2018M3C7A1021858, and NRF-2017R1A2A2A05069364), and Yonsei University (2018-22-0022).
© 2019 American Chemical Society.
All Science Journal Classification (ASJC) codes
- Cognitive Neuroscience
- Cell Biology