Differential Effects of Structural Modifications on the Competition of Chalcones for the PIB Amyloid Imaging Ligand-Binding Site in Alzheimer's Disease Brain and Synthetic Aβ Fibrils

Marina Y. Fosso, Katie McCarty, Elizabeth Head, Sylvie Garneau-Tsodikova, Harry LeVine

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Alzheimer's disease (AD) is a complex brain disorder that still remains ill defined. In order to understand the significance of binding of different clinical in vivo imaging ligands to the polymorphic pathological features of AD brain, the molecular characteristics of the ligand interacting with its specific binding site need to be defined. Herein, we observed that tritiated Pittsburgh Compound B (3H-PIB) can be displaced from synthetic Aβ(1-40) and Aβ(1-42) fibrils and from the PIB binding complex purified from human AD brain (ADPBC) by molecules containing a chalcone structural scaffold. We evaluated how substitution on the chalcone scaffold alters its ability to displace 3H-PIB from the synthetic fibrils and ADPBC. By comparing unsubstituted core chalcone scaffolds along with the effects of bromine and methyl substitution at various positions, we found that attaching a hydroxyl group on the ring adjacent to the carbonyl group (ring I) of the parent member of the chalcone family generally improved the binding affinity of chalcones toward ADPBC and synthetic fibrils F40 and F42. Furthermore, any substitution on ring I at the ortho-position of the carbonyl group greatly decreases the binding affinity of the chalcones, potentially as a result of steric hindrance. Together with the finding that neither our chalcones nor PIB interact with the Congo Red/X-34 binding site, these molecules provide new tools to selectively probe the PIB binding site that is found in human AD brain, but not in brains of AD pathology animal models. Our chalcone derivatives also provide important information on the effects of fibril polymorphism on ligand binding.

Original languageEnglish
Pages (from-to)171-176
Number of pages6
JournalACS Chemical Neuroscience
Issue number2
StatePublished - Feb 17 2016

Bibliographical note

Funding Information:
This work was supported by startup funds from the University of Kentucky (to S.G.-T.), by NIH Grant AI90048 (to S.G.-T.), and by NIH Grant 1R21 NS080576-01A1 (to H.L.), and NIH Center Core Grant P30AG028383 (Alzheimer''s Disease Center).We thank Dr. David S. Watt for initial compounds implicating chalcones as PIB-displacing Aβ ligands. We acknowledge Linda Van Eldik, Ph.D. Sanders-Brown Director, Peter Nelson, M.D., Ph.D., Neuropathology Core Director, and Sonya Anderson, Brain Bank Coordinator for human brain tissue and their contributions on behalf of the ADC. We are forever in debt to the patients whose brain donations made this investigation possible.

Publisher Copyright:
© 2015 American Chemical Society.


  • Displacement assay
  • Pittsburgh compound B
  • neurodegenerative disorder
  • radioactive assay
  • structure'activity relationships

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology


Dive into the research topics of 'Differential Effects of Structural Modifications on the Competition of Chalcones for the PIB Amyloid Imaging Ligand-Binding Site in Alzheimer's Disease Brain and Synthetic Aβ Fibrils'. Together they form a unique fingerprint.

Cite this