title: 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.
abstract: 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 ((3)H-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 (3)H-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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky , 789 South Limestone Street, Lexington, Kentucky 40536-0596, United States.
authors.forename: Marina Y
authors.initials: MY
authors.lastname: Fosso
authors.forename: Katie
authors.initials: K
authors.lastname: McCarty
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Head
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky , 789 South Limestone Street, Lexington, Kentucky 40536-0596, United States.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Garneau-Tsodikova
authors.forename: Harry
authors.initials: H
authors.lastname: LeVine
mesh_terms: D000368:Aged; D000475:Alkenes / Q000493:pharmacokinetics; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D058227:Amyloidogenic Proteins / Q000378:metabolism*; D000814:Aniline Compounds / Q000493:pharmacokinetics*; D001565:Benzoates / Q000493:pharmacokinetics; D052160:Benzothiazoles; D001665:Binding Sites / Q000187:drug effects; D001921:Brain / Q000000981:diagnostic imaging*; D047188:Chalcones / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D006801:Humans; D008024:Ligands; D010446:Peptide Fragments / Q000378:metabolism; D049268:Positron-Emission Tomography; D013844:Thiazoles / Q000378:metabolism / Q000493:pharmacokinetics*; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: C413183:1,4-bis(3-carboxy-4-hydroxyphenylethenyl)-benzene; C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D000475:Alkenes; D016229:Amyloid beta-Peptides; D058227:Amyloidogenic Proteins; D000814:Aniline Compounds; D001565:Benzoates; D052160:Benzothiazoles; D047188:Chalcones; D005456:Fluorescent Dyes; D008024:Ligands; D010446:Peptide Fragments; D013844:Thiazoles; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D014316:Tritium; C009462:thioflavin T
keywords: Displacement assay; Pittsburgh compound B; neurodegenerative disorder; radioactive assay; structure−activity relationships