Author: Klunk, W.E.; Wang, Y.; Huang, G.F.; Debnath, M.L.; Holt, D.P.; Mathis, C.A.
Description: In vivo assessment of the beta-sheet proteins deposited in amyloid plaques (A beta peptide) or neurofibrillary tangles (tau protein) presents a target for the development of biological markers for Alzheimer’s disease (AD). In an effort to develop in vivo beta-sheet imaging probes, derivatives of thioflavin-T (ThT) were synthesized and evaluated. These compounds lack the positively charged quaternary heterocyclic nitrogen of ThT and are therefore uncharged at physiological pH. They are 600-fold more lipophilic than ThT. These ThT derivatives bind to A beta(1-40) fibrils with higher affinity (Ki = 20.2 nM) than ThT (Ki = 890 nM). The uncharged ThT derivatives stained both plaques and neurofibrillary tangles in post-mortem AD brain, showing some preference for plaque staining. A carbon-11 labeled compound, [N-methyl-11C]6-Me-BTA-1, was prepared, and its brain entry and clearance were studied in Swiss-Webster mice. This compound entered the brain at levels comparable to commonly used neuroreceptor imaging agents (0.223 %ID-kg/g or 7.61 %ID/g at 2 min post-injection) and showed good clearance of free and non-specifically bound radioactivity in normal rodent brain tissue (brain clearance t(1,2) = 20 min). The combination of relatively high affinity for amyloid, specificity for staining plaques and neurofibrillary tangles in post-mortem AD brain, and good brain entry and clearance makes [N-methyl-11C]6-Me-BTA-1 a promising candidate as an in vivo positron emission tomography (PET) beta-sheet imaging agent.
Subject Headings: Alzheimer Disease/metabolism; Amyloid beta-Peptides/metabolism; Animals; Brain/metabolism; Chemical Phenomena; Chemistry, Physical; Female; Fluorescent Dyes; Histocytochemistry; Hydrogen-Ion Concentration; Mice; Protein Binding; Solubility; Spectrometry, Fluorescence; Thiazoles/metabolism; Tomography, Emission-Computed
Keywords: Uncharged thioflavin-T derivatives bind to amyloid-beta protein with high affinity and readily enter the brain
Publication year: 2001
Journal or book title: Life Sciences
Find the full text : https://www.sciencedirect.com/science/article/pii/S0024320501012322
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Type: Journal Article
Serial number: 2598