Sep 14, 2001

Uncharged thioflavin-T derivatives bind to amyloid-beta protein with high affinity and readily enter the brain

Life Sciences
William E KlunkChester A Mathis

Abstract

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 relativel...Continue Reading

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Mentioned in this Paper

Familial Alzheimer Disease (FAD)
Derivatives
APP protein, human
Positron-Emission Tomography
Neurofibrillary Degeneration (Morphologic Abnormality)
Brain
Plaque, Amyloid
Tomography, Emission-Computed
Alzheimer's Disease
Dental Plaque

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