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

William E. Klunk, Yanming Wang, Guo feng Huang, Manik L. Debnath, Daniel Holt, Chester A. Mathis

Research output: Contribution to journalArticle

Abstract

In vivo assessment of the beta-sheet proteins deposited in amyloid plaques (Aβ 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 Aβ(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-11 C]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 t1/2 = 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.

Original languageEnglish (US)
Pages (from-to)1471-1484
Number of pages14
JournalLife Sciences
Volume69
Issue number13
DOIs
Publication statusPublished - Aug 17 2001
Externally publishedYes

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Keywords

  • Alzheimer's disease
  • Amyloid beta-protein
  • Benzothiazole
  • Carbon-11
  • Neurofibrillary tangles
  • Positron emission tomography
  • Thioflavin-T

ASJC Scopus subject areas

  • Pharmacology

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