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

Life Sci. 2001 Aug 17;69(13):1471-84. doi: 10.1016/s0024-3205(01)01232-2.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Benzothiazoles
  • Brain / metabolism*
  • Chemical Phenomena
  • Chemistry, Physical
  • Female
  • Fluorescent Dyes
  • Histocytochemistry
  • Hydrogen-Ion Concentration
  • Mice
  • Protein Binding
  • Solubility
  • Spectrometry, Fluorescence
  • Thiazoles / metabolism*
  • Tomography, Emission-Computed


  • Amyloid beta-Peptides
  • Benzothiazoles
  • Fluorescent Dyes
  • Thiazoles
  • thioflavin T