Uncharged thioflavin-T derivatives bind to amyloid-beta protein with high affinity and readily enter the brain.
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.
Klunk
W E
WE
Department of Psychiatry, University of Pittsburgh School of Medicine, PA 15213, USA. Klunkwe@msx.upmc.edu
Wang
Y
Y
Huang
G F
GF
Debnath
M L
ML
Holt
D P
DP
Mathis
C A
CA
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D052160:Benzothiazoles; D001921:Brain / Q000378:metabolism*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D005260:Female; D005456:Fluorescent Dyes; D006651:Histocytochemistry; D006863:Hydrogen-Ion Concentration; D051379:Mice; D011485:Protein Binding; D012995:Solubility; D013050:Spectrometry, Fluorescence; D013844:Thiazoles / Q000378:metabolism*; D014055:Tomography, Emission-Computed
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D005456:Fluorescent Dyes; D013844:Thiazoles; C009462:thioflavin T