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 (AP 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 (K-i = 20.2 nM) than ThT (K-i = 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-C-11](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-C-11]6-Me-BTA-1 a promising candidate as an in vivo positron emission tomography (PET) beta-sheet imaging agent. (C) 2001 Elsevier Science Inc. All rights reserved.