We. Klunk et al., Uncharged thioflavin-T derivatives bind to amyloid-beta protein with high affinity and readily enter the brain, LIFE SCI, 69(13), 2001, pp. 1471-1484
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 thiofla
vin-T (ThT) were synthesized and evaluated. These compounds lack the positi
vely charged quaternary heterocyclic nitrogen of ThT and are therefore unch
arged at physiological pH. They are 600-fold more lipophilic than ThT. Thes
e 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 bo
th plaques and neurofibrillary tangles in post-mortem AD brain, showing, so
me 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 stu
died in Swiss-Webster mice. This compound entered the brain at levels compa
rable 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-s
pecifically bound radioactivity in normal rodent brain tissue (brain cleara
nce t(1/2) = 20 min), The combination of relatively high affinity for amylo
id, specificity for staining plaques and neurofibrillary tangles in post-mo
rtem 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 (PE
T) beta-sheet imaging agent. (C) 2001 Elsevier Science Inc. All rights rese
rved.