The binding of 2-(4'-methylaminophenyl)benzothiazole to postmortem brain homogenates is dominated by the amyloid component.
2-(4'-methylaminophenyl)benzothiazole (BTA-1) is an uncharged derivative of thioflavin-T that has high affinity for Abeta fibrils and shows very good brain entry and clearance. In this study, we asked whether BTA-1, at concentrations typical of those achieved during positron emission tomography (PET) studies, could specifically bind to amyloid deposits in the complex milieu of human brain or whether amyloid binding was overshadowed by nonspecific binding, found even in brains that did not contain amyloid deposits. We quantitatively assessed [3H]BTA-1 binding to crude homogenates of postmortem brain obtained from nine Alzheimer's disease (AD) subjects, eight controls, and six subjects with non-AD dementia. BTA-1 binding was >10-fold higher in AD brain, and the majority (94%) of the binding was specific (displaceable). High-affinity [3H]BTA-1 was observed only in AD brain gray matter and was not present in control brain gray matter, AD brain white matter, or cerebellum. The K(d) of [3H]BTA-1 for binding to AD brain (5.8 +/- 0.90 nm) was very similar to the K(d) for binding to synthetic Abeta fibrils. In addition, the K(i) of various BTA analogs for inhibition of [3H]BTA-1 binding to AD brain homogenates was very similar to their K(i) for inhibition of [3H]BTA-1 binding to synthetic Abeta fibrils. Nanomolar concentrations of [3H]BTA-1 did not appear to bind to neurofibrillary tangles. Finally, BTA-1 did not appear to bind significantly to common neuroreceptors or transporter sites. These data suggest that the binding of BTA-1 to AD brain is dominated by a specific interaction with Abeta amyloid deposits.
Klunk
William E
WE
Laboratory of Molecular Neuropharmacology, Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213, USA. klunkwe@msx.upmc.edu
Wang
Yanming
Y
Huang
Guo-feng
GF
Debnath
Manik L
ML
Holt
Daniel P
DP
Shao
Li
L
Hamilton
Ronald L
RL
Ikonomovic
Milos D
MD
DeKosky
Steven T
ST
Mathis
Chester A
CA
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D000814:Aniline Compounds / Q000737:chemistry*; D052160:Benzothiazoles; D001667:Binding, Competitive / Q000502:physiology; D001923:Brain Chemistry; D002531:Cerebellum / Q000737:chemistry / Q000473:pathology; D003704:Dementia / Q000378:metabolism / Q000473:pathology; D018728:Entorhinal Cortex / Q000737:chemistry / Q000473:pathology; D005456:Fluorescent Dyes / Q000737:chemistry; D005625:Frontal Lobe / Q000737:chemistry / Q000473:pathology; D006801:Humans; D008024:Ligands; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000737:chemistry / Q000378:metabolism; D012016:Reference Values; D013379:Substrate Specificity; D013844:Thiazoles / Q000737:chemistry*; D014316:Tritium
C473078:2-(4'-methylaminophenyl)benzothiazole; D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D052160:Benzothiazoles; D005456:Fluorescent Dyes; D008024:Ligands; D013844:Thiazoles; D014316:Tritium