Uncharged thioflavin-T derivatives bind to amyloid-beta protein with high affinity and readily enter the brain
Abstract
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) b…
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Aβ fibrils obtained from the Aβ40 peptide form more homogenous fibrillar structures without any non-fibrillar aggregates.
“These studies were performed with Aβ fibrils obtained from the Aβ40 peptide, which forms more homogenous fibrillar structures without any non-fibrillar aggregates (Figure S21a).83,84”
From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide (2012) · cites this paper as [83]
L1 exhibits a high affinity for Aβ fibrils comparable to other neutral ThT derivatives, suggesting that appending a metal-binding group to the 2-phenylbenzothiazole fragment does not limit its amyloid binding affinity.
“This value suggests that L1 exhibits a high affinity for the Aβ fibrils comparable to other neutral ThT derivatives,83,85 suggesting that appending a metal-binding group to the 2-phenylbenzothiazole fragment does not limit its amyloid binding affinity.”
From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide (2012) · cites this paper as [83]
Performing the same titration of Aβ fibrils with ThT yields a Kd of 1.17±0.14 μM, a value similar to those reported previously.
“By comparison, performing the same titration of Aβ fibrils with ThT yields a Kd of 1.17±0.14 μM (Figure S21b), a value similar to those reported previously.83,85”
From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide (2012) · cites this paper as [83]
Most previous studies have employed the Aβ40 peptide that follows a more direct aggregation pathway to form homogenous, well-defined fibrillar structures.
“However, most of these previous studies have employed the Aβ40 peptide that follows a more direct aggregation pathway to form homogenous, well-defined fibrillar structures.83,84”
From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide (2012) · cites this paper as [83]
Both compounds L1 and L2 contain a 2-phenylbenzothiazole fragment reminiscent of the fluorescent dye ThT used to detect the β-sheet structure of fibrillar Aβ aggregates.
“Both compounds L1 and L2 contain a 2-phenylbenzothiazole fragment reminiscent of the fluorescent dye ThT used to detect the β-sheet structure of fibrillar Aβ aggregates.45,46”
From Small Bifunctional Chelators That Do Not Disaggregate Amyloid β Fibrils Exhibit Reduced Cellular Toxicity (2014) · cites this paper as [45]
Aβ40 fibrils form more homogeneous fibrillar structures without any nonfibrillar aggregates.
“These studies were performed with Aβ40 fibrils, which form more homogeneous fibrillar structures without any nonfibrillar aggregates.45,47”
From Small Bifunctional Chelators That Do Not Disaggregate Amyloid β Fibrils Exhibit Reduced Cellular Toxicity (2014) · cites this paper as [45]
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Cited by 457
- Authors
- Klunk, W. E., Wang, Y., Huang, G.-F., Debnath, M. L., Holt, D. P., & Mathis, C. A.
- Affiliations
- University of Pittsburgh (US)
- Corresponding author
- Klunk, William E.
- Venue
- Life Sciences
- Publisher
- Elsevier BV
- Published
- 2001-08
- Volume
- 69
- Issue
- 13
- Pages
- 1471-1484
- ISSN
- 0024-3205 (ISSN-L)
- OpenAlex
- W2123021161
- Cited by
- 457
- References
- 0
- Citations by year
- 2026: 1 · 2025: 19 · 2024: 13 · 2023: 16 · 2022: 12 · 2021: 19 · 2020: 24 · 2019: 14 · 2018: 19 · 2017: 23 · 2016: 12 · 2015: 13 · 2014: 22 · 2013: 24 · 2012: 21
- FWCI
- 9.37
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Life Sciences (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG 05-133, P50AG005133)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Radiopharmaceutical Chemistry and Applications
- Keywords
- amyloid-beta, Alzheimer's disease, PET imaging agents, neurofibrillary tangles, amyloid plaques, brain penetration, brain clearance, lipophilicity
- MeSH terms
- Alzheimer Disease, Animals, Brain, Chemistry, Physical, Female, Fluorescent Dyes, Histocytochemistry, Hydrogen-Ion Concentration, Protein Binding, Solubility, Spectrometry, Fluorescence, Thiazoles, Tomography, Emission-Computed, Amyloid beta-Peptides, Mice, Benzothiazoles, Chemical Phenomena
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