Evidence for the Presence of Three Distinct Binding Sites for the Thioflavin T Class of Alzheimer's Disease PET Imaging Agents on β-Amyloid Peptide Fibrils
Open accessAbstract
Imaging the progression of Alzheimer's disease would greatly facilitate the discovery of therapeutics, and a wide range of ligands are currently under development for the detection of beta-amyloid peptide (Abeta)-containing plaques by using positron emission tomography. Here we report an in-depth characterization of the binding of seven previously described ligands to in vitro generated Abeta-(1-40) polymers. All of the compounds were derived from the benzothiazole compound thioflavin T and include 2-[4'-(methylamino)phenyl]benzothiazole and 2-(4'-dimethylamino-)phenyl-imidazo[1,2-a]-pyridine derivatives, 2-[4'-(dimethylamino)phenyl]-6-iodobenzothiazole and 2-[4'-(4''-methylpiperazin-1-yl)phenyl]-6-iodobenzothiazole, and a benzofuran compound (5-bromo-2-(4-dimethylaminophenyl)benzofuran). By using a range of fluorescent and radioligand binding assays, we find that these compounds display a more complex binding pattern than described previously and are consistent with three classes of binding sites on the Abeta fibrils. All of the compounds bound with very high affinity (low nm K(d)) to a low capacity site (BS3) (1 ligand-binding site per approximately 300 Abeta-(1-40) monomers) consistent with the previously recognized binding site for these compounds on the fibrils. However, the compounds also bound with high affinity (K(d) approximately 100 nm) to either one of two additional binding sites on the Abeta-(1-40) polymer. The properties of these sites, BS1 and BS2, suggest they are adjacent or partially overlapping and have a higher capacity than BS3, occurring every approximately 35 or every approximately 4 monomers of Abeta-(1-40)-peptide, respectively. Compounds appear to display selectivity for BS2 based on the presence of a halogen substitution (2-[4'-(dimethylamino)phenyl]-6-iodobenzothiazole, 2-[4'-(4''-methylpiperazin-1-yl)phenyl]-6-iodobenzothiazole, and 5-bromo-2-(4-dimethylaminophenyl)benzofuran) on their aromatic ring system. The presence of additional ligand-binding sites presents potential new targets for ligand development and may allow a more complete modeling of the current positron emission tomography data.
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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 [84]
Materials and Methods (page unavailable) confirms that the authors prepared fibrils from Aβ(1–40) peptide. The results describe two populations of high-molecular-mass species in that preparation; they do not establish that Aβ40 forms more homogeneous fibrils than another peptide or that non-fibrillar aggregates are absent. (LLM, conf=0.86)
Experimental — accuracy not yet measuredTitrations with various amounts of compounds reveal competitive binding curves that yield Ki values 180±25 nM and 36±6 nM for L1 and L2, respectively.
“Titrations with various amounts of compounds reveal competitive binding curves that yield Ki values 180±25 nM and 36±6 nM for L1 and L2, respectively (Figure 6b).84,85”
From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide (2012) · cites this paper as [84]
The Materials and Methods section describes competition assays using varying competitor concentrations to derive Ki values. Table I reports Ki values for the compounds studied, but it does not identify L1 or L2 or report 180±25 nM and 36±6 nM for them. Page numbers were unavailable in our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measuredMost 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 [84]
The introductory passage reports that multiple laboratories studied ligands on Aβ(1–40) fibrils, and Materials and Methods describes this paper’s use of Aβ(1–40). The paper does not say that most previous studies used Aβ40, or that it follows a more direct aggregation pathway and forms homogeneous, well-defined fibrils. Page numbers are unavailable in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe Ki value for L1 is smaller than the Kd value, most likely because ThT binds with different affinities to more than one site on Aβ fibrils.
“It should be noted that the Ki value for L1 is smaller than the Kd value, which is most likely due to the fact that ThT binds with different affinities to more than one site to the Aβ fibrils.47”
From Small Bifunctional Chelators That Do Not Disaggregate Amyloid β Fibrils Exhibit Reduced Cellular Toxicity (2014) · cites this paper as [47]
The Discussion (page unavailable) reports multiple ligand-binding sites on Aβ fibrils and differences between fluorescence- and radioligand-derived binding values, supporting the proposed explanation in general. However, the paper does not report a Ki or Kd for L1 or establish that its particular Ki–Kd difference is caused by ThT binding at sites with different affinities. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAβ40 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 [47]
The Materials and Methods section (page not provided) confirms that the authors prepared Aβ40 fibrils. The section on binding constants (page not provided) reports uniformly distributed ligand-binding sites, but also identifies two populations of high-molecular-mass species. It does not establish that the fibrillar structures are more homogeneous or free of nonfibrillar aggregates. (LLM, conf=0.82)
Experimental — accuracy not yet measured
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- Authors
- Lockhart, A., Ye, L., Judd, D. B., Merritt, A. T., Lowe, P. N., Morgenstern, J. L., Hong, G., Gee, A. D., & Brown, J.
- Affiliations
- GlaxoSmithKline (United Kingdom) (GB)
- Corresponding author
- Lockhart, Andrew
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2005-03
- Volume
- 280
- Issue
- 9
- Pages
- 7677-7684
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1972816877
- Cited by
- 213
- References
- 30
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 5 · 2023: 11 · 2022: 6 · 2021: 6 · 2020: 8 · 2019: 3 · 2018: 9 · 2017: 11 · 2016: 13 · 2015: 10 · 2014: 10 · 2013: 10 · 2012: 13
- FWCI
- 6.80
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Keywords
- Alzheimer's disease, thioflavin T, amyloid-beta fibrils, Aβ(1-40), PET imaging agents, benzothiazole ligands, binding sites, ligand binding affinity, halogen substitution, amyloid plaques, radioligand binding, imidazo[1,2-a]pyridine derivatives
- MeSH terms
- Alzheimer Disease, Binding Sites, Binding, Competitive, Centrifugation, Density Gradient, Dose-Response Relationship, Drug, Humans, Kinetics, Ligands, Models, Biological, Models, Chemical, Peptide Fragments, Peptides, Protein Binding, Spectrometry, Fluorescence, Thiazoles, Amyloid beta-Peptides, Fluorescence Resonance Energy Transfer, Positron-Emission Tomography, Benzothiazoles
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