The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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 Aβ42Peptide (2012) · cites this paper as [84]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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 Aβ42Peptide (2012) · cites this paper as [84]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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 Aβ42Peptide (2012) · cites this paper as [84]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Neuropathological stageing of Alzheimer-related changes.
Braak, H., & Braak, E. (1991) · Acta Neuropathologica · doi:10.1007/bf00308809 · Cited by 16,123
Yung-Chi, C., & Prusoff, W. H. (1973) · Biochemical Pharmacology · doi:10.1016/0006-2952(73)90196-2 · Cited by 12,922
Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound‐B
Klunk, W. E., Engler, H., Nordberg, A., Wang, Y., Blomqvist, G., Holt, D. P., Bergström, M., Savitcheva, I., Huang, G., Estrada, S., et al. (2004) · Annals of Neurology · doi:10.1002/ana.20009 · Cited by 4,496
LeVine, H. (1993) · Protein Science · doi:10.1002/pro.5560020312 · Cited by 2,284
Correlation Between Elevated Levels of Amyloid β-Peptide in the Brain and Cognitive Decline
Näslund, J. (2000) · JAMA · doi:10.1001/jama.283.12.1571 · Cited by 1,268
Fluorometric determination of amyloid fibrils in vitro using the fluorescent dye, thioflavine T
Naiki, H., Higuchi, K., Hosokawa, M., & Takeda, T. (1989) · Analytical Biochemistry · doi:10.1016/0003-2697(89)90046-8 · Cited by 1,244
Synthesis and Evaluation of 11C-Labeled 6-Substituted 2-Arylbenzothiazoles as Amyloid Imaging Agents
Mathis, C. A., Wang, Y., Holt, D. P., Huang, G.-F., Debnath, M. L., & Klunk, W. E. (2003) · Journal of Medicinal Chemistry · doi:10.1021/jm030026b · Cited by 976
Alzheimer’s amyloid fibrils: structure and assembly
Serpell, L. C. (2000) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/s0925-4439(00)00029-6 · Cited by 973
Alzheimer's Disease: Molecular Understanding Predicts Amyloid-Based Therapeutics
Selkoe, D. J., & Schenk, D. (2003) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.43.100901.140248 · Cited by 829
PET imaging of amyloid in Alzheimer's disease
Nordberg, A. K. (2004) · The Lancet Neurology · doi:10.1016/s1474-4422(04)00853-1 · Cited by 462
Klunk, W. E., Wang, Y., Huang, G.-F., Debnath, M. L., Holt, D. P., & Mathis, C. A. (2001) · Life Sciences · doi:10.1016/s0024-3205(01)01232-2 · Cited by 457
Agdeppa, E. D., Kepe, V., Liu, J., Flores-Torres, S., Satyamurthy, N., Petrič, A., Cole, G. M., Small, G. W., Huang, S., & Barrio, J. R. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-24-j0004.2001 · Cited by 421
Klunk, W. E., Bacskai, B. J., Mathis, C. A., Kajdasz, S. T., McLellan, M. E., Frosch, M. P., Debnath, M. L., Holt, D. P., Wang, Y., & Hyman, B. T. (2002) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/61.9.797 · Cited by 412
Mathis, C. A., Bacskai, B. J., Kajdasz, S. T., McLellan, M. E., Frosch, M. P., Hyman, B. T., Holt, D. P., Wang, Y., Huang, G.-F., Debnath, M. L., et al. (2002) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/s0960-894x(01)00734-x · Cited by 404
Styren, S. D., Hamilton, R. L., Styren, G. C., & Klunk, W. E. (2000) · Journal of Histochemistry & Cytochemistry · doi:10.1177/002215540004800906 · Cited by 279
The cause of neuronal degeneration in Alzheimer’s disease
Vickers, J. (2000) · Progress in Neurobiology · doi:10.1016/s0301-0082(99)00023-4 · Cited by 254
Homogeneous fluorescence readouts for miniaturized high-throughput screening: theory and practice
Pope, A. (1999) · Drug Discovery Today · doi:10.1016/s1359-6446(99)01340-9 · Cited by 199
IMPY: an improved thioflavin-T derivative for in vivo labeling of β-amyloid plaques
Kung, M., Hou, C., Zhuang, Z., Zhang, B., Skovronsky, D., Trojanowski, J. Q., Lee, V. M. ‐., & Kung, H. F. (2002) · Brain Research · doi:10.1016/s0006-8993(02)03436-4 · Cited by 196
Radioiodinated Styrylbenzenes and Thioflavins as Probes for Amyloid Aggregates
Zhuang, Z.-P., KUNG, M. ‐., Hou, C., Skovronsky, D., Gur, T., Plößl, K., Trojanowski, J. Q., Lee, V. M.-Y., & Kung, H. F. (2001) · Journal of Medicinal Chemistry · doi:10.1021/jm010045q · Cited by 196
Novel Stilbenes as Probes for Amyloid Plaques
Kung, H. F., Lee, C., Zhuang, Z., Kung, M., Hou, C., & Plöessl, K. (2001) · Journal of the American Chemical Society · doi:10.1021/ja0167147 · Cited by 179
Agdeppa, E. D., Kepe, V., Petri, A., Satyamurthy, N., Liu, J., Huang, S. C., Small, G. W., Cole, G. M., & Barrio, J. R. (2003) · Neuroscience · doi:10.1016/s0306-4522(02)00907-7 · Cited by 172
Ward, R. V., JENNINGS, K. H., Jepras, R., Neville, W. A., OWEN, D. E., HAWKINS, J., Christie, G., Davis, J. B., George, A. R., Karran, E. H., et al. (2000) · Biochemical Journal · doi:10.1042/bj3480137 · Cited by 153
Benzofuran derivatives as Aβ-aggregate-specific imaging agents for Alzheimer’s disease
Ono, M., Kung, M., Hou, C., & Kung, H. F. (2002) · Nuclear Medicine and Biology · doi:10.1016/s0969-8051(02)00326-8 · Cited by 131
Hong, G., Lockhart, A., Davis, B., Rahmoune, H., Baker, S. F., Liang, Y. S., Thompson, P., Shou, Y., O’Shaughnessy, K. M., Ronco, P. M., et al. (2003) · The FASEB Journal · doi:10.1096/fj.03-0181fje · Cited by 109
Self-citationON THE HISTOCHEMISTRY OF AZO GROUP-FREE THIAZOLE DYES
KELIÉNYI, G. (1967) · Journal of Histochemistry & Cytochemistry · doi:10.1177/15.3.172 · Cited by 86
Clinical Validity of Aß-Protein Deposition Staging in Brain Aging and Alzheimer Disease
Gold, G., Kövari, E., Corte, G., Herrmann, F. R., Canuto, A., Bussière, T., Hof, P. R., Bouras, C., & Giannakopoulos, P. (2001) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/60.10.946 · Cited by 67
The Neuropathological Spectrum of Neurodegenerative Tauopathies
Tolnay, M., & Probst, A. (2003) · IUBMB Life · doi:10.1080/1521654032000114348 · Cited by 59
In vivo labeling of amyloid with BF-108
Suemoto, T., Okamura, N., Shiomitsu, T., Suzuki, M., Shimadzu, H., Akatsu, H., Yamamoto, T., Kudo, Y., & Sawada, T. (2003) · Neuroscience Research · doi:10.1016/j.neures.2003.09.005 · Cited by 58
In Vivo Brain Imaging of Tangle Burden in Humans
Small, G. W., Agdeppa, E. D., Kepe, V., Satyamurthy, N., Huang, S., & Barrio, J. R. (2002) · Journal of Molecular Neuroscience · doi:10.1385/jmn:19:3:321 · Cited by 52
Iodinated tracers for imaging amyloid plaques in the brain
Kung, H. F. (2003) · Molecular Imaging and Biology · doi:10.1016/j.mibio.2003.09.003 · Cited by 39
Research works printed but not linked: 3
- Small, 2002, J. Mol. Neurosci., 19, 323
- Nilsson, 2004, Methods (Orlando), 34, 151
- Vassar, 1959, Arch. Pathol., 68, 487
Cited by
Sorted by citations
Alzheimer's Disease and the Amyloid-β Peptide
Murphy, M. P., & LeVine, H. (2010) · Journal of Alzheimer's Disease · doi:10.3233/jad-2010-1221 · Cited by 1,750
Groenning, M. (2009) · Journal of Chemical Biology · doi:10.1007/s12154-009-0027-5 · Cited by 655
Two-year follow-up of amyloid deposition in patients with Alzheimer's disease
Engler, H., Forsberg, A., Almkvist, O., Blomquist, G., Larsson, E., Savitcheva, I., Wall, A. E., Ringheim, A., Långström, B., & Nordberg, A. K. (2006) · Brain · doi:10.1093/brain/awl178 · Cited by 614
Reinke, A. A., & Gestwicki, J. E. (2007) · Chemical Biology & Drug Design · doi:10.1111/j.1747-0285.2007.00557.x · Cited by 335
PIB is a non-specific imaging marker of amyloid-beta (A ) peptide-related cerebral amyloidosis
Lockhart, A., Lamb, J. R., Osredkar, T., Sue, L. I., Joyce, J. N., Ye, L., Libri, V., Leppert, D., & Beach, T. G. (2007) · Brain · doi:10.1093/brain/awm191 · Cited by 302
Self-citation
Metadata
- 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
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
