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Development of Positron Emission Tomography β-Amyloid Plaque Imaging Agents
Open accessAbstract
For 100 years, β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs) have been recognized as the neuropathological hallmarks of Alzheimer’s disease (AD), and their presence or absence could only be assessed postmortem using stains and dyes that identified these microscopic structures. Approximately 10 years ago, the first successful Aβ plaque–specific positron emission tomography (PET) imaging study was conducted in a living human subject clinically diagnosed with probable AD using the 11C-labeled radiopharmaceutical Pittsburgh Compound B (PiB). Laboratory studies and preclinical evaluations to design PiB began a decade earlier than the first human PiB PET study and involved chemical modifications of different well-known dyes that bound specifically to the extended β-pleated sheets that comprise the fibrils of amyloid proteins such as Aβ plaques, NFTs, β-synuclein deposits, and prions. These preclinical studies were conducted in our laboratories at the University of Pittsburgh, starting with Congo red derivatives, followed by Chrysamine G derivatives, followed by X-series compounds, and finally with neutral derivatives of thioflavin-T. The in vitro and in vivo evaluations of the different derivatives as candidate PET radioligands for imaging Aβ plaques and neurofibrillary tangles in human brain are described in this review, along with the specific evaluation criteria by which the candidate radioligands were judged. Out of these studies came PiB, a PET radioligand that binds selectively and with high affinity to only fibrillar forms of Aβ. PiB has been used in many different human research protocols throughout the world and has demonstrated the usefulness of assessing the Aβ plaque status of subjects many years before the clinical diagnosis of probable AD. Recently, longer-lived 18F-radiolabeled Aβ-selective radiopharmaceuticals have been developed. It is likely that the full clinical impact of these imaging agents will be realized by identifying presymptomatic subjects who would benefit from early drug treatments with future disease-modifying AD therapeutics.
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Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade
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Self-citation[ 11 C]PIB in a nondemented population: Potential antecedent marker of Alzheimer disease
Mintun, M. A., LaRossa, G. N., Sheline, Y. I., Dence, C. S., Lee, S. Y., Mach, R. H., Klunk, W. E., Mathis, C. A., DeKosky, S. T., & Morris, J. C. (2006) · Neurology · doi:10.1212/01.wnl.0000228230.26044.a4 · Cited by 1,036
Self-citationRapid appearance and local toxicity of amyloid-β plaques in a mouse model of Alzheimer’s disease
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Amyloid imaging results from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging
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Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer's disease
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Self-citationLongitudinal assessment of Aβ and cognition in aging and Alzheimer disease
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Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade
Chiti, F., & Dobson, C. M. (2017) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-061516-045115 · Cited by 2,629
Palmqvist, S., Mattsson, N., Hansson, O., & Initiative, F. T. A. D. N. (2016) · Brain · doi:10.1093/brain/aww015 · Cited by 400
Zhang, X., Tian, Y., Li, Z., Tian, X., Sun, H., Liu, H., Moore, A., & Ran, C. (2013) · Journal of the American Chemical Society · doi:10.1021/ja405239v · Cited by 354
Cui, M., Ono, M., Watanabe, H., Kimura, H., Liu, B., & Saji, H. (2014) · Journal of the American Chemical Society · doi:10.1021/ja4052922 · Cited by 282
Huynh, T.-P. V., Davis, A. A., Ulrich, J. D., & Holtzman, D. M. (2017) · Journal of Lipid Research · doi:10.1194/jlr.r075481 · Cited by 210
Metadata
- Authors
- Mathis, C. A., Mason, N. S., Lopresti, B. J., & Klunk, W. E.
- Venue
- Seminars in Nuclear Medicine
- Publisher
- Elsevier BV
- Published
- 2012-11
- Volume
- 42
- Issue
- 6
- Pages
- 423-432
- ISSN
- 0001-2998 (ISSN-L)
- OpenAlex
- W1976922222
- Cited by
- 175
- References
- 20
- FWCI
- 10.00
- Type
- journal article
- Language
- en
- Open access
- green
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