Document Detail


Development of positron emission tomography β-amyloid plaque imaging agents.
MedLine Citation:
PMID:  23026364     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 (11)C-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, α-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 (18)F-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.
Authors:
Chester A Mathis; N Scott Mason; Brian J Lopresti; William E Klunk
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Review    
Journal Detail:
Title:  Seminars in nuclear medicine     Volume:  42     ISSN:  1558-4623     ISO Abbreviation:  Semin Nucl Med     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-10-02     Completed Date:  2013-04-04     Revised Date:  2014-04-08    
Medline Journal Info:
Nlm Unique ID:  1264464     Medline TA:  Semin Nucl Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  423-32     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Inc. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Animals
Humans
Plaque, Amyloid / radionuclide imaging*
Positron-Emission Tomography / methods*
Radiopharmaceuticals / diagnostic use*
Grant Support
ID/Acronym/Agency:
K01 MH001976/MH/NIMH NIH HHS; K01 MH001976/MH/NIMH NIH HHS; K02 AG001039/AG/NIA NIH HHS; K02 AG001039/AG/NIA NIH HHS; P01 AG025204/AG/NIA NIH HHS; P01 AG025204/AG/NIA NIH HHS; P50 AG005133/AG/NIA NIH HHS; P50 AG005133/AG/NIA NIH HHS; R01 AG018402/AG/NIA NIH HHS; R01 AG018402/AG/NIA NIH HHS; R01 AG020226/AG/NIA NIH HHS; R01 AG020226/AG/NIA NIH HHS; R01 MH070729/MH/NIMH NIH HHS; R01 MH070729/MH/NIMH NIH HHS; R37 AG025516/AG/NIA NIH HHS; R37 AG025516/AG/NIA NIH HHS
Chemical
Reg. No./Substance:
0/Radiopharmaceuticals
Comments/Corrections

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