TITLE

Binding of the Radioligand SIL23 to α-Synuclein Fibrils in Parkinson Disease Brain Tissue Establishes Feasibility and Screening Approaches for Developing a Parkinson Disease Imaging Agent

AUTHOR(S)
Bagchi, Devika P.; Yu, Lihai; Perlmutter, Joel S.; Xu, Jinbin; Mach, Robert H.; Tu, Zhude; Kotzbauer, Paul T.
PUB. DATE
February 2013
SOURCE
PLoS ONE;Feb2013, Vol. 8 Issue 2, p1
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Accumulation of α-synuclein (α-syn) fibrils in Lewy bodies and Lewy neurites is the pathological hallmark of Parkinson disease (PD). Ligands that bind α-syn fibrils could be utilized as imaging agents to improve the diagnosis of PD and to monitor disease progression. However, ligands for α-syn fibrils in PD brain tissue have not been previously identified and the feasibility of quantifying α-syn fibrils in brain tissue is unknown. We report the identification of the 125I-labeled α-syn radioligand SIL23. [125I]SIL23 binds α-syn fibrils in postmortem brain tissue from PD patients as well as an α-syn transgenic mouse model for PD. The density of SIL23 binding sites correlates with the level of fibrillar α-syn in PD brain tissue, and [125I]SIL23 binding site densities in brain tissue are sufficiently high to enable in vivo imaging with high affinity ligands. These results identify a SIL23 binding site on α-syn fibrils that is a feasible target for development of an α-syn imaging agent. The affinity of SIL23 for α-syn and its selectivity for α-syn versus Aβ and tau fibrils is not optimal for imaging fibrillar α-syn in vivo, but we show that SIL23 competitive binding assays can be used to screen additional ligands for suitable affinity and selectivity, which will accelerate the development of an α-syn imaging agent for PD.
ACCESSION #
87623575

 

Related Articles

  • A Personalized BEST: Characterization of Latent Clinical Classes of Nonischemic Heart Failure That Predict Outcomes and Response to Bucindolol. Kao, David P.; Wagner, Brandie D.; Robertson, Alastair D.; Bristow, Michael R.; Lowes, Brian D. // PLoS ONE;Nov2012, Vol. 7 Issue 11, Special section p1 

    Background: Heart failure patients with reduced ejection fraction (HFREF) are heterogenous, and our ability to identify patients likely to respond to therapy is limited. We present a method of identifying disease subtypes using high-dimensional clinical phenotyping and latent class analysis that...

  • Localization and characterization of renal calcitonin receptors by in vitro autoradiography. Sexton, Patrick M.; Adam, William R.; Moseley, Jane M.; Martin, T. John; Mendelsohn, Frederick A. O. // Kidney International;Dec1987, Vol. 32 Issue 6, p862 

    Calcitonin receptor binding sites were identified in renal cortex and medulla using the radioligand 125I-salmon calcitonin. Microscopic localization of these receptors revealed binding over medullary and cortical thick ascending limb of the loop of Henle and in distal convoluted tubule. A number...

  • Fragment-based lead generation: identification of seed fragments by a highly efficient fragment screening technology. Neumann, Lars; Ritscher, Allegra; Müller, Gerhard; Hafenbradl, Doris // Journal of Computer-Aided Molecular Design;Aug2009, Vol. 23 Issue 8, p501 

    For the detection of the precise and unambiguous binding of fragments to a specific binding site on the target protein, we have developed a novel reporter displacement binding assay technology. The application of this technology for the fragment screening as well as the fragment evolution...

  • α-Synuclein Protects Against Manganese Neurotoxic Insult During the Early Stages of Exposure in a Dopaminergic Cell Model of Parkinson’s Disease. Harischandra, Dilshan S.; Jin, Huajun; Anantharam, Vellareddy; Kanthasamy, Arthi; Kanthasamy, Anumantha G. // Toxicological Sciences;Feb2015, Vol. 143 Issue 2, p454 

    The pathological role of α-synuclein (α-Syn) aggregation in neurodegeneration is well recognized, but the physiological function of normal α-Syn remains unknown. As α-Syn protein contains multiple divalent metal binding sites, herein we conducted a comprehensive characterization of...

  • Radiosynthesis and in Vivo Evaluation of Two PET Radioligands for Imaging α-Synuclein. Xiang Zhang; Hongjun Jin; Padakanti, Prashanth K.; Junfeng Li; Hao Yang; Jinda Fan; Mach, Robert H.; Kotzbauer, Paul; Zhude Tu // Applied Sciences (2076-3417);Mar2014, Vol. 4 Issue 1, p66 

    Two α-synuclein ligands, 3-methoxy-7-nitro-10H-phenothiazine (2a, Ki = 32.1 ± 1.3 nM) and 3-(2-fluoroethoxy)-7-nitro-10H-phenothiazine (2b, Ki = 49.0 ± 4.9 nM), were radiolabeled as potential PET imaging agents by respectively introducing 11C and 18F. The syntheses of [11C]2a and...

  • T1rho (T) MR imaging in Alzheimer' disease and Parkinson's disease with and without dementia. Haris, Mohammad; Singh, Anup; Cai, Kejia; Davatzikos, Christos; Trojanowski, John; Melhem, Elias; Clark, Christopher; Borthakur, Arijitt // Journal of Neurology;Mar2011, Vol. 258 Issue 3, p380 

    In the current study, we aim to measure T1rho ( T) in the hippocampus in the brain of control, Alzheimer's disease (AD), Parkinson's disease (PD), and PD patients with dementia (PDD), and to determine efficacy of T in differentiating these cohorts. With informed consent, 53 AD patients, 62 PD...

  • Effects of ATPM-ET, a novel κ agonist with partial μ activity, on physical dependence and behavior sensitization in mice. Sun, Jian-feng; Wang, Yu-hua; Li, Fu-ying; Lu, Gang; Tao, Yi-min; Cheng, Yun; Chen, Jie; Xu, Xue-jun; Chi, Zhi-qiang; Neumeyer, John L; Zhang, Ao; Liu, Jing-gen // Acta Pharmacologica Sinica;Dec2010, Vol. 31 Issue 12, p1547 

    Aim:To investigate the effects of ATPM-ET [(−)-3-N-Ethylaminothiazolo [5,4-b]-N-cyclopropylmethylmorphinan hydrochloride] on physical dependence and behavioral sensitization to morphine in mice.Methods:The pharmacological profile of ATPM-ET was characterized using competitive binding and...

  • Rethinking screening. Kodadek, Thomas // Nature Chemical Biology;Mar2010, Vol. 6 Issue 3, p162 

    In this article, the author discusses the development of pharmacological tools in determining the selectivity of a newly discovered bioactive compounds. He stresses the potential significance of screening approaches such as simple chemistry, binding screens and covalent inhibitors in maximizing...

  • Differential effects of short- and long-term zolpidem treatment on recombinant α1β2γ2s subtype of GABAA receptors in vitro. Vlainić, Josipa; Jembrek, Maja Jazvinšćak; Vlainić, Toni; Štrac, Dubravka Švob; Peričić, Danka // Acta Pharmacologica Sinica;Dec2012, Vol. 33 Issue 12, p1469 

    Aim:Zolpidem is a non-benzodiazepine agonist at benzodiazepine binding site in GABAA receptors, which is increasingly prescribed. Recent studies suggest that prolonged zolpidem treatment induces tolerance. The aim of this study was to explore the adaptive changes in GABAA receptors following...

Share

Read the Article

Courtesy of THE LIBRARY OF VIRGINIA

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics