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

被引:102
作者
Bagchi, Devika P. [1 ,2 ,3 ]
Yu, Lihai [3 ,4 ]
Perlmutter, Joel S. [1 ,3 ,4 ,5 ,6 ,7 ,8 ]
Xu, Jinbin [3 ,4 ]
Mach, Robert H. [3 ,4 ]
Tu, Zhude [3 ,4 ]
Kotzbauer, Paul T. [1 ,2 ,3 ]
机构
[1] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA
[2] Washington Univ, Sch Med, Dept Dev Biol, St Louis, MO USA
[3] Washington Univ, Sch Med, Hope Ctr Neurol Disorders, St Louis, MO USA
[4] Washington Univ, Sch Med, Dept Radiol, St Louis, MO 63110 USA
[5] Washington Univ, Sch Med, Dept Anat & Neurobiol, St Louis, MO 63110 USA
[6] Program Occupat Therapy, St Louis, MO USA
[7] Washington Univ, Sch Med, St Louis, MO 63110 USA
[8] Washington Univ, Sch Med, Program Phys Therapy, St Louis, MO 63110 USA
关键词
MULTIPLE SYSTEM ATROPHY; PITTSBURGH COMPOUND-B; ALZHEIMERS-DISEASE; LEWY BODIES; IN-VITRO; CLINICAL-DIAGNOSIS; DEMENTIA; TAU; NEURODEGENERATION; PATHOLOGY;
D O I
10.1371/journal.pone.0055031
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Accumulation of alpha-synuclein (alpha-syn) fibrils in Lewy bodies and Lewy neurites is the pathological hallmark of Parkinson disease (PD). Ligands that bind alpha-syn fibrils could be utilized as imaging agents to improve the diagnosis of PD and to monitor disease progression. However, ligands for alpha-syn fibrils in PD brain tissue have not been previously identified and the feasibility of quantifying alpha-syn fibrils in brain tissue is unknown. We report the identification of the I-125-labeled alpha-syn radioligand SIL23. [I-125]SIL23 binds alpha-syn fibrils in postmortem brain tissue from PD patients as well as an alpha-syn transgenic mouse model for PD. The density of SIL23 binding sites correlates with the level of fibrillar alpha-syn in PD brain tissue, and [I-125] 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 alpha-syn fibrils that is a feasible target for development of an alpha-syn imaging agent. The affinity of SIL23 for alpha-syn and its selectivity for alpha-syn versus Ab and tau fibrils is not optimal for imaging fibrillar alpha-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 alpha-syn imaging agent for PD.
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页数:13
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