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.
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 (125)I-labeled α-syn radioligand SIL23. [(125)I]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 [(125)I]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.
authors: Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
authors: Devika P
authors: DP
authors: Bagchi
authors: Lihai
authors: L
authors: Yu
authors: Joel S
authors: JS
authors: Perlmutter
authors: Jinbin
authors: J
authors: Xu
authors: Robert H
authors: RH
authors: Mach
authors: Zhude
authors: Z
authors: Tu
authors: Paul T
authors: PT
authors: Kotzbauer
mesh_terms: D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D003952:Diagnostic Imaging / Q000379:methods; D005260:Female; D006801:Humans; D007456:Iodine Isotopes; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010300:Parkinson Disease / Q000175:diagnosis / Q000000981:diagnostic imaging* / Q000378:metabolism; D011869:Radioligand Assay / Q000379:methods; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals; D051844:alpha-Synuclein / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D007456:Iodine Isotopes; D019275:Radiopharmaceuticals; D051844:alpha-Synuclein; D016875:tau Proteins
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