Identification of a nanomolar affinity a-synuclein fibril imaging probe by ultra-high throughput: In silico screening

John J. Ferrie, Zsofia Lengyel-Zhand, Bieneke Janssen, Marshall G. Lougee, Sam Giannakoulias, Chia Ju Hsieh, Vinayak Vishnu Pagar, Chi Chang Weng, Hong Xu, Thomas J.A. Graham, Virginia M.Y. Lee, Robert H. Mach, E. James Petersson*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

29 Scopus citations


Small molecules that bind with high affinity and specificity to fibrils of the a-synuclein (aS) protein have the potential to serve as positron emission tomography (PET) imaging probes to aid in the diagnosis of Parkinson's disease and related synucleinopathies. To identify such molecules, we employed an ultra-high throughput in silico screening strategy using idealized pseudo-ligands termed exemplars to identify compounds for experimental binding studies. For the top hit from this screen, we used photo-crosslinking to confirm its binding site and studied the structure-activity relationship of its analogs to develop multiple molecules with nanomolar affinity for aS fibrils and moderate specificity for aS over Aß fibrils. Lastly, we demonstrated the potential of the lead analog as an imaging probe by measuring binding to aS-enriched homogenates from mouse brain tissue using a radiolabeled analog of the identified molecule. This study demonstrates the validity of our powerful new approach to the discovery of PET probes for challenging molecular targets.

Original languageEnglish
Pages (from-to)12746-12754
Number of pages9
JournalChemical Science
Issue number47
StatePublished - 21 12 2020
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2020 The Royal Society of Chemistry.


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