Development of an α-synuclein positron emission tomography tracer for imaging synucleinopathies

Cell. 2023 Aug 3;186(16):3350-3367.e19. doi: 10.1016/j.cell.2023.06.004. Epub 2023 Jul 7.


Synucleinopathies are characterized by the accumulation of α-synuclein (α-Syn) aggregates in the brain. Positron emission tomography (PET) imaging of synucleinopathies requires radiopharmaceuticals that selectively bind α-Syn deposits. We report the identification of a brain permeable and rapid washout PET tracer [18F]-F0502B, which shows high binding affinity for α-Syn, but not for Aβ or Tau fibrils, and preferential binding to α-Syn aggregates in the brain sections. Employing several cycles of counter screenings with in vitro fibrils, intraneuronal aggregates, and neurodegenerative disease brain sections from several mice models and human subjects, [18F]-F0502B images α-Syn deposits in the brains of mouse and non-human primate PD models. We further determined the atomic structure of the α-Syn fibril-F0502B complex by cryo-EM and revealed parallel diagonal stacking of F0502B on the fibril surface through an intense noncovalent bonding network via inter-ligand interactions. Therefore, [18F]-F0502B is a promising lead compound for imaging aggregated α-Syn in synucleinopathies.

Keywords: Lewy body; PET tracer; cryoelectron microscopy; protein aggregation; synucleinopathies.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Brain / diagnostic imaging
  • Brain / metabolism
  • Humans
  • Neurodegenerative Diseases* / metabolism
  • Positron-Emission Tomography
  • Synucleinopathies* / diagnostic imaging
  • Synucleinopathies* / metabolism
  • alpha-Synuclein / metabolism


  • alpha-Synuclein