2. Academic Validation
  3. Development of [18F]ACI-19626 as a first-in-class brain PET tracer for imaging TDP-43 pathology

Development of [18F]ACI-19626 as a first-in-class brain PET tracer for imaging TDP-43 pathology

  • Nat Commun. 2025 Oct 24;16(1):9358. doi: 10.1038/s41467-025-64540-6.
Efthymia Vokali 1,  Elodie Chevalier 1,  Nicolas Dreyfus 1,  Dorian Charmey 1,  Tania Melly 1,  Jacqueline Kocher 1,  Monisha Ratnam 1,  Andreia M Serra 1,  Thomas Jaquier 1,  Christophe Delgado 1,  Myriam Ravache 1,  Carlo Scialò 2,  Sara Cappelli 3,  Heiko Kroth 1,  Francesca Capotosti 1,  Ruth Luthi-Carter 1,  Tariq Afroz 1,  Madiha Derouazi 1,  Cristian C Constantinescu 4,  Harro Seelaar 5,  Emanuele Buratti 3,  Peter T Nelson 6,  Magdalini Polymenidou 2,  Andrea Pfeifer 1,  Marie Kosco-Vilbois 1,  Tamara Seredenina 7
Affiliations

Affiliations

  • 1 AC Immune SA, EPFL Innovation Park, Building B, Lausanne, Switzerland.
  • 2 Department of Quantitative Biomedicine, University of Zurich, Zurich, Switzerland.
  • 3 Molecular Pathology, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.
  • 4 Perceptive Inc., New Haven, CT, USA.
  • 5 Department of Neurology, Erasmus University Medical Centre, Rotterdam, The Netherlands.
  • 6 Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
  • 7 AC Immune SA, EPFL Innovation Park, Building B, Lausanne, Switzerland. [email protected].
PMID: 41136425 DOI: 10.1038/s41467-025-64540-6
Abstract

Aggregated TDP-43 is a hallmark of frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and limbic-predominant age-related TDP-43 encephalopathy (LATE), and a common co-pathology in Other neurodegenerative diseases. Currently, no specific biomarkers exist to assess TDP-43 pathology in vivo. We developed two small-molecule radiopharmaceuticals, [18F]ACI-19278 and [18F]ACI-19626, for visualizing TDP-43 inclusions by positron emission tomography (PET). Both ligands bind with high affinity to aggregated, but not soluble, TDP-43 in patient brain samples from diverse TDP-43 proteinopathies, including frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), ALS, and LATE, and in cell models. Both compounds display excellent selectivity for TDP-43 over Aβ, Tau, and α-synuclein aggregates. In non-human primates, [18F]ACI-19278 and [18F]ACI-19626 show a pharmacokinetic profile suitable for brain PET imaging (rapid brain uptake; fast and complete washout). ACI-19278 and ACI-19626 are promising first-in-class TDP-43 PET tracers with the potential to revolutionize the diagnosis and treatment of neurodegenerative proteinopathies, enabling a precision medicine approach.

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