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
  • 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.

Products