Development of [18F]ACI-19626 as a first-in-class brain PET tracer for imaging TDP-43 pathology
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, [<sup>18</sup>F]ACI-19278 and [<sup>18</sup>F]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, [<sup>18</sup>F]ACI-19278 and [<sup>18</sup>F]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.
Authors
- Myriam Ravache
- Carlo Scialò (ORCID: https://orcid.org/0000-0003-2393-4546)
- Nicolas Dreyfus
- Peter T. Nelson (ORCID: https://orcid.org/0000-0002-6161-1265)
- Efthymia Vokali
- Heiko Kroth (ORCID: https://orcid.org/0000-0002-6936-3921)
- Christophe Delgado
- Madiha Derouazi (ORCID: https://orcid.org/0000-0001-9412-9558)
- Emanuele Buratti (ORCID: https://orcid.org/0000-0002-1356-9074)
- Sara Cappelli (ORCID: https://orcid.org/0000-0002-5001-3905)
- Harro Seelaar (ORCID: https://orcid.org/0000-0003-1989-7527)
- Cristian Constantinescu (ORCID: https://orcid.org/0000-0001-5709-9476)
- Monisha Ratnam
- Tamara Seredenina
- Andreia M. Serra (ORCID: https://orcid.org/0000-0002-6738-303X)
- Francesca Capotosti (ORCID: https://orcid.org/0000-0003-2819-3206)
- Jacqueline Kocher
- Thomas Jaquier
- Ruth Luthi‐Carter
- Magdalini Polymenidou (ORCID: https://orcid.org/0000-0003-1271-9445)
- Tariq Afroz (ORCID: https://orcid.org/0009-0004-1238-4854)
- Tania Melly
- Marie Kosco‐Vilbois
- Andréa Pfeifer
- Elodie Chevalier
- Dorian Charmey
Institutions
- University of Kentucky (US)
- University of Zurich (CH)
- AC Immune (Switzerland) (CH)
- Perceptive Engineering (United Kingdom) (GB)
- École Polytechnique Fédérale de Lausanne (CH)
- International Centre for Genetic Engineering and Biotechnology (IT)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-10-24
- DOI
- https://doi.org/10.1038/s41467-025-64540-6
- Citations
- 9
- Primary Topic
- Amyotrophic Lateral Sclerosis Research
- Type
- article
- Field-Weighted Citation Impact
- 12.50
Funders
- Michael J. Fox Foundation for Parkinson's Research
- Target ALS
- EU Joint Programme – Neurodegenerative Disease Research
- International Centre for Genetic Engineering and Biotechnology
- Universität Zürich
- National Institutes of Health
- University of California, San Francisco
- National Institute on Aging
- Reta Lila Weston Institute of Neurological Studies, UCL Queen Square Institute of Neurology,University College London