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

Efthymia Vokali, Elodie Chevalier, Nicolas Dreyfus, Dorian Charmey, Tania Melly, Jacqueline Kocher, Monisha Ratnam, Andreia M. Serra, Thomas Jaquier, Christophe Delgado, Myriam Ravache, Carlo Scialò, Sara Cappelli, Heiko Kroth, Francesca Capotosti, Ruth Luthi-Carter, Tariq Afroz, Madiha Derouazi, Cristian C. Constantinescu, Harro Seelaar, Emanuele Buratti, Peter T. Nelson, Magdalini Polymenidou, Andrea Pfeifer, Marie Kosco-Vilbois and Tamara Seredenina ()
Additional contact information
Efthymia Vokali: Building B
Elodie Chevalier: Building B
Nicolas Dreyfus: Building B
Dorian Charmey: Building B
Tania Melly: Building B
Jacqueline Kocher: Building B
Monisha Ratnam: Building B
Andreia M. Serra: Building B
Thomas Jaquier: Building B
Christophe Delgado: Building B
Myriam Ravache: Building B
Carlo Scialò: University of Zurich
Sara Cappelli: International Centre for Genetic Engineering and Biotechnology
Heiko Kroth: Building B
Francesca Capotosti: Building B
Ruth Luthi-Carter: Building B
Tariq Afroz: Building B
Madiha Derouazi: Building B
Cristian C. Constantinescu: Perceptive Inc.
Harro Seelaar: Erasmus University Medical Centre
Emanuele Buratti: International Centre for Genetic Engineering and Biotechnology
Peter T. Nelson: University of Kentucky
Magdalini Polymenidou: University of Zurich
Andrea Pfeifer: Building B
Marie Kosco-Vilbois: Building B
Tamara Seredenina: Building B

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-64540-6

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