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

A novel PET imaging agent enabling in vivo visualization of TDP-43 proteinopathies to advance diagnosis, patient stratification, and precision neurodegenerative drug development

Authors: 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; Tamara Seredenina

Aggregated TDP-43 is a defining pathological hallmark across multiple neurodegenerative disorders, including frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and limbic-predominant age-related TDP-43 encephalopathy (LATE), yet no validated in vivo biomarkers currently exist to measure this pathology in living patients. In this study, the authors report the development and characterization of two small-molecule radiotracers—[18F]ACI-19278 and [18F]ACI-19626—designed to selectively bind aggregated TDP-43 and enable brain imaging by positron emission tomography (PET).

Through extensive validation in postmortem human tissue, cellular systems, and non-human primates, both ligands demonstrate high affinity for pathological TDP-43 aggregates with strong selectivity over common co-pathologies such as amyloid-β, tau, and α-synuclein. Favorable brain uptake and rapid washout profiles support clinical translation, with [18F]ACI-19626 prioritized for first-in-human studies. Together, these first-in-class tracers offer a powerful new tool to visualize TDP-43 in vivo—opening opportunities for earlier diagnosis, patient stratification, and precision therapeutic development across the ALS-FTD spectrum and related proteinopathies.

Why read this article

• Introduces the first PET tracers targeting TDP-43, addressing a major biomarker gap in ALS, FTD, and LATE
• Demonstrates high specificity and selectivity, with minimal off-target binding versus amyloid-β, tau, or α-synuclein
• Shows translational readiness, including favorable pharmacokinetics and brain penetration in non-human primates
• Enables precision neurology workflows, supporting differential diagnosis, patient selection, target engagement, and therapeutic trial design

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