HAI Book 2025 - Flipbook - Page 273
Capotosti, Francesca
Discovery and preclinical development of [18F]ACI-19626, a first-in-class
TDP-43 PET tracer
Francesca Capotosti1, Efthymia Vokali1, Nicolas Dreyfus1, Elodie Chevallier1, Dorian Charmey1,
Tania Melly1, Monisha Rathnam1, Andreia Monica Serra1, Thomas Jaquier1, Carlo Scialo2, Harro
Seelaar3, Emanuele Buratti4, Peter Nelson5, Magdalini Polymenidou2, Madiha Derouazi1,
Andrea Pfeifer1, Marie Kosco-Vilbois1, Tamara Seredenina1
1
AC Immune SA, EPFL Innovation Park, Building B, Lausanne, CH
Department of Quantitative Biomedicine, University of Zurich, Zurich, CH
3
Department of Neurology, Erasmus University Medical Centre, Rotterdam, NL
4
Molecular Pathology, International Centre for Genetic Engineering and Biotechnology, Trieste, IT
5
University of Kentucky, Lexington, KY, US
2
Background: Aggregated TDP-43 is a pathological hallmark of amyotrophic lateral sclerosis (ALS), frontotemporal
dementia (FTD) and limbic-predominant age-related TDP-43 encephalopathy (LATE), and a co-pathology in other
neurodegenerative diseases, including Alzheimer9s disease (AD). There are currently no validated biofluid or
imaging biomarkers of TDP-43 pathology. Direct detection of TDP-43 aggregates will revolutionize precision
medicine via accurate diagnosis, patient stratification and assessment of therapeutic efficacy in clinical trials.
Methods: Using our Morphomer® small molecule library of brain-penetrant and beta sheet binding compounds,
initial hits were identified using patients9 brain material. Orthogonal radiobinding and autoradiography assays
were used to assess binding affinity and target engagement on brain samples from diverse cases with FTLD-TDP,
ALS and LATE-NC-ADNC, and selectivity over other aggregation-prone proteins on AD and Parkinson9s disease
(PD) tissue. Brain pharmacokinetic profiles were obtained in mice, followed by assessment of brain uptake,
distribution and washout for selected 18F radiolabeled compounds in non-human primates (NHP).
Results: Medicinal chemistry optimization enabled the discovery of the TDP-43 tracer, ACI-19626, that binds with
high affinity (low nM Kd) to human brain-derived aggregated TDP-43, but not soluble physiological TDP-43. It
differentiates FTLD-TDP type A and B patient samples from age-matched controls and can visualize target
engagement to TDP-43 inclusions in ALS and LATE-NC-ADNC brain tissue. ACI-19626 displays excellent selectivity
for TDP-43 over Abeta, Tau and alpha-synuclein aggregates, and no binding to common off-target proteins,
including monoamine oxidase A and B. [18F]ACI-19626 rapidly enters the brain of NHPs and shows fast and
complete washout, a profile suitable for brain PET imaging. Toxicology studies showed a desired safety profile.
Conclusions: [18F]ACI-19626 was identified as a promising first-in-class TDP-43 PET tracer for the detection and
monitoring of TDP-43 pathology in living patients. Based on its excellent profile, it was selected for evaluation in a
First-in-Human study.
Keywords: TDP-43, new tracer, ALS, FTD
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