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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月24日

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  • 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

摘要

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.