Synthesis and assessment of novel probes for imaging tau pathology in transgenic mouse and rat models

Lindsay McMurray, Jennifer A. Macdonald, Nisha Kuzhuppilly Ramakrishnan, Yanyan Zhao, David W. Williamson, Ole Tietz, Xiaoyun Zhou, Steven Kealey, Steven G. Fagan, Tomáš Smolek, Veronika Cubinkova, Norbert Žilka, Maria Grazia Spillantini, Aviva M. Tolkovsky, Michel Goedert, Franklin I. Aigbirhio*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Aggregated tau protein is a core pathology present in several neurodegenerative diseases. Therefore, the development and application of positron emission tomography (PET) imaging radiotracers that selectively bind to aggregated tau in fibril form is of importance in furthering the understanding of these disorders. While radiotracers used in human PET studies offer invaluable insight, radiotracers that are also capable of visualizing tau fibrils in animal models are important tools for translational research into these diseases. Herein, we report the synthesis and characterization of a novel library of compounds based on the phenyl/pyridinylbutadienylbenzothiazoles/benzothiazolium (PBB3) backbone developed for this application. From this library, we selected the compound LM229, which binds to recombinant tau fibrils with high affinity (Kd = 3.6 nM) and detects with high specificity (a) pathological 4R tau aggregates in living cultured neurons and mouse brain sections from transgenic human P301S tau mice, (b) truncated human 151-351 3R (SHR24) and 4R (SHR72) tau aggregates in transgenic rat brain sections, and (c) tau neurofibrillary tangles in brain sections from Alzheimer's disease (3R/4R tau) and progressive supranuclear palsy (4R tau). With LM229 also shown to cross the blood-brain barrier in vivo and its effective radiolabeling with the radioisotope carbon-11, we have established a novel platform for PET translational studies using rodent transgenic tau models.

Original languageEnglish
Pages (from-to)1885-1893
Number of pages9
JournalACS Chemical Neuroscience
Volume12
Issue number11
Early online date10 Mar 2021
DOIs
Publication statusPublished - 2 Jun 2021
Externally publishedYes

Bibliographical note

Copyright the Author(s) 2021. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

  • PET
  • imaging
  • tau
  • neurodegeneration
  • mouse
  • rat

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