Open AccessSynthesis and Assessment of Novel Probes for Imaging Tau Pathology in Transgenic Mouse and Rat Models
Author(s) -
Lindsay McMurray,
Jennifer A. Macdonald,
Nisha K. Ramakrishnan,
Yanyan Zhao,
David Williamson,
Ole Tietz,
Xiaochi Zhou,
Steven Kealey,
Steven G. Fagan,
Tomáš Smolek,
Veronika Cubinkova,
Norbert Žilka,
Maria Grazia Spillantini,
Aviva M. Tolkovsky,
Michel Goedert,
Franklin I. Aigbirhio
Publication year - 2021
Publication title -
acs chemical neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.158
H-Index - 69
ISSN - 1948-7193
DOI - 10.1021/acschemneuro.0c00790
Subject(s) - progressive supranuclear palsy , tau pathology , genetically modified mouse , tauopathy , tau protein , transgene , chemistry , fibril , neuroscience , positron emission tomography , in vivo , pathology , alzheimer's disease , biochemistry , neurodegeneration , biology , medicine , disease , gene , genetics
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 ( K d = 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.