Synthesis and Assessment of Novel Probes for Imaging Tau Pathology in Transgenic Mouse and Rat Models.

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

doi:10.1021/acschemneuro.0c00790

Lindsay Mcmurray, Franklin I Aigbirhio + Show 14 more

Open Access

https://doi.org/10.1021/acschemneuro.0c00790

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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.

Highlights

Imaging protein aggregates, characteristic features of a variety of neurodegenerative diseases,[1] has become a powerful means of investigating their pathology
To improve the development of positron emission tomography (PET) imaging probes for visualizing tau pathology in transgenic models of neurodegeneration, we report the synthesis and characterization of a novel series of compounds based on the phenyl/pyridinylbutadienylbenzothiazoles/benzothiazolium (PBB3) structure (Scheme 1A), which has been shown to bind to tau aggregates in both mouse models and humans.[10]
In order to establish transgenic tau rodent models as a translational platform for PET imaging research in neurodegenerative disorders, we have developed a range of novel compounds based on the PBB3 structure

Summary

■ INTRODUCTION

Characteristic features of a variety of neurodegenerative diseases,[1] has become a powerful means of investigating their pathology. Compared to the SHR24 rat brain sections, there were less inclusions detected, which seems to indicate the compounds have preferential binding toward the three repeat forms of tau in these rat models To our knowledge, this is the first time that tau PET imaging compounds have been shown to bind to pathological tau in a rat transgenic model. This is the first time that tau PET imaging compounds have been shown to bind to pathological tau in a rat transgenic model These results establish the basis to perform in vivo PET imaging studies, including further investigations into the selectivity of LM229 toward the three and four repeat forms of tau. Further PET studies are required to fully characterize the in vivo pharmacokinetics of the radiotracer in both mice and rats

■ CONCLUSION

■ ACKNOWLEDGMENTS

Findings

■ REFERENCES