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Synthesis and Assessment of Novel Probes for Imaging Tau Pathology in Transgenic Mouse and Rat Models
[Image: see text] 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...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176454/ https://www.ncbi.nlm.nih.gov/pubmed/33689290 http://dx.doi.org/10.1021/acschemneuro.0c00790 |
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author | McMurray, Lindsay Macdonald, Jennifer A. Ramakrishnan, Nisha Kuzhuppilly Zhao, Yanyan Williamson, David W. Tietz, Ole Zhou, Xiaoyun Kealey, Steven Fagan, Steven G. Smolek, Tomáš Cubinkova, Veronika Žilka, Norbert Spillantini, Maria Grazia Tolkovsky, Aviva M. Goedert, Michel Aigbirhio, Franklin I. |
author_facet | McMurray, Lindsay Macdonald, Jennifer A. Ramakrishnan, Nisha Kuzhuppilly Zhao, Yanyan Williamson, David W. Tietz, Ole Zhou, Xiaoyun Kealey, Steven Fagan, Steven G. Smolek, Tomáš Cubinkova, Veronika Žilka, Norbert Spillantini, Maria Grazia Tolkovsky, Aviva M. Goedert, Michel Aigbirhio, Franklin I. |
author_sort | McMurray, Lindsay |
collection | PubMed |
description | [Image: see text] 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. |
format | Online Article Text |
id | pubmed-8176454 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-81764542021-06-07 Synthesis and Assessment of Novel Probes for Imaging Tau Pathology in Transgenic Mouse and Rat Models McMurray, Lindsay Macdonald, Jennifer A. Ramakrishnan, Nisha Kuzhuppilly Zhao, Yanyan Williamson, David W. Tietz, Ole Zhou, Xiaoyun Kealey, Steven Fagan, Steven G. Smolek, Tomáš Cubinkova, Veronika Žilka, Norbert Spillantini, Maria Grazia Tolkovsky, Aviva M. Goedert, Michel Aigbirhio, Franklin I. ACS Chem Neurosci [Image: see text] 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. American Chemical Society 2021-03-10 /pmc/articles/PMC8176454/ /pubmed/33689290 http://dx.doi.org/10.1021/acschemneuro.0c00790 Text en © 2021 The Authors. Published by American Chemical Society Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | McMurray, Lindsay Macdonald, Jennifer A. Ramakrishnan, Nisha Kuzhuppilly Zhao, Yanyan Williamson, David W. Tietz, Ole Zhou, Xiaoyun Kealey, Steven Fagan, Steven G. Smolek, Tomáš Cubinkova, Veronika Žilka, Norbert Spillantini, Maria Grazia Tolkovsky, Aviva M. Goedert, Michel Aigbirhio, Franklin I. Synthesis and Assessment of Novel Probes for Imaging Tau Pathology in Transgenic Mouse and Rat Models |
title | Synthesis and Assessment of Novel Probes for Imaging
Tau Pathology in Transgenic Mouse and Rat Models |
title_full | Synthesis and Assessment of Novel Probes for Imaging
Tau Pathology in Transgenic Mouse and Rat Models |
title_fullStr | Synthesis and Assessment of Novel Probes for Imaging
Tau Pathology in Transgenic Mouse and Rat Models |
title_full_unstemmed | Synthesis and Assessment of Novel Probes for Imaging
Tau Pathology in Transgenic Mouse and Rat Models |
title_short | Synthesis and Assessment of Novel Probes for Imaging
Tau Pathology in Transgenic Mouse and Rat Models |
title_sort | synthesis and assessment of novel probes for imaging
tau pathology in transgenic mouse and rat models |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176454/ https://www.ncbi.nlm.nih.gov/pubmed/33689290 http://dx.doi.org/10.1021/acschemneuro.0c00790 |
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