TY - JOUR
T1 - Synthesis and assessment of novel probes for imaging tau pathology in transgenic mouse and rat models
AU - McMurray, Lindsay
AU - Macdonald, Jennifer A.
AU - Ramakrishnan, Nisha Kuzhuppilly
AU - Zhao, Yanyan
AU - Williamson, David W.
AU - Tietz, Ole
AU - Zhou, Xiaoyun
AU - Kealey, Steven
AU - Fagan, Steven G.
AU - Smolek, Tomáš
AU - Cubinkova, Veronika
AU - Žilka, Norbert
AU - Spillantini, Maria Grazia
AU - Tolkovsky, Aviva M.
AU - Goedert, Michel
AU - Aigbirhio, Franklin I.
N1 - 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.
PY - 2021/6/2
Y1 - 2021/6/2
N2 - 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.
AB - 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.
KW - PET
KW - imaging
KW - tau
KW - neurodegeneration
KW - mouse
KW - rat
UR - http://www.scopus.com/inward/record.url?scp=85103512230&partnerID=8YFLogxK
U2 - 10.1021/acschemneuro.0c00790
DO - 10.1021/acschemneuro.0c00790
M3 - Article
C2 - 33689290
VL - 12
SP - 1885
EP - 1893
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
SN - 1948-7193
IS - 11
ER -