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

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 ( 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.

PET Imaging in Animal Models of Alzheimer’s Disease

“…[ 11 C]LM229 showed high specificity for 4R tau aggregated in the brain sections of P301S tau mice and truncated human 151–351 3R (SHR24) and 4R (SHR72) tau aggregates in tau transgenic rat brain sections. Preliminary PET studies with [ 11 C]LM229 in both WT and transgenic P310S tau mice confirmed BBB penetration by the radiotracer with maximum brain uptake (%ID/g max; WT = 1.56, P301S = 2.38) within the first minute, followed by washout during the 90-min scan ( McMurray et al, 2021 ).…”

Positron Emission Tomography in Animal Models of Tauopathies

“…Among the other second-generation tau tracers, [ 18 F]JNJ-64349311 (Declercq et al, 2017) and [ 18 F]PI-6240 (Kroth et al, 2019) have so far been reported in wild-type mice for brain uptake and biodistribution assessment. In addition, several new tau probes are underdevelopment such as [ 18 F]IBIPF1 (Kaide et al, 2019), [ 18 F]PI-2014 (Gabellieri et al, 2020), [ 18 F]PPQ (Lerdsirisuk et al, 2021), [ 11 C]LM229 (McMurray et al, 2021), [ 18 F]2-phenylquinoxaline derivatives (Zhou K. et al, 2021), antibody-based imaging (Krishnaswamy et al, 2014), and 4R-tau specific tracer [ 18 F]CBD-2115 (Lindberg et al, 2021). Maruyama et al, 2013;Ishikawa et al, 2018;Ni et al, 2018;Takuwa et al, 2020PS19 mice Maruyama et al, 2013Barron et al, 2020;Fairley et al, 2021;Ji et al, 2021 [ 18…”

Recent advancements in chromone as a privileged scaffold towards the development of small molecules for neurodegenerative therapeutics

“…, and disaggregation of misfolded proteins, 22,23 i.e. , τ-protein, 24,25 amyloid-β (Aβ), 26,27 TAR DNA binding protein 43 (TDP-43), 28 α-synuclein, 29,30 etc. , using small therapeutic molecules.…”

“…However, effective treatments are desperately needed to support and improve the lives of people with dementia and their carers and families. As related to medicinal chemistry, several studies were reported on the development of new inhibitors of known biological targets related to neurodegenerative diseases, such as acetylcholinesterase (AChE), 16,17 butyrylcholinesterase (BuChE), 18 glycogen synthase kinase 3 beta (GSK3β), 19 monoamine oxidase A and B (MAO-A and MAO-B), 20 plasma membrane redox enzymes, 21 etc., and disaggregation of misfolded proteins, 22,23 i.e., τ-protein, 24,25 amyloid-β (Aβ), 26,27 TAR DNA binding protein 43 (TDP-43), 28 α-synuclein, 29,30 etc., using small therapeutic molecules. Most of the small molecules were synthesized using privileged scaffolds of medicinal importance such as pyrimidine, 31 pyrazine, 32 acridine, 33 triazolopyrimidine, 34,35 triazene, 36 coumarin, 37 chromones, etc.…”