Longitudinal Assessment of Tau-Associated Pathology by 18F-THK5351 PET Imaging: A Histological, Biochemical, and Behavioral Study

Abstract

Several common and debilitating neurodegenerative disorders are characterized by the intracellular accumulation of neurofibrillary tangles (NFTs), which are composed of hyperphosphorylated tau protein. In Alzheimer’s disease (AD), NFTs are accompanied by extracellular amyloid-beta (Aβ), but primary tauopathy disorders are marked by the accumulation of tau protein alone, including forms of frontotemporal dementia (FTD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP), among others. 18F-THK5351 has been reported to bind pathological tau as well as associated reactive astrogliosis. The goal of this study was to validate the ability of the PET tracer 18F-THK5351 to detect early changes in tau-related pathology and its relation to other pathological hallmarks. We demonstrated elevated in vivo 18F-THK5351 PET signaling over time in transgenic P301S tau mice from 8 months that had a positive correlation with histological and biochemical tau changes, as well as motor, memory, and learning impairment. This study indicates that 18F-THK5351 may help fill a critical need to develop PET imaging tracers that detect aberrant tau aggregation and related neuropathology in order to diagnose the onset of tauopathies, gain insights into their underlying pathophysiologies, and to have a reliable biomarker to follow during treatment trials.

Positron Emission Tomography in Animal Models of Tauopathies

“…However, Eckenweber et al (2020) reported that in PS19 mice at 6 month-of-age, (S)-[ 18 F]THK5117 was not able to detect the tau accumulation, although presence of tau accumulation was validated by using ex vivo immunohistochemical staining. Moreno-Gonzalez et al (2021) recently showed an elevated regional [ 18 F]THK5351 PET signaling in brain of PS19 tau mice, correlating with histological levels of tau. However, both the binding assays as well as in silico experiment showed that [ 18 F]THK5351 had the limitation of off-target binding to monoamine oxidase B ( Ng et al, 2017 ; Murugan et al, 2019 ).…”

“…MicroPET imaging of tau in tauopathy rodent models has contributed to the development of novel PET tracers, understanding of disease mechanism, and monitoring of treatment effect. Several tau tracers have been tested in tau mouse models including 2,6-disubstituted naphthalene derivative [ 18 F]FDDNP ( Teng et al, 2011 ), pyridinyl-butadienyl-benzothiazole 3 derivatives [ 18 F]PM-PBB3 (APN-1607), [ 11 C]PBB3, [ 11 C]mPBB5 ( Maruyama et al, 2013 ; Ishikawa et al, 2018 ; Ni et al, 2018 ; Barron et al, 2020 ; Tagai et al, 2020 ), arylquinoline derivatives [ 18 F]THK523 ( Fodero-Tavoletti et al, 2011 ), [ 18 F]THK5351 ( Moreno-Gonzalez et al, 2021 ), [ 18 F]THK5317 ( Filip et al, 2021 ), [ 18 F]THK5117 ( Brendel et al, 2016 ; Chaney et al, 2021 ), pyridoindole derivative [ 18 F]flortaucipir ( Brendel et al, 2018 ), and lansoprazole derivative [ 18 F]NML ( Shao et al, 2012 ; Fawaz et al, 2014 ; Table 1 ). Using [ 18 F]THK523, Brendel et al (2018) showed significantly higher tracer retentions in brains of 6-month-old rTg4510 mice compared with non-transgenic mice or PS1/APP mice with Aβ pathology, indicating specific detection of tau.…”

PET Imaging in Animal Models of Alzheimer’s Disease

“…Thus, [ 18 F]T807 appeared to be more sensitive than [ 18 F]THK5117 to detect tau pathology in this model. Recently, [ 18 F]THK5351 PET signal was found to correlate well with histological and biochemical tau changes, as well as motor, memory, and learning impairment, in P301S tau mice from 8 months over time ( Moreno-Gonzalez et al, 2021 ).…”