Comparison of 18F-T807 and 18F-THK5117 PET in a Mouse Model of Tau Pathology

Matthias Brendel,Nobuyuki Okamura,Finn Peters,Alexander Drzezga,Jochen Herms,Behrooz H Yousefi,Tanja Blume,Maximilian Deussing,Igor Yakushev,Michael Herz,Peter Bartenstein,Christian Haass,Carola Focke,Simon Lindner,Axel Rominger,Barbara Von Ungern-Sternberg

doi:10.3389/fnagi.2018.00174

Abstract

Positron-emission-tomography (PET) imaging of tau pathology has facilitated development of anti-tau therapies. While members of the arylquinoline and pyridoindole families have been the most frequently used tau radioligands so far, analyses of their comparative performance in vivo are scantly documented. Here, we conducted a head-to-head PET comparison of the arylquinoline 18FT807 and the pyridoindole 18FTHK5117 PET in a mouse model of tau pathology. PET recordings were obtained in groups of (N = 5–7) P301S and wild-type (WT) mice at 6 and 9 months of age. Volume-of-interest based analysis (standard-uptake-value ratio, SUVR) was used to calculate effect sizes (Cohen’s d) for each tracer and age. Statistical parametric mapping (SPM) was used to assess regional similarity (dice coefficient) of tracer binding alterations for the two tracers. Immunohistochemistry staining of neurofibrillary tangles was performed for validation ex vivo. Significantly elevated 18F-T807 binding in the brainstem of P301S mice was already evident at 6 months (+14%, p < 0.01, d = 1.64), and increased further at 9 months (+23%, p < 0.001, d = 2.70). 18F-THK5117 indicated weaker increases and effect sizes at 6 months (+5%, p < 0.05, d = 1.07) and 9 months (+10%, p < 0.001, d = 1.49). Regional similarity of binding of the two tracers was high (71%) at 9 months. 18F-T807 was more sensitive than 18F-THK5117 to tau pathology in this model, although both tracers present certain obstacles, which need to be considered in the design of longitudinal preclinical tau imaging studies.

Highlights

Neurofibrillary tangles constitute one of the most characteristic neuropathological findings in Alzheimer’s disease (AD), which is the most frequent form of dementia, and likewise occur in certain non-AD forms of dementia known as tauopathies (Duyckaerts et al, 2009)
Relative to the mean peak activity, 57% remained at 10 min and 11% remained at 60 min after 18F-THK5117 injection, while 72% remained at 10 min and 26% at 60 min after 18F-T807 injection
We found moderately superior sensitivity of 18F-T807 for the contrast of P301S versus age-matched WT mice, compared to 18F-THK5117

Summary

Introduction

Neurofibrillary tangles constitute one of the most characteristic neuropathological findings in Alzheimer’s disease (AD), which is the most frequent form of dementia, and likewise occur in certain non-AD forms of dementia known as tauopathies (Duyckaerts et al, 2009). Whereas AD is characterized by paired helical filaments containing equal amounts of 3R and 4R isoforms, non-AD tauopathies present with other tau ultrastructures and isoforms. The pathology in Preclinical Tau Tracer Comparison progressive supranuclear palsy and corticobasal degeneration consists of 4R tau aggregating into straight filaments (Murray et al, 2014). The recent development of 18F-fluorinated radioligands for positron-emission-tomography (PET) studies of tau aggregates intensely accelerated research in the field of tau imaging in AD and non-AD tauopathies (Villemagne and Okamura, 2016). Tau PET has been hindered due to off-target binding of ligands to neuromelanin (Hansen et al, 2016) and MAO-B (Ng et al, 2017), both tracer classes can differentiate AD and non-AD tauopathy patients from healthy controls

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Conclusion