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Review
. 2018;6(4):305-316.
doi: 10.1007/s40336-018-0290-y. Epub 2018 Jul 20.

The development and validation of tau PET tracers: current status and future directions

Nobuyuki Okamura  1   2 , Ryuichi Harada  3 , Aiko Ishiki  2 , Akio Kikuchi  4 , Tadaho Nakamura  1 , Yukitsuka Kudo  2
Affiliations
Review

The development and validation of tau PET tracers: current status and future directions

Nobuyuki Okamura et al. Clin Transl Imaging. 2018.

Abstract

Purpose: To provide an overview on positron emission tomography (PET) imaging of tau pathology in Alzheimer's disease (AD) and other neurodegenerative disorders.

Results: Different classes of tau tracers such as flortaucipir, THK5317, and PBB3 have been developed and utilized in previous clinical studies. In AD, the topographical distribution of tracer binding follows the known distribution of neurofibrillary tangles and is closely associated with neurodegeneration as well as the clinical phenotype of dementia. Significant retention of tracers has also been observed in the frequent site of the 4-repeat (4R) tau isoform deposits in non-AD tauopathies, such as in progressive supranuclear palsy. However, in vitro binding studies indicate that most tau tracers are less sensitive to straight tau filaments, in contrast to their high binding affinity to paired helical filaments of tau (PHF-tau). The first-generation of tau tracers shows off-target binding in the basal ganglia, midbrain, thalamus, choroid plexus, and venous sinus. Off-target binding of THK5351 to monoamine oxidase B (MAO-B) has been observed in disease-associated brain regions linked to neurodegeneration and is associated with astrogliosis in areas of misfolded protein accumulation. The second generation of tau tracers, such as [18F]MK-6240, is highly selective to PHF-tau with little off-target binding and have enabled the reliable assessment of PHF-tau burden in aging and AD.

Conclusions: Tau PET tracers have enabled in vivo quantification of PHF-tau burden in human brains. Tau PET can help in understanding the underlying cause of dementia symptoms, and in patient selection for clinical trials of anti-dementia therapies.

Keywords: Aging; Alzheimer’s disease; Neurodegeneration; Neurofibrillary tangles; Positron emission tomography; Tau.

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Conflict of interest statement

Nobuyuki Okamura and Yukitsuka Kudo have received research support from Clino Ltd. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008.Informed consent was obtained from all patients for being included in the study.

Figures

Fig. 1
Fig. 1
Chemical structures of tau PET tracers
Fig. 2
Fig. 2
[18F]THK5351 PET images in patients with Alzheimer’s disease (AD), corticobasal syndrome (CBS), and progressive supranuclear palsy (PSP). In AD patients, THK5351 retention was high in the basal ganglia and the thalamus, reflecting the off-target binding to monoamine oxidase B (MAO-B). CBS patients showed prominent tracer retention in the basal ganglia, the precentral gyrus, and the midbrain. THK5351 retention in the midbrain was also elevated in PSP
Fig. 3
Fig. 3
[18F]THK5351 PET images in patient with semantic variant primary progressive aphasia. Significant tracer retention was observed in the left anterior temporal pole. Figure courtesy of Dr. Ryota Kobayashi, Yamagata University
Fig. 4
Fig. 4
[18F]Flortaucipir PET images in patient with Alzheimer’s disease (AD) and healthy control (HC). Tracer retention was markedly elevated in the neocortex of AD patient Figure courtesy of Dr. Victor Villemagne, University of Melbourne
See this image and copyright information in PMC

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