PET imaging of tau proteins

Tau (tubulin-associated unit) proteins include six isoforms produced by alternative mRNA splicing of the MAPT (microtubule-associated protein tau) gene. Tau proteins are natively unfolded and contain 352-441 amino acids, having up to 85 potential phosphorylation sites (serine, threonine and tyrosine). The relative activities of kinases and phosphatases, and conformation of the tau protein itself, determine the phosphorylation status. Tau proteins are involved in microtubule assembly and stabilization, and in regulation of motor-driven intracellular transport in neuronal axons. Increased phosphorylation leads to decreased binding to microtubules and subsequently disruption of microtubules. In addition to phosphorylation, tau proteins are regulated by also other post-translational modification such as glycation, nitration, acetylation, and proteolytic truncation.

Tau proteins are widely expressed in the central and peripheral nervous system, especially in neuronal axons, but also in the kidneys and lungs. Hyperphosphorylated tau proteins accumulate in the somatodendritic compartments of neurons, forming aggregates and eventually neurofibrillary tangles. These neurofibrillary tangles in the brain are found in several neurodegenerative diseases (tauopathies, proteinopathies), including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and traumatic brain injuries. In AD the tau proteins are surrounded by the more abundantly present amyloid β protein.

Neurofibrillary tangles, composed of tau, may not cause the neurodegeneration, but soluble tau oligomers are toxic to synapses, possibly by glutamate excitotoxicity and Ca2+ dysregulation (Forner et al., 2017). Neurofibrillary tangles are commonly observed in brainstem nuclei in subjects without dementia, and in medial temporal lobe of almost all people older than 70 years, but tau pathology especially in medial temporal areas is still associated with memory decline and lower regional volume (Ziontz et al., 2019).

Severe loss of synaptic density is evident in patients with the primary tauopathies of PSP and amyloid-negative corticobasal syndrome, as shown using [11C]UCB-J PET (Holland et al., 2020). In patients with mild cognitive impairment, the brain regions with higher uptake of tau protein radioligand [18F]MK-6240 have shown lower uptake of [11C]UCB-J (Vanhaute et al., 2021).

PET radiopharmaceuticals

Tau protein aggregates

Development of PET radiopharmaceuticals for tau protein aggregates has been hindered by the post-transitional modifications and resulting multiple 3D structures that the tau proteins can adopt in the aggregates. Multiple binding sites on Tau fibrils are present. Another problem is the abundance of amyloid β in the aggregates; therefore most of the tau radioligands are developed for other tauopathies than AD where amyloid β deposits are not present. Radiopharmaceutical must also be able to pass the blood-brain barrier, and show low or no specificity to α-synuclein.

Despite of the problems, several PET radiopharmaceuticals targeting abnormal conformations of the tau proteins have been developed (Villemagne et al., 2015), including [18F]THK523, [18F]THK5105, [18F]THK5117, [18F]THK5351, [18F]T807 (also known as [18F]AV-1451 and Flortaucipir), [18F]T808, and [11C]PBB3 and its 18F-labelled versions.

Radioligand affinities to different tau aggregate types may vary, and therefore certain radiopharmaceuticals may be better suited for certain tauopathies (Bischof et al., 2017). [18F]THK523, [18F]THK5105, [18F]THK5117/[18F]THK5317, and [18F]THK5351 are selective to the AD tau aggregates, and do not bind to α-synuclein deposits. MAO-B has a binding site for many tau radioligands (Murugan et al., 2019).

[18F]THK5351 has lower nonspecific uptake in the white matter, and faster kinetics than the other THK ligands (Harada et al., 2016). However, [18F]THK5351 binds to MAO-B, which may limit its usability in studies of cortex and basal ganglia (Bischof et al., 2017). [18F]THK5351 and [18F]AV-1451 bind to melanin-containing cells (Tago et al., 2019).

[18F]T807 and [18F]T808 seem to have good selectivity for AD and non-AD tau aggregates over amyloid β. However, [18F]T807 binds also to MAO-A and MAO-B with high affinity (Barrio, 2018).

[11C]PBB3 is selective for a relatively broad range of tau structures, but it may have some specificity to α-synuclein deposits, too (Bischof et al., 2017).

[18F]MK6240 binds specifically to neurofibrillary tangles (Malarte et al., 2021).

[18F]PI-2620 is able to detect aggregated tau isoforms in AD, PSP, and corticobasal syndrome (CBS) (Kroth et al., 2019; Mueller et al., 2020; Brendel et al., 2020; Mormino et al., 2021; Song et al., 2021a). Binding characteristics can differentiate 3/4R- and 4R-tauopathies, because binding affinity to 4R tau isoform is lower (Song et al., 2021b).

Amyloid β radioligand [18F]FDDNP binds to both extracellular amyloid β plaques and the intracellular neurofibrillary tangles.

O-GlcNAc hydrolase (OGA)

O-GlcNAcylation stabilizes the microtubule-associated tau protein, hindering abnormal phosphorylation and aggregation of tau. O-GlcNAc transferase catalyses the attachment of O-GlcNAc (O-linked β-N-acetylglucosamine) at the serine and threonine residues of the tau protein. O-GlcNAc hydrolase (O-GlcNAcase, OGA) catalyses the opposite reaction. Upregulation of O-GlcNAcylation by OGA inhibitors reduces pathologic tau phosphorylation and aggregation and prevents neurodegeneration in animal models.

[18F]LSN3316612 is a specific radioligand for imaging OGA in vivo (Paul et al., 2019; Lee et al., 2020). Quantification requires arterial plasma sampling, and Logan plot can be used compute parametric VT images, with moderate to good test-retest reliability (Lee et al., 2021).


Global tau load in human brain can be quantified from static PET scan as a single parameter TauL, which can be calculated using automated algorithm TauIQ (Whittington et al., 2021). Similar method is used to calculate global amyloid burden.

See also:


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Updated at: 2022-01-24
Created at: 2015-08-17
Written by: Vesa Oikonen