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In vitro evidence for a nonselective 4R tau PET tracer

Molecular Psychiatry volume 28, pages 1398–1399 (2023)Cite this article

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Aggregation of misfolded brain proteins is a common feature of several neurodegenerative diseases with the types of proteins, morphology, and spatial distribution often forming the defining pathological features for a given disease. Over the past two decades, considerable progress has been made towards developing positron emission tomography (PET) neuroimaging radioligands (i.e., radiotracers) targeting beta-amyloid (Aβ) plaques and neurofibrillary tau tangles, the pathological hallmarks of Alzheimer’s disease. PET imaging of Aβ and tau aggregates provides in vivo quantification of the density of underlying protein aggregates throughout the entire three-dimensional volume of the brain. To date, amyloid and tau PET imaging have been widely adopted to study the effects of Aβ and tau proteins on neurodegeneration and cognitive decline in Alzheimer’s disease, including use in clinical trials as inclusion/exclusion criteria, confirmation of target engagement, and as secondary trial endpoints. The interpretation of in vivo Aβ and tau PET imaging is highly informed by in vitro studies that characterize several aspects of PET tracers including binding affinity and selectivity of the radioligands to their designed molecular targets (see Mathis et al., for review [1]).

Developing sensitive and selective PET tracers for tau protein aggregates is complicated by the six tau isoforms expressed in humans and the many ultrastructures and spatial deposition patterns that arise in different tauopathies (see Goedert et al. [2]). The majority of tau PET imaging research has focused on developing tau PET ligands selective for AD-type neurofibrillary tangles comprised of 3R/4R paired-helical filaments, but recent studies have begun to explore the use of tau PET tracers to detect tau aggregates in non-AD tauopathies such as chronic traumatic encephalopathy, progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD) with mixed results for some tracers. In a recent work by Malarte et al. [3], researchers compare the binding profiles of three promising tau PET tracers (PI-2620, MK-6240, and RO-948) using in vitro binding assays, autoradiography, and immunohistochemistry to ascertain the extent to which these tracers might bind to tau aggregates present in CBD and PSP in addition to AD. Their results move the field forward in understanding the limitations of current-generation tau tracers for non-AD tauopathies and provide valuable insights to consider when developing tau PET tracers for non-AD tauopathies.

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Authors and Affiliations

  1. Division of Geriatrics, Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA

    Tobey J. Betthauser

  2. Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA

    Tobey J. Betthauser

  3. Department of Medical Physics, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA

    Tobey J. Betthauser

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All contributions to this article including drafting and revising the manuscript were made by TJB.

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Correspondence to Tobey J. Betthauser.

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Competing interests

TJB has received funding from the Alzheimer’s Association and the National Institute on Aging under the grants listed below but has no other relevant disclosures. NIH/NIA R01AG021155, RF1AG027161, R01AG062285, P30AG062715, R01AG070883 and the Alzheimer’s Association AARF-19-614533.

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Cite this article

Betthauser, T.J. In vitro evidence for a nonselective 4R tau PET tracer. Mol Psychiatry 28, 1398–1399 (2023). https://doi.org/10.1038/s41380-023-01950-2

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