Discovery and preclinical characterization of [ 18 F]PI-2620, a next-generation tau PET tracer for the assessment of tau pathology in Alzheimer’s disease and other tauopathies

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Abstract

Purpose

Tau deposition is a key pathological feature of Alzheimer’s disease (AD) and other neurodegenerative disorders. The spreading of tau neurofibrillary tangles across defined brain regions corresponds to the observed level of cognitive decline in AD. Positron-emission tomography (PET) has proved to be an important tool for the detection of amyloid-beta (Aβ) aggregates in the brain, and is currently being explored for detection of pathological misfolded tau in AD and other non-AD tauopathies. Several PET tracers targeting tau deposits have been discovered and tested in humans. Limitations have been reported, especially regarding their selectivity.

Methods

In our screening campaign we identified pyrrolo[2,3- b:4,5- c’]dipyridine core structures with high affinity for aggregated tau. Further characterization showed that compounds containing this moiety had significantly reduced monoamine oxidase A (MAO-A) binding compared to pyrido[4,3- b]indole derivatives such as AV-1451.

Results

Here we present preclinical data of all ten fluoropyridine regioisomers attached to the pyrrolo[2,3- b:4,5- c’]dipyridine scaffold, revealing compounds 4 and 7 with superior properties. The lead candidate [ ¹⁸F]PI-2620 (compound 7) displayed high affinity for tau deposits in AD brain homogenate competition assays. Specific binding to pathological misfolded tau was further demonstrated by autoradiography on AD brain sections (Braak I-VI), Pick’s disease and progressive supranuclear palsy (PSP) pathology, whereas no specific tracer binding was detected on brain slices from non-demented donors. In addition to its high affinity binding to tau aggregates, the compound showed excellent selectivity with no off-target binding to Aβ or MAO-A/B. Good brain uptake and fast washout were observed in healthy mice and non-human primates.

Conclusions

Therefore, [ ¹⁸F]PI-2620 was selected for clinical validation.

Electronic supplementary material

The online version of this article (10.1007/s00259-019-04397-2) contains supplementary material, which is available to authorized users.

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Author and article information

Contributors

Andrew Stephens:

ORCID: http://orcid.org/0000-0001-5052-6586

+49 30 461124604 , a.stephens@life-mi.com

Journal

Journal ID (nlm-ta): Eur J Nucl Med Mol Imaging

Journal ID (iso-abbrev): Eur. J. Nucl. Med. Mol. Imaging

Title: European Journal of Nuclear Medicine and Molecular Imaging

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 1619-7070

ISSN (Electronic): 1619-7089

Publication date (Electronic): 1 July 2019

Publication date PMC-release: 1 July 2019

Publication date (Print): 2019

Volume: 46

Issue: 10

Pages: 2178-2189

Affiliations

[1 ]GRID grid.476060.3, AC Immune SA, ; Lausanne, Switzerland

[2 ]Life Molecular Imaging, GmbH, Berlin, Germany

[3 ]GRID grid.476553.6, Piramal Imaging GmbH, ; Berlin, Germany

[4 ]ISNI 0000 0001 0672 7022, GRID grid.39009.33, Present Address: Merck KGaA, ; Darmstadt, Germany

[5 ]GRID grid.452597.8, Invicro LLC, ; New Haven, USA

[6 ]Present Address: XingImaging LLC, Beijing, China

Author information

Andrew Stephens http://orcid.org/0000-0001-5052-6586

Article

Publisher ID: 4397

DOI: 10.1007/s00259-019-04397-2

PMC ID: 6667408

PubMed ID: 31264169

SO-VID: dbcda55a-185b-4225-9388-421a401de785

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 11 December 2018

Date accepted : 10 June 2019

Custom metadata

ScienceOpen disciplines: Radiology & Imaging

Keywords: tau,pet,positron-emission tomography,ad,alzheimer’s disease,tauopathies,fluorine-18,pet tracer,pi-2620

Data availability:

ScienceOpen disciplines: Radiology & Imaging

Keywords: tau, pet, positron-emission tomography, ad, alzheimer’s disease, tauopathies, fluorine-18, pet tracer, pi-2620