Radiosynthesis, In Vitro Characterization, and In Vivo PET Neuroimaging of [18F]F‑4 for Tau Protein: A First-in-Human PET Study

[18F]­PI-2620 is a promising radiopharmaceutical for positron emission tomography (PET) imaging of both Alzheimer’s disease (AD) and non-Alzheimer’s disease (non-AD) tauopathies in humans. An array of fluorinated derivatives of the carbazole scaffold of PI-2620 were synthesized and evaluated. In vit...

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Published inACS chemical neuroscience Vol. 16; no. 6; pp. 1182 - 1189
Main Authors Lindberg, Anton, Tong, Junchao, Zheng, Chao, Mueller, Andre, Kroth, Heiko, Stephens, Andrew, Mathis, Chester A., Vasdev, Neil
Format Journal Article
LanguageEnglish
Published United States American Chemical Society 19.03.2025
Subjects
Alzheimer Disease - diagnostic imaging
Alzheimer Disease - metabolism
Animals
Brain - diagnostic imaging
Brain - metabolism
Female
Fluorine Radioisotopes
Humans
Male
Neuroimaging - methods
Positron-Emission Tomography - methods
Radiopharmaceuticals - chemical synthesis
Radiopharmaceuticals - pharmacokinetics
Rats
Supranuclear Palsy, Progressive - diagnostic imaging
Supranuclear Palsy, Progressive - metabolism
tau Proteins - metabolism
Tauopathies - diagnostic imaging
Tauopathies - metabolism
tau
fluorine-18
[18F]PI-2620
positron emission tomography
[18F]F-4
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Summary:[18F]­PI-2620 is a promising radiopharmaceutical for positron emission tomography (PET) imaging of both Alzheimer’s disease (AD) and non-Alzheimer’s disease (non-AD) tauopathies in humans. An array of fluorinated derivatives of the carbazole scaffold of PI-2620 were synthesized and evaluated. In vitro binding assays with [3H]­PI-2620 in human tissues with AD, progressive supranuclear palsy, and corticobasal degeneration, combined with in silico predictions of blood–brain barrier permeability, led to the selection and radiosynthesis of [18F]­F-4 as a promising radiotracer. In vivo PET imaging with [18F]­F-4 in healthy rats showed brain uptake and kinetics suitable for neuroimaging, similar to those of [18F]­PI-2620. A first-in-human PET imaging study in a healthy subject as well as a patient with AD, in comparison with [18F]­PI-2620 in the same AD subject, confirmed that [18F]­F-4 is an alternative radiopharmaceutical for imaging tau protein.
ISSN:1948-7193
1948-7193
DOI:10.1021/acschemneuro.4c00866