Introduction: Aggregation of tau is a hallmark of many neurodegenerative diseases, and tau imaging with positron emission tomography (PET) may allow early diagnosis and treatment monitoring. We assessed binding of the PET tracer [¹⁸F]AV‐1451 in a range of dementias.Methods: Phosphorimaging was used to quantify binding to postmortem brain tissue from 33 patients with different, histopathologically characterized, neurodegenerative dementias.Results: [¹⁸F]AV‐1451 showed high specific binding in cases with Alzheimer's disease (AD), moderate binding in Pick's disease and frontotemporal dementia with parkinsonism‐17, and low but displaceable binding in corticobasal degeneration, progressive supranuclear palsy, non–tau proteinopathies, and in controls without pathology. Tracer binding did not correlate with tau load within disease groups.Discussion: [¹⁸F]AV‐1451 binds to tau in AD, and some other tauopathies. However, evidence for a non–tau binding site and lack of correlation between tracer binding and antibody staining suggest that reliable quantification of tau load with this tracer is problematic.

Herein, we report a novel intramolecular ring-closing reaction of biaryl thioethers that give access to highly functionalized dibenzothiophene sulfonium salts under mild conditions. The resulting precursors react regioselectively with [¹⁸F]fluoride to give [¹⁸F]fluoroarenes in predictable radiochemical yields. The strategy expands the available radiochemical space and provides superior labeling efficiency for clinically relevant PET tracers.

Positron emission tomography (PET) is unique in that it allows quantification of biochemical processesin vivo, but difficulties with preparing suitably labelled radiotracers limit its scientific and diagnostic applications. Aromatic [¹⁸F]fluorination of drug-like small molecules is particularly challenging as their functional group compositions often impair the labelling efficiency. Herein, we report a new strategy for incorporation of¹⁸F into highly functionalized aromatic compounds using sulfonium salts as leaving groups. The method is compatible with pharmacologically relevant functional groups, including aliphatic amines and basic heterocycles. Activated substrates react with [¹⁸F]fluoride at room temperature and with heating the reaction proceeds in the presence of hydrogen bond donors. Furthermore, the use of electron rich spectator ligands allows efficient and regioselective [¹⁸F]fluorination of non-activated aromatic moieties. The method provides a broadly applicable route for¹⁸F labelling of biologically active small molecules and offers immediate practical benefits for drug discovery and imaging with PET.

Herein, we report that iron(II)/ammonium persulfate in aqueous acetonitrile mediates the Newman–Kwart rearrangement of O-aryl carbamothioates. Electron-rich substrates react rapidly under moderate heating to afford the rearranged products in excellent yields. The mild conditions, rapid reaction rates, and suitability for scale up offers immediate practical benefits to access functionalized thiophenols.

Background: Flumazenil (FMZ) is a functionally silent imidazobenzodiazepine which binds to the benzodiazepine binding site of approximately 75% of the brain γ-aminobutyric acid-A receptors (GABA_ARs). Positron Emission Tomography (PET) imaging of the GABAARs with [¹¹C]FMZ has been used to evidence alterations in neuronal density, to assess target engagement of novel pharmacological agents, and to study disorders such as epilepsy and Huntington’s disease. Despite the potential of FMZ PET imaging the short half-life (t_1/2) of carbon-11 (20 min) has limited the more widespread clinical use of [¹¹C]FMZ. The fluorine-18 (¹⁸F) isotopologue with a longer t_1/2 (110 min) is ideally suited to address this drawback. However, the majority of current radiochemical methods for the synthesis of [¹⁸F]FMZ are non-trivial and low yielding. We report a robust, automated protocol that is good manufacturing practice (GMP) compatible, and yields multi-patient doses of [¹⁸F]FMZ. Results: The fully automated synthesis was developed on the Trasis AllinOne (AIO) platform using a single-use cassette. [¹⁸F]FMZ was synthesized in a one-step procedure from [¹⁸F]fluoride, via a copper-mediated ¹⁸F-fluorination of a boronate ester precursor. Purification was performed by semi-preparative radio-HPLC and the collected fraction formulated directly into the final product vial. The overall process from start of synthesis to delivery of product is approximately 55 min. Starting with an initial activity of 23.6 ± 5.8 GBq (n = 3) activity yields of [¹⁸F]FMZ were 8.0 ± 1 GBq (n = 3). The synthesis was successfully reproduced at two independent sites, where the product passed quality control release criteria in line with the European Pharmacopoeia standards and ICH Q3D(R1) guidelines to be suitable for human use. Conclusion: Reported is a fully automated cassette-based synthesis of [¹⁸F]FMZ that is Good Manufacturing Practice (GMP) compatible and produces multi-patient doses of [¹⁸F]FMZ.