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.

Synaptic pathology is associated with several brain disorders, thus positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A) using the radioligand [¹¹C]UCB-J may provide a tool to measure synaptic alterations. Given the pivotal role of mouse models in understanding neuropsychiatric and neurodegenerative disorders, this study aims to validate and characterize [¹¹C]UCB-J in mice. We performed a blocking study to verify the specificity of the radiotracer to SV2A, examined kinetic models using an image-derived input function (IDIF) for quantification of the radiotracer, and investigated the in vivo metabolism. Regional TACs during baseline showed rapid uptake of [¹¹C]UCB-J into the brain. Pretreatment with levetiracetam confirmed target engagement in a dose-dependent manner. V_{T (IDIF)} values estimated with one- and two-tissue compartmental models (1TCM and 2TCM) were highly comparable (r=0.999, p < 0.0001), with 1TCM performing better than 2TCM for K_{1 (IDIF)}. A scan duration of 60 min was sufficient for reliable V_{T (IDIF)} and K_{1 (IDIF)} estimations. In vivo metabolism of [¹¹C]UCB-J was relatively rapid, with a parent fraction of 22.5 ± 4.2% at 15 min p.i. In conclusion, our findings show that [¹¹C]UCB-J selectively binds to SV2A with optimal kinetics in the mouse representing a promising tool to noninvasively quantify synaptic density in comparative or therapeutic studies in neuropsychiatric and neurodegenerative disorder models.

Huntington’s disease (HD) is a fatal neurodegenerative disease caused by a CAG expansion mutation in the huntingtin gene. As a result, intranuclear inclusions of mutant huntingtin protein are formed, which damage striatal medium spiny neurons (MSNs). A review of Positron Emission Tomography (PET) studies relating to HD was performed, including clinical and preclinical data. PET is a powerful tool for visualisation of the HD pathology by non-invasive imaging of specific radiopharmaceuticals, which provide a detailed molecular snapshot of complex mechanistic pathways within the brain. Nowadays, radiochemists are equipped with an impressive arsenal of radioligands to accurately recognise particular receptors of interest. These include key biomarkers of HD: adenosine, cannabinoid, dopaminergic and glutamateric receptors, microglial activation, phosphodiesterase 10 A and synaptic vesicle proteins. This review aims to provide a radiochemical picture of the recent developments in the field of HD PET, with significant attention devoted to radiosynthetic routes towards the tracers relevant to this disease.

Background: The translocator protein 18 kDa is recognised as an important biomarker for neuroinflammation due to its soaring expression in microglia. This process is common for various neurological disorders. DPA-714 is a potent TSPO-specific ligand which found its use in Positron Emission Tomography following substitution of fluorine-19 with fluorine-18, a positron-emitting radionuclide. [¹⁸F]DPA-714 enables visualisation of inflammatory processes in vivo non-invasively. Radiolabelling of this tracer is well described in literature, including validation for clinical use. Here, we report significant enhancements to the process which resulted in the design of a fully GMP-compliant robust synthesis of [¹⁸F]DPA-714 on a popular cassette-based system, Trasis AllinOne, boosting reliability, throughput, and introducing a significant degree of simplicity. Results: [¹⁸F]DPA-714 was synthesised using the classic nucleophilic aliphatic substitution on a good leaving group, tosylate, with [¹⁸F]fluoride using tetraethylammonium bicarbonate in acetonitrile at 100^∘C. The process was fully automated on a Trasis AllinOne synthesiser using an in-house designed cassette and sequence. With a relatively small precursor load of 4 mg, [¹⁸F]DPA-714 was obtained with consistently high radiochemical yields of 55-71% (n=6) and molar activities of 117-350 GBq/µmol at end of synthesis. With a single production batch, starting with 31-42 GBq of [¹⁸F]fluoride, between 13-20 GBq of the tracer can be produced, enabling multi-centre studies. Conclusion: To the best of our knowledge, the process presented herein is the most efficient [¹⁸F]DPA-714 synthesis, with advantageous GMP compliance. The use of a Trasis AllinOne synthesiser increases reliability and allows rapid training of production staff.