The Influence of Size on the Intracranial Distribution of Biomedical Nanoparticles Administered by Convection-enhanced Delivery in Minipigs.

Because of the blood-brain barrier (BBB), successful drug delivery to the brain has long been a key objective for the medical community, calling for pioneering technologies to overcome this challenge. Convection-enhanced delivery (CED), a form of direct intraparenchymal microinfusion, shows promise but requires optimal infusate design and real-time distribution monitoring. The size of the infused substances appears to be especially critical, with current knowledge being limited.

[F]Difluorocarbene for positron emission tomography.

The advent of total-body positron emission tomography (PET) has vastly broadened the range of research and clinical applications of this powerful molecular imaging technology. Such possibilities have accelerated progress in fluorine-18 (F) radiochemistry with numerous methods available to F-label (hetero)arenes and alkanes. However, access to F-difluoromethylated molecules in high molar activity is mostly an unsolved problem, despite the indispensability of the difluoromethyl group for pharmaceutical drug discovery.

multi-patient dose synthesis of [18F]Flumazenil via a copper-mediated F-fluorination.

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 (GABARs). Positron Emission Tomography (PET) imaging of the GABAARs with [C]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) of carbon-11 (20 min) has limited the more widespread clinical use of [C]FMZ.

Novel Bifunctional [16]aneS-Derived Chelators for Soft Radiometals.

The field of targeted radionuclide therapy is rapidly growing, highlighting the need for wider radionuclide availability. Soft Lewis acid ions, such as radioisotopes of platinum, rhodium and palladium, are particularly underdeveloped. This is due in part to a lack of compatible bifunctional chelators.

Late-stage difluoromethylation: concepts, developments and perspective.

This review describes the recent advances made in difluoromethylation processes based on X-CFH bond formation where X is C(sp), C(sp), C(sp), O, N or S, a field of research that has benefited from the invention of multiple difluoromethylation reagents. The last decade has witnessed an upsurge of metal-based methods that can transfer CFH to C(sp) sites both in stoichiometric and catalytic mode. Difluoromethylation of C(sp)-H bond has also been accomplished through Minisci-type radical chemistry, a strategy best applied to heteroaromatics.

Synthesis of Fluorinated Alkyl Aryl Ethers by Palladium-Catalyzed C-O Cross-Coupling.

Herein, we report a highly effective protocol for the cross-coupling of (hetero)aryl bromides with fluorinated alcohols using the commercially available precatalyst BuBrettPhos Pd G3 and CsCO in toluene. This Pd-catalyzed coupling features a short reaction time, excellent functional group tolerance, and compatibility with electron-rich and -poor (hetero)arenes. The method provides access to F-labeled trifluoroethyl ethers by cross-coupling with [F]trifluoroethanol.

Organophotoredox Hydrodefluorination of Trifluoromethylarenes with Translational Applicability to Drug Discovery.

Molecular editing such as insertion, deletion, and single atom exchange in highly functionalized compounds is an aspirational goal for all chemists. Here, we disclose a photoredox protocol for the replacement of a single fluorine atom with hydrogen in electron-deficient trifluoromethylarenes including complex drug molecules. A robustness screening experiment shows that this reductive defluorination tolerates a range of functional groups and heterocycles commonly found in bioactive molecules.

Synthesis of F-difluoromethylarenes using aryl boronic acids, ethyl bromofluoroacetate and [F]fluoride.

Herein, we report the radiosynthesis of F-difluoromethylarenes the assembly of three components, a boron reagent, ethyl bromofluoroacetate, and cyclotron-produced non-carrier added [F]fluoride. The two key steps are a copper-catalysed cross-coupling reaction, and a Mn-mediated F-fluorodecarboxylation.

Practical Photocatalytic Trifluoromethylation and Hydrotrifluoromethylation of Styrenes in Batch and Flow.

Styrenes represent a challenging class of substrates for current radical trifluoromethylation and hydrotrifluoromethylation methods due to a myriad of potential side reactions. Herein, we describe the development of mild, selective and broadly applicable photocatalytic trifluoromethylation and hydrotrifluoromethylation protocols for these challenging substrates. The methods use fac-Ir(ppy) , visible light and inexpensive CF I and can be applied to a diverse set of vinylarene substrates.

Applications of Continuous-Flow Photochemistry in Organic Synthesis, Material Science, and Water Treatment.

Continuous-flow photochemistry in microreactors receives a lot of attention from researchers in academia and industry as this technology provides reduced reaction times, higher selectivities, straightforward scalability, and the possibility to safely use hazardous intermediates and gaseous reactants. In this review, an up-to-date overview is given of photochemical transformations in continuous-flow reactors, including applications in organic synthesis, material science, and water treatment. In addition, the advantages of continuous-flow photochemistry are pointed out and a thorough comparison with batch processing is presented.

Accelerated gas-liquid visible light photoredox catalysis with continuous-flow photochemical microreactors.

In this protocol, we describe the construction and use of an operationally simple photochemical microreactor for gas-liquid photoredox catalysis using visible light. The general procedure includes details on how to set up the microreactor appropriately with inlets for gaseous reagents and organic starting materials, and it includes examples of how to use it to achieve continuous-flow preparation of disulfides or trifluoromethylated heterocycles and thiols. The reported photomicroreactors are modular, inexpensive and can be prepared rapidly from commercially available parts within 1 h even by nonspecialists.

Photochemical transformations accelerated in continuous-flow reactors: basic concepts and applications.

Continuous-flow photochemistry is used increasingly by researchers in academia and industry to facilitate photochemical processes and their subsequent scale-up. However, without detailed knowledge concerning the engineering aspects of photochemistry, it can be quite challenging to develop a suitable photochemical microreactor for a given reaction. In this review, we provide an up-to-date overview of both technological and chemical aspects associated with photochemical processes in microreactors.

Rapid trifluoromethylation and perfluoroalkylation of five-membered heterocycles by photoredox catalysis in continuous flow.

Trifluoromethylated and perfluoroalkylated heterocycles are important building blocks for the synthesis of numerous pharmaceutical products, agrochemicals and are widely applied in material sciences. To date, trifluoromethylated and perfluoroalkylated hetero-aromatic systems can be prepared utilizing visible light photoredox catalysis methodologies in batch. While several limitations are associated with these batch protocols, the application of microflow technology could greatly enhance and intensify these reactions.