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Fluorine-18 is the predominant radionuclide used to label Positron Emission Tomography (PET) tracers. One outstanding challenge in nucleophilic aromatic radiofluorination reactions is the sensitivity of precursors and catalysts for basic reaction conditions, which are necessary for the work-up of [ 18 F]fluoride, resulting in limited reproducibility. Triflyl [ 18 F]fluoride is a new [ 18 F]fluoride source that allows freedom in choice of type and amounts of base and cryptand. The aim of the current work is to explore the scope and limitations of triflyl [ 18 F]fluoride in the late-stage nucleophilic aromatic 18 F-fluorination of various functionalized precursors, exploring reduced amounts of base and cryptand. The assessment allowed for the application of this new nucleophilic [ 18 F]fluoride reagent to the successful radiosynthesis of boron, stannane, hypervalent iodonium ylide and phenol substrates bearing electron-deficient, -neutral and -rich functional groups as well as the clinically relevant PET tracers [ 18 F]FPEB, [ 18 F]mFBG and [ 18 F]SynVesT-1., (© 2024 The Author(s). Chemistry - A European Journal published by Wiley-VCH GmbH.)

The increasing exposure to nanoplastics (NPs) raises significant concerns for human health, primarily due to their potential bioaccumulative properties. While NPs have recently been detected in human blood, their interactions with specific immune cell subtypes and their impact on immune regulation remain unclear. In this proof-of-concept study, model palladium-doped polystyrene NPs (PS-Pd NPs) are utilized to enable single-cell mass cytometry (CyTOF) detection. The size-dependent impact of carboxylate polystyrene NPs (50-200 nm) is investigated across 15 primary immune cell subpopulations using CyTOF. By taking advantage of Pd-doping for detecting PS-Pd NPs, this work evaluates their impact on human immune-cells at the single-cell level following blood exposure. This work traces PS-Pd NPs in 37 primary immune-cell subpopulations from human blood, quantifying the palladium atom count per cell by CyTOF while simultaneously assessing the impact of PS-Pd NPs on cell viability, functionality, and uptake. These results demonstrate that NPs can interact with, interfere with, and translocate into several immune cell subpopulations after exposure. In vivo distribution experiments in mice further confirmed their accumulation in immune cells within the liver, blood, and spleen, particularly in monocytes, macrophages, and dendritic cells. These findings provide valuable insights into the impact of NPs on human health., (© 2024 The Author(s). Advanced Materials published by Wiley‐VCH GmbH.)

A set of 211 At-astatoarenes were synthesized from corresponding trimethylgermyl arenes with an average radiochemical conversion (RCC) of ca. 50 % for electron-rich and approx. 70 % in case of electron-deficient arenes. Both electron rich and electron poor substrates were successfully radiolabeled at room temperature (RT) using relatively low precursor amounts (0.15 μmol/0.02 mL solvent (7.5 mM)). Ready access to ortho-, para- and meta- astatinated arenes was achievable. Optimized reaction conditions were successfully applied to label a poly (ADP-ribose) polymerase (PARP) inhibitor with a RCC of approx. 50 %. We believe that trimethylgermyl derivatives are a viable addition to the astatination precursor toolbox and facilitate astatination of arenes. The developed labeling method should easily be applicable for productions under good manufacturing practice (GMP)., (© 2024 The Authors. ChemPlusChem published by Wiley-VCH GmbH.)

The human microbiome significantly influences drug metabolism through the gut-liver axis, leading to modified drug responses and potential toxicity. Due to the complex nature of the human gut environment, the understanding of microbiome-driven impacts on these processes is limited. To address this, a multiorgan-on-a-chip (MOoC) platform that combines the human microbial-crosstalk (HuMiX) gut-on-chip (GoC) and the Dynamic42 liver-on-chip (LoC), mimicking the bidirectional interconnection between the gut and liver known as the gut-liver axis, is introduced. This platform supports the viability and functionality of intestinal and liver cells. In a proof-of-concept study, the metabolism of irinotecan, a widely used colorectal cancer drug, is imitated within the MOoC. Utilizing liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), irinotecan metabolites are tracked, confirming the platform's ability to represent drug metabolism along the gut-liver axis. Further, using the authors' gut-liver platform, it is shown that the colorectal cancer-associated gut bacterium, Escherichia coli, modifies irinotecan metabolism through the transformation of its inactive metabolite SN-38G into its toxic metabolite SN-38. This platform serves as a robust tool for investigating the intricate interplay between gut microbes and pharmaceuticals, offering a representative alternative to animal models and providing novel drug development strategies., (© 2024 The Authors. Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

Positron emission tomography (PET) is becoming increasingly important in nuclear medicine and drug discovery. To date, the development of many potential PET tracers is hampered by the lack of suitable synthetic pathways for their preparation. This is particularly true for the highly desired radiolabeling of compounds bearing [ 18 F]CF 3 -groups. For instance, S(O) n CF 3 -groups (n=0, 1, 2) serve as structural motif in a range of biologically active compounds, but their radiosynthesis remains largely unprecedented (for n=1, 2). Herein, we describe general methods for the radiosynthesis of 18 F-labeled aryl trifluoromethyl sulfones, -sulfoxides, and -sulfides. All three methods are operationally straightforward, start from widely available precursors, i.e., sulfonyl fluorides and thiophenols, and make use of the recently established [ 18 F]Ruppert-Prakash reagent. Further, the syntheses display good functional group tolerance as demonstrated by the 18 F-labeling of more than 40 compounds. The applicability of the new method is demonstrated by the radiolabeling of three bioactive molecules, optionally to be used as PET tracers. In a broader context, this work presents a substantial expansion of the chemical space of radiofluorinated structural motifs to be used for the development of new PET tracers., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

α,β-aromatic lactams are highly abundant in biologically active molecules, yet so far they cannot be radiolabeled with short-lived (t 1/2 =20.3 min), β + -decaying carbon-11, which has prevented their application as positron emission tomography tracers. Herein, we developed, optimized, and applied a widely applicable, one-pot, quick, robust and automatable radiolabeling method for α,β-aromatic lactams starting from [ 11 C]CO 2 using the reagent POCl 3 ⋅AlCl 3 . This method proceeds via intramolecular Friedel-Crafts acylation of in situ formed [ 11 C]isocyanates and shows a broad substrate scope for the formation of five- and six-membered rings. We implemented our developed labeling method for the radiosynthesis of the potential PARP1 PET tracer [carbonyl- 11 C]DPQ in a clinical radiotracer production facility following the standards of the European Pharmacopoeia., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

We report the development of BioPhysical and Active Learning Screening (BioPALS); a rapid and versatile hit identification protocol combining AI-powered virtual screening with a GCI-driven biophysical confirmation workflow. Its application to the BRPF1b bromodomain afforded a range of novel micromolar binders with favorable ADMET properties. In addition to the excellent in silico/in vitro confirmation rate demonstrated with BRPF1b, binding kinetics were determined, and binding topologies predicted for all hits. BioPALS is a lean, data-rich, and standardized approach to hit identification applicable to a wide range of biological targets., (© 2024 Wiley‐VCH GmbH.)

Fluorine-18 ( 18 F) is the most favorable positron emitter for radiolabeling Positron Emission Tomography (PET) probes. However, conventional 18 F labeling through covalent C-F bond formation is challenging, involving multiple steps and stringent conditions unsuitable for sensitive biomolecular probes whose integrity may be altered. Over the past decade, an elegant new approach has been developed involving the coordination of an aluminum fluoride {Al 18 F} species in aqueous media at a late-stage of the synthetic process. The objective of this study was to implement this method and to optimize radiolabeling efficiency using a Design of Experiments (DoE). To assess the impact of various experimental parameters on {Al 18 F} incorporation, a pentadentate chelating agent NODA-MP-C4 was prepared as a model compound. This model carried a thiourea function present in the final conjugates resulting from the grafting of the chelating agent onto the probe. The formation of the radioactive complex Al 18 F-NODA-MP-C4 was studied to achieve the highest radiochemical conversion. A complementary "cold" series study using the natural isotope 19 F was also conducted to guide the radiochemical operating conditions. Ultimately, Al 18 F-NODA-MP-C4 was obtained with a reproducible and satisfactory radiochemical conversion of 79±3.5 % (n=5)., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

We report a general method for the labeling of both CF 3 and CF 2 H groups in a broad range of chemical settings (aryl, oxide, sulfide). The method utilizes frustrated Lewis pair mediated selective C-F activation to formally substitute fluorine-19 with fluorine-18 in a two-step defluorination/radiofluorination process, and as such can utilize the target compounds as starting materials. The radiotracer precursors can be isolated as stable salts prior to radiofluorination. The method delivers good radiochemical yields and molar activities (up to 35.2±6.5 % non-decay corrected isolated activity yields and 12.0±1.7 GBq μmol -1 molar activities) and is shown to be applicable to biologically relevant compounds. The ability to utilize the target compound as the starting material and the synthetic simplicity of the method coupled with the ever-increasing use of CF 3 and CF 2 H groups in pharmaceuticals makes this method attractive for drug and radiotracer development., (© 2022 Wiley-VCH GmbH.)

Excising epileptic foci (EF) is the most efficient approach for treating drug-resistant epilepsy (DRE). However, owing to the vast heterogeneity of epilepsies, EF in one-third of patients cannot be accurately located, even after exhausting all current diagnostic strategies. Therefore, identifying biomarkers that truly represent the status of epilepsy and fabricating probes with high targeting specificity are prerequisites for identifying the "concealed" EF. However, no systematic summary of this topic has been published. Herein, the potential biomarkers of EF are first summarized and classified into three categories: functional, molecular, and structural aberrances during epileptogenesis, a procedure of nonepileptic brain biasing toward epileptic tissue. The materials used to fabricate these imaging probes and their performance in defining the EF in preclinical and clinical studies are highlighted. Finally, perspectives for developing the next generation of probes and their challenges in clinical translation are discussed. In general, this review can be helpful in guiding the development of imaging probes defining EF with improved accuracy and holds promise for increasing the number of DRE patients who are eligible for surgical intervention., (© 2022 Wiley-VCH GmbH.)

In order to accommodate the growing demand for positron emission tomography (PET), it will be necessary to create innovative radiochemical and engineering technologies to optimize the manufacture and development of PET probes. Microfluidic devices allow radiosynthesis to be performed in microscale amounts, significantly impacting PET tracer production. Compared to traditional methods, microfluidic devices can produce PET tracers in a shorter time, higher yields, with lower reagent consumption, higher molar activity, and faster purification. This review examines microfluidic devices from an engineering perspective. Recently developed microfluidic radiosynthesis devices are classified into three categories according to their reaction volume: continuous-flow, batch-flow, and droplet-based microreactors. The principles of device architecture, radiosynthesis process, and the relative strengths and limitations of each category are emphasized by citing typical examples. Finally, the possible future applications of this technology are outlined. A flexible, miniature, fully automated radiochemical microfluidic platform will offer more straightforward and cheaper molecular imaging procedures and the potential for precision medicine that could allow operators to create customized tracers for individual patient doses., (© 2022 Wiley-VCH GmbH.)

Functionalization of macromolecules (antibodies, polymers, nanoparticles) with click-reactive groups greatly enhances the versatility of their potential applications. Click chemistry based on tetrazine - trans-cyclooctene (TCO) ligation is especially promising and is already widely applied for pretargeted imaging and therapy. Indirect radiolabeling of TCO-functionalized macromolecules with substoichiometric amounts of radioactive tetrazines is a convenient way to monitor the fate of those macromolecules by means of positron emission tomography (PET) imaging after their administration into the test subject. In this work, the preparation is reported of TCO-containing graft copolymers, namely PeptoBrushes (polyglutamic acid-graft-polysarcosine), novel [ 11 C]carboxylated tetrazines, and their combined use in radiolabeling the polymer by inverse electron demand Diels Alder reaction, to investigate it is potential for an application in pretarget imaging or injectable brachytherapy. The procedure for [ 11 C]tetrazine production is easy and scalable, while indirect TCO-PeptoBrushes labeling with these [ 11 C]tetrazines is mild, fast, and quantitative. This strategy allows facile 11 C-labeling of diverse TCO-functionalized macromolecules, so that their localization and distribution shortly after injection can be assessed by PET., (© 2021 The Authors. Macromolecular Rapid Communications published by Wiley-VCH GmbH.)

Nuclear medicine is defined as the use of radionuclides for diagnostic and therapeutic applications. The imaging modalities positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are based on γ-emissions of specific energies. The therapeutic technologies are based on β - -particle-, α-particle-, and Auger electron emitters. In oncology, PET and SPECT are used to detect cancer lesions, to determine dosimetry, and to monitor therapy effectiveness. In contrast, radiotherapy is designed to irreparably damage tumor cells in order to eradicate or control the disease's progression. Radiometals are being explored for the development of diagnostic and therapeutic radiopharmaceuticals. Strategies that combine both modalities (diagnostic and therapeutic), referred to as theranostics, are promising candidates for clinical applications. This review provides an overview of the basic concepts behind therapeutic and diagnostic radiopharmaceuticals and their significance in contemporary oncology. Select radiometals that significantly impact current and upcoming cancer treatment strategies are grouped as clinically suitable theranostics pairs. The most important physical and chemical properties are discussed. Standard production methods and current radionuclide availability are provided to indicate whether a cost-efficient use in a clinical routine is feasible. Recent preclinical and clinical developments and outline perspectives for the radiometals are highlighted in each section., (© 2021 Wiley-VCH GmbH.)

Aliphatic fluorine-18 radiolabeling is the most commonly used method to synthesize tracers for PET-imaging. With an increasing demand for 18 F-radiotracers for clinical applications, new labeling strategies aiming to increase radiochemical yields of established tracers or, more importantly, to enable 18 F-labeling of new scaffolds have been developed. In recent years, increased attention has been focused on the direct aliphatic 18 F-fluorination of base-sensitive substrates in this respect. This minireview gives a concise overview of the recent advances within this field and aims to highlight the advantages and limitations of these methods., (© 2021 Wiley-VCH GmbH.)

Structural analysis of modern pharmaceutical practices allows for the identification of two rapidly growing trends: the introduction of tailor-made amino acids and the exploitation of fluorinated motifs. Curiously, the former represents one of the most ubiquitous classes of naturally occurring compounds, whereas the latter is the most xenobiotic and comprised virtually entirely of man-made derivatives. Herein, 39 selected compounds, featuring both of these traits in the same molecule, are profiled. The total synthesis, source of the corresponding amino acids and fluorinated residues, and medicinal chemistry aspects and biological properties of the molecules are discussed., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The downsides of conventional cancer monotherapies are profound and enormously consequential, as drug-resistant cancer cells and cancer stem cells (CSC) are typically not eliminated. Here, a targeted theranostic nano vehicle (TTNV) is designed using manganese-doped mesoporous silica nanoparticle with an ideal surface area and pore volume for co-loading an optimized ratio of antineoplastic doxorubicin and a drug efflux inhibitor tariquidar. This strategically framed TTNV is chemically conjugated with folic acid and hyaluronic acid as a dual-targeting entity to promote folate receptor (FR) mediated cancer cells and CD44 mediated CSC uptake, respectively. Interestingly, surface-enhanced Raman spectroscopy is exploited to evaluate the molecular changes associated with therapeutic progression. Tumor microenvironment selective biodegradation and immunostimulatory potential of the MSN-Mn core are safeguarded with a chitosan coating which modulates the premature cargo release and accords biocompatibility. The superior antitumor response in FR-positive syngeneic and CSC-rich human xenograft murine models is associated with a tumor-targeted biodistribution, favorable pharmacokinetics, and an appealing bioelimination pattern of the TTNV with no palpable signs of toxicity. This dual drug-loaded nano vehicle offers a feasible approach for efficient cancer therapy by on demand cargo release in order to execute complete wipe-out of tumor reinitiating cancer stem cells., (© 2020 Wiley-VCH GmbH.)