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The importance of the sulfur-fluorine bond is starting to increase in modern medicinal chemistry literature. This is due to a better understanding of the stability and reactivity of this moiety depending on the various oxidation states of sulfur. Furthermore, several commercial reagents used for mild and selective fluorination of organic molecules are based on the known reactivity of S-F groups. In this review, we will show how these examples are translating into the 18 F field, both for use as stable tags in finished radiopharmaceuticals and as mildly reactive fluoride-relay intermediates. Finally, we also discuss current opportunities where examples of non-radioactive S-F applications/chemistry may be translated into future 18 F radiochemistry applications.

Docosahexaenoic acid (DHA, 22:6n‐3) is known to protect against a range of degenerative disease conditions and aid in the development of eye and brain function in infants. In dietary lipids DHA is found primarily in the triacylglycerol (TAG) form. However, the effects of the positional distribution of DHA in TAG on lipid functional properties such as bioactivity and oxidative stability are not clearly understood. Studies on this subject for the most part are limited by a lack of regioisomerically pure TAG model compounds containing DHA or similar long‐chain (LC)‐polyunsaturated fatty acids (PUFA). This paper reports on the development of a practical procedure, based on chemical and enzymatic reactions, for the syntheses of regioisomerically enriched, symmetrical and unsymmetrical TAG isomers containing two palmitic acid and one of linoleic acid, linolenic acid, or DHA. 1,3‐Selective acylation of glycerol with vinyl esters of fatty acids catalyzed by Candida antarctica lipase and direct coupling with fatty acids in the presence of the coupling agents 1‐(3‐dimethylaminopropyl)‐3‐ethylcarbodiimide hydrochloride and 4‐dimethylaminopyridine furnished 1,3‐dihexadecanoyl‐2‐docosahexaenoyl glycerol and its unsymmetrical isomer 1,2‐dihexadecanoyl‐3‐docosahexaenoyl glycerol in 99 and 60% yield, respectively. Critical to the success of the unsymmetrical TAG synthesis is the demonstration that PUFA‐containing glycerol acetonides can readily survive appropriately tailored acid‐catalyzed conditions. In this way, sufficient quantities of highly regioisomerically enriched PUFA‐containing unsymmetrical monoacylglycerols (MAG) and TAG have now become routinely accessible. The methods are amenable to scale‐up and could be adopted for regioenriched synthesis of a wide range of TAG.

Microfluidic techniques are increasingly being used to synthesize positron-emitting radiopharmaceuticals. Several reports demonstrate higher incorporation yields, with shorter reaction times and reduced amounts of reagents compared with traditional vessel-based techniques. Microfluidic techniques, therefore, have tremendous potential for allowing rapid and cost- effective optimization of new radiotracers. This protocol describes the implementation of a suitable microfluidic process to optimize classical [sup.18]F radiofluorination reactions by rationalizing the time and reagents used. Reaction optimization varies depending on the systems used, and it typically involves 5-10 experimental days of up to 4 h of sample collection and analysis. In particular, the protocol allows optimization of the key fluidic parameters in the first tier of experiments: reaction temperature, residence time and reagent ratio. Other parameters, such as solvent, activating agent and precursor concentration need to be stated before the experimental runs. Once the optimal set of parameters is found, repeatability and scalability are also tested in the second tier of experiments. This protocol allows the standardization of a microfluidic methodology that could be applied in any radiochemistry laboratory, in order to enable rapid and efficient radiosynthesis of new and existing [[sup.18]F]-radiotracers. Here we show how this method can be applied to the radiofluorination optimization of [[sup.18]F]-MEL050, a melanoma tumor imaging agent. This approach, if integrated into a good manufacturing practice (GMP) framework, could result in the reduction of materials and the time required to bring new radiotracers toward preclinical and clinical applications.

Purpose The first biological evaluation of two potent fluorine-18 radiolabelled inhibitors of caspase-3/7 was achieved in a cerebral stroke rat model to visualize apoptosis. Procedures In vivo characteristics of isatins [ 18 F]- 2 and [ 18 F]- 3 were studied and compared by μPET to previously described 1-[4-(2-[ 18 F]fluoroethyl)benzyl]-5-(2-methoxymethylpyrrolidin-1-ylsulfonyl)isatin ([ 18 F]- 1 ) and to 2-(5-[ 18 F]fluoropentyl)-2-methyl-malonic acid ([ 18 F]ML-10) used as a reference radiotracer in a rat stroke model. Results [ 18 F]- 2 and [ 18 F]- 3 were radiolabelled with high radiochemical purity and high specific radioactivity. Radioactivity uptakes in ischemic and contralateral brain regions were weak for the three radiolabelled isatins and lower for [ 18 F]ML-10. In μPET, time activity curves showed significant uptake differences between both regions of interest for [ 18 F]- 1 after 45 min. No differences were observed for [ 18 F]ML-10. Conclusions Radiolabelled isatins are more promising radiotracers to image apoptosis than [ 18 F]ML-10 in this stroke animal model without craniectomy. In particular, [ 18 F]- 1 presented significant uptake in apoptotic area 45 min after administration

A quick route towards new radiofluorinated tracers is important for the development of PET imaging. An efficient, reliable method for optimizing radiofluorination conditions using a microfluidic chemistry approach is described in this protocol. Microfluidic techniques are increasingly being used to synthesize positron-emitting radiopharmaceuticals. Several reports demonstrate higher incorporation yields, with shorter reaction times and reduced amounts of reagents compared with traditional vessel-based techniques. Microfluidic techniques, therefore, have tremendous potential for allowing rapid and cost-effective optimization of new radiotracers. This protocol describes the implementation of a suitable microfluidic process to optimize classical 18 F radiofluorination reactions by rationalizing the time and reagents used. Reaction optimization varies depending on the systems used, and it typically involves 5–10 experimental days of up to 4 h of sample collection and analysis. In particular, the protocol allows optimization of the key fluidic parameters in the first tier of experiments: reaction temperature, residence time and reagent ratio. Other parameters, such as solvent, activating agent and precursor concentration need to be stated before the experimental runs. Once the optimal set of parameters is found, repeatability and scalability are also tested in the second tier of experiments. This protocol allows the standardization of a microfluidic methodology that could be applied in any radiochemistry laboratory, in order to enable rapid and efficient radiosynthesis of new and existing [ 18 F]-radiotracers. Here we show how this method can be applied to the radiofluorination optimization of [ 18 F]-MEL050, a melanoma tumor imaging agent. This approach, if integrated into a good manufacturing practice (GMP) framework, could result in the reduction of materials and the time required to bring new radiotracers toward preclinical and clinical applications.

The first biological evaluation of two potent fluorine-18 radiolabelled inhibitors of caspase-3/7 was achieved in a cerebral stroke rat model to visualize apoptosis.PURPOSEThe first biological evaluation of two potent fluorine-18 radiolabelled inhibitors of caspase-3/7 was achieved in a cerebral stroke rat model to visualize apoptosis.In vivo characteristics of isatins [(18)F]-2 and [(18)F]-3 were studied and compared by μPET to previously described 1-[4-(2-[(18)F]fluoroethyl)benzyl]-5-(2-methoxymethylpyrrolidin-1-ylsulfonyl)isatin ([(18)F]-1) and to 2-(5-[(18)F]fluoropentyl)-2-methyl-malonic acid ([(18)F]ML-10) used as a reference radiotracer in a rat stroke model.PROCEDURESIn vivo characteristics of isatins [(18)F]-2 and [(18)F]-3 were studied and compared by μPET to previously described 1-[4-(2-[(18)F]fluoroethyl)benzyl]-5-(2-methoxymethylpyrrolidin-1-ylsulfonyl)isatin ([(18)F]-1) and to 2-(5-[(18)F]fluoropentyl)-2-methyl-malonic acid ([(18)F]ML-10) used as a reference radiotracer in a rat stroke model.[(18)F]-2 and [(18)F]-3 were radiolabelled with high radiochemical purity and high specific radioactivity. Radioactivity uptakes in ischemic and contralateral brain regions were weak for the three radiolabelled isatins and lower for [(18)F]ML-10. In μPET, time activity curves showed significant uptake differences between both regions of interest for [(18)F]-1 after 45 min. No differences were observed for [(18)F]ML-10.RESULTS[(18)F]-2 and [(18)F]-3 were radiolabelled with high radiochemical purity and high specific radioactivity. Radioactivity uptakes in ischemic and contralateral brain regions were weak for the three radiolabelled isatins and lower for [(18)F]ML-10. In μPET, time activity curves showed significant uptake differences between both regions of interest for [(18)F]-1 after 45 min. No differences were observed for [(18)F]ML-10.Radiolabelled isatins are more promising radiotracers to image apoptosis than [(18)F]ML-10 in this stroke animal model without craniectomy. In particular, [(18)F]-1 presented significant uptake in apoptotic area 45 min after administration.CONCLUSIONSRadiolabelled isatins are more promising radiotracers to image apoptosis than [(18)F]ML-10 in this stroke animal model without craniectomy. In particular, [(18)F]-1 presented significant uptake in apoptotic area 45 min after administration.

Purpose: Neutron Capture Enhanced Particle Therapy (NCEPT) is a proposed augmentation of charged particle therapy which exploits thermal neutrons generated internally, within the treatment volume via nuclear fragmentation, to deliver a biochemically targeted radiation dose to cancer cells. This work is the first experimental demonstration of NCEPT, performed using both carbon and helium ion beams with two different targeted neutron capture agents (NCAs). Materials and Methods: Human glioblastoma cells (T98G) were irradiated by carbon and helium ion beams in the presence of NCAs, [10B]-BPA and [157Gd]-DOTA-TPP. Cells were positioned within a PMMA phantom either laterally adjacent to, or within, a 100 × 100 × 60 mm spread out Bragg peak (SOBP). The impact of NCAs and location relative to the SOBP on the cells was measured by cell growth and survival assays in six independent experiments. Neutron fluence within the phantom was characterised by quantifying the neutron activation of gold foil. Results: Cells placed inside the treatment volume reached 10% survival by 2 Gy of C or 2-3 Gy of He in the presence of NCAs compared to 5 Gy of C and 7 Gy of He with no NCA. Cells placed adjacent to the treatment volume showed a dose-dependent decrease in cell growth when treated with NCAs, reaching 10% survival by 6 Gy of C or He (to the treatment volume), compared to a no detectable effect on cells without NCA. The mean thermal neutron fluence at the centre of the SOBP was approximately 2.2 × 109 n/cm2/Gy(RBE) for the carbon beam and 5.8 × 109 n/cm2/Gy(RBE) for the helium beam and gradually decreased in all directions. Conclusions: The addition of NCAs to cancer cells during C and He beam irradiation has a measurable impact on cell survival and growth in-vitro. Through the capture of internally generated neutrons, NCEPT introduces the concept of a biochemically targeted radiation dose to charged particle therapy. NCEPT enables the established pharmaceuticals and concepts of neutron capture therapy to be applied to a wider range of deeply situated and diffuse tumours, by targeting this dose to micro-infiltrates and cells outside of defined treatment regions. These results also demonstrate the potential for NCEPT to provide an increased dose to tumour tissue within the treatment volume, with a reduction in radiation doses to off target tissue.Competing Interest StatementThe authors have declared no competing interest.Footnotes* https://bitbucket.org/mitra_safavi/ncept-in-vitro-data/

Useful materials must satisfy multiple objectives, where the optimization of one objective is often at the expense of another. The Pareto front reports the optimal trade-offs between these conflicting objectives. Here we use a self-driving laboratory, Ada, to define the Pareto front of conductivities and processing temperatures for palladium films formed by combustion synthesis. Ada discovers new synthesis conditions that yield metallic films at lower processing temperatures (below 200 °C) relative to the prior art for this technique (250 °C). This temperature difference makes possible the coating of different commodity plastic materials (e.g., Nafion, polyethersulfone). These combustion synthesis conditions enable us to to spray coat uniform palladium films with moderate conductivity (1.1 × 10 5  S m −1 ) at 191 °C. Spray coating at 226 °C yields films with conductivities (2.0 × 10 6  S m −1 ) comparable to those of sputtered films (2.0 to 5.8 × 10 6  S m −1 ). This work shows how a self-driving laboratoy can discover materials that provide optimal trade-offs between conflicting objectives. Useful materials must satisfy multiple objectives. The Pareto front expresses the trade-offs of competing objectives. This work uses a self-driving laboratory to map out the Pareto front for making highly conductive coatings at low temperatures.

Moist convection is a physical process in planetary atmospheres where the latent heat released by condensation acts as a buoyancy source that can enhance or even trigger an overturning convective instability. Since the saturation temperature often decreases with height, condensation releases latent heat preferentially in regions of upflow. Due to this inhomogeneous heat source, moist convection may be more sensitive to changes in flow morphology, such as those induced by rotation, than dry Rayleigh–Bénard convection. In rotating systems, like Jupiter’s weather layer, the effects of rotation on moist convection may be significant. In order to study the effects of rotation on flows driven by latent heat release, we present a suite of numerical simulations that solve the Rainy–Bénard equations. We identify three morphological regimes: a cellular regime and a plume regime broadly analogous to those found in rotating Rayleigh–Bénard convection, and a novel funnel regime found at Rossby numbers appropriate for Jupiter’s weather layer that lacks a clear analog within the regimes exhibited by dry convection. We measure energy fluxes through the system and report rotational scalings of the Reynolds and moist Nusselt numbers. We find that moist static energy transport, as measured by a moist Nusselt number, is significantly enhanced in the funnel regime without a corresponding enhancement in Reynolds number, indicating that this funnel regime produces structures with more favorable correlations between the temperature and vertical velocity.

Polluted white dwarfs (WDs) with small surface convection zones deposit significant concentrations of heavy elements to the underlying radiative interior, presumably driving thermohaline convection. Current models of polluted WDs frequently fail to account for this effect, although its inclusion can increase the inferred accretion rate by orders of magnitude. It has been argued that this instability cannot be treated as a continuous mixing process and thus should not be considered in these models. In this work, we study 3D simulations of a thermohaline-unstable layer propagating into an underlying stable region, approximating the polluted WD scenario. We find that although thermohaline convection works to reduce driving gradients somewhat, the front continues to propagate and the system remains unstable. Importantly, the turbulent flux of metals broadly dominates over the diffusive flux in quantitative agreement with existing mixing prescriptions implemented in some stellar evolution models (except slightly below the boundary of the propagating front, where recent prescriptions neglect overshoot-like effects). Thus, our results broadly support polluted WD models that include thermohaline mixing in their estimates of the settling rate.