Direct Cu-mediated aromatic 18F-labeling of highly reactive tetrazines for pretargeted bioorthogonal PET imaging

Pretargeted imaging can be used to visualize and quantify slow-accumulating targeting vectors with short-lived radionuclides such as fluorine-18 – the most popular clinically applied Positron Emission Tomography (PET) radionuclide. Pretargeting results in higher target-to-background ratios compared to conventional imaging approaches using long-lived radionuclides. Currently, the tetrazine ligation is the most popular bioorthogonal reaction for pretargeted imaging, but a direct ¹⁸F-labeling strategy for highly reactive tetrazines, which would be highly beneficial if not essential for clinical translation, has thus far not been reported. In this work, a simple, scalable and reliable direct ¹⁸F-labeling procedure has been developed. We initially studied the applicability of different leaving groups and labeling methods to develop this procedure. The copper-mediated ¹⁸F-labeling exploiting stannane precursors showed the most promising results. This approach was then successfully applied to a set of tetrazines, including highly reactive H-tetrazines, suitable for pretargeted PET imaging. The labeling succeeded in radiochemical yields (RCYs) of up to approx. 25%. The new procedure was then applied to develop a pretargeting tetrazine-based imaging agent. The tracer was synthesized in a satisfactory RCY of ca. 10%, with a molar activity of 134 ± 22 GBq μmol⁻¹ and a radiochemical purity of >99%. Further evaluation showed that the tracer displayed favorable characteristics (target-to-background ratios and clearance) that may qualify it for future clinical translation.

A simple, scalable and reliable direct ¹⁸F-labeling procedure has been developed and applied to obtain a pretargeting tetrazine-based imaging agent with favorable in vivo characteristics.     

The flow over a thin airfoil subjected to elevated levels of freestream turbulence at low Reynolds numbers

Micro Air Vehicles (MAVs) can be difficult to control in the outdoor environment as they fly at relatively low speeds and are of low mass, yet exposed to high levels of freestream turbulence present within the Atmospheric Boundary Layer. In order to examine transient flow phenomena, two turbulence conditions of nominally the same longitudinal integral length scale (Lxx/c?=?1) but with significantly different intensities (Ti?=?7.2?% and 12.3?%) were generated within a wind tunnel; time-varying surface pressure measurements, smoke flow visualization, and wake velocity measurements were made on a thin flat plate airfoil. Rapid changes in oncoming flow pitch angle resulted in the shear layer to separate from the leading edge of the airfoil even at lower geometric angles of attack. At higher geometric angles of attack, massive flow separation occurred at the leading edge followed by enhanced roll up of the shear layer. This lead to the formation of large Leading Edge Vortices (LEVs) that advected at a rate much lower than the mean flow speed while imparting high pressure fluctuations over the airfoil. The rate of LEV formation was dependent on the angle of attack until 10° and it was independent of the turbulence properties tested. The fluctuations in surface pressures and consequently aerodynamic loads were considerably limited on the airfoil bottom surface due to the favorable pressure gradient.     

Enantiomeric separation of citalopram analogues by HPLC using macrocyclic glycopeptide and cyclodextrin based chiral stationary phases

The enantiomeric separation of a novel series of twenty-eight racemic mixtures of citalopram analogues was performed by high performance liquid chromatography (HPLC). Due to the effectiveness of citalopram as an antidepressant drug, the development of new compounds based on its chemical structure is interesting, and their enantiomeric separation is needed to allow further pharmacokinetic studies. Several bonded cyclodextrin (both native and derivatized) and macrocyclic glycopeptide based chiral stationary phases (CSPs) were evaluated for their ability to separate this set of compounds via HPLC. Polar ionic, polar organic, and reversed phase modes were tested. Twenty-five of the racemic mixtures were separated with resolutions and enantiomeric selectivities up to 2.9 and 1.33, respectively. A total of eighteen baseline separations were achieved, while seven compounds were partially separated. Vancomycin based columns operated in the polar ionic mode resulted in the greatest number of separations. Lastly, the chromatographic behaviors of similar compounds were compared based on their chemical structure and also on the chiral selectors used.     

Investigation of Alien Wavelength Quality in Live Multi-Domain,Multi-Vendor Link Using Advanced Simulation Tool

Abstract

This article presents an advanced optical model for simulation of alien wavelengths in multi-domain and multi-vendor dense wavelength-division multiplexing networks. The model aids optical network planners with a better understanding of the non-linear effects present in dense wavelength-division multiplexing systems and better utilization of alien wavelengths in future applications. The limiting physical effects for alien wavelengths are investigated in relation to power levels, channel spacing, and other factors. The simulation results are verified through experimental setup in live multi-domain dense wavelength-division multiplexing systems between two national research networks: SURFnet in Holland and NORDUnet in Denmark.     

Ambient Schmittel cyclization promoted by chemoselective triazole-gold catalyst

The Schmittel cyclization was achieved at room temperature through triazole-gold (TA-Au) catalyzed propargyl vinyl ether rearrangement. Other tested [L-Au](+) catalysts gave complex reaction mixtures under identical conditions with no desired products observed. Importantly, because of the employment of mild conditions, sterically hindered groups (such as t-Bu) on allene termini were no longer required, which allowed successful synthesis of previously challenging substrates.     

A bis(heptafulvenyl)-dicyanoethylene thermoswitch with two sites for ring closure

Suitably functionalized vinylheptafulvenes (VHFs) act as thermoswitches undergoing ring closure to the corresponding dihydroazulenes (DHAs). Here we present the synthesis of a new such thermoswitch incorporating two heptafulvene rings on a dicyanoethylene unit. The synthetic protocol explores both the tropylium species as an electrophile and as a leaving group in the generation of the heptafulvene units. The thermally induced ring closure was enhanced as a result of two accessible sites for the reaction to occur.     

Electronic coherence within the semiclassical field-induced surface hopping method: strong field quantum control in K2

We demonstrate that the semiclassical field-induced surface hopping (FISH) method (Mitri?et al., Phys. Rev. A: At., Mol., Opt. Phys., 2009, 79, 053416.) accurately describes the selective coherent control of electronic state populations. With the example of the strong field control in the potassium dimer using phase-coherent double pulse sequences, we present a detailed comparison between FISH simulations and exact quantum dynamics. We show that for short pulses the variation of the time delay between the subpulses allows for a selective population of the desired final state with high efficiency. Furthermore, also for pulses of longer time duration, when substantial nuclear motion takes place during the action of the pulse, optimized pulse shapes can be obtained which lead to selective population transfer. For both types of pulses, the FISH method almost perfectly reproduces the exact quantum mechanical electronic population dynamics, fully taking account of the electronic coherence, and describes the leading features of the nuclear dynamics accurately. Due to the significantly higher computational efficiency of FISH as a trajectory-based method compared to full quantum dynamics simulations, this offers the possibility to theoretically investigate control experiments on realistic systems including all nuclear degrees of freedom.     

Facile formation of five-membered N-heterocyclic zirconacycloallenoids

The reaction of η(2)-iminozirconocene chloride complexes with trimethylsilylethynyl lithium leads to rapid C-C coupling at room temperature to yield the corresponding five-membered aza-zirconacycloallenoids. Such compounds were also obtained by trapping of in situ generated zirconocene with alkynyl imines.     

Particlization in hybrid models

In hybrid models, which combine hydrodynamical and transport approaches to describe different stages of heavy-ion collisions, conversion of fluid to individual particles, particlization, is a non-trivial technical problem. We describe in detail how to find the particlization hypersurface in a 3+1 dimensional model, and how to sample the particle distributions evaluated using the Cooper-Frye procedure to create an ensemble of particles as an initial state for the transport stage. We also discuss the role and magnitude of the negative contributions in the Cooper-Frye procedure.     

Liquid-phase microextraction in a microfluidic-chip – High enrichment and sample clean-up from small sample volumes based on three-phase extraction

In this work, a microfluidic-chip based system for liquid-phase microextraction (LPME-chip) was developed. Sample solutions were pumped into the LPME-chip with a micro-syringe pump at a flow rate of 3–4 μL min⁻¹. Inside the LPME chip, the sample was in direct contact with a supported liquid membrane (SLM) composed of 0.2 μL dodecyl acetate immobilized in the pores of a flat membrane of polypropylene (25 μm thickness). On the other side of the SLM, the acceptor phase was present. The acceptor phase was either pumped at 1 μL min⁻¹ during extraction or kept stagnant (stop-flow). Amitriptyline, methadone, haloperidol, loperamide, and pethidine were selected as model analytes, and they were extracted from alkaline sample solution, through the SLM, and into 10 mM HCl or 100 mM HCOOH functioning as acceptor phase. Subsequently, the acceptor phase was either analyzed off-line by capillary electrophoresis for exact quantification, or on-line by UV detection or electrospray ionization mass spectrometry for time profiling of concentrations. The LPME-chip was found to be highly effective, and extraction efficiencies were in the range of 52–91%. When the flow of acceptor phase was turned off during extraction (stop-flow), analyte enrichment increased linearly with the extraction time. After 10 min as an example, amitriptyline was enriched by a factor of 42 from only 30 μL sample solution, and after 120 min amitriptyline was enriched by a factor of 500 from 320 μL sample solution. This suggested that the LPME-chip has great potentials for very efficient analyte enrichments from limited sample volumes in the future.