Fully automated radiosynthesis of [<Superscript>18</Superscript>F]Fluoromisonidazole with single neutral alumina column purification: optimization of reaction parameters

1-H-1-(3-[¹⁸F]fluoro-2-hydroxypropyl)-2-nitroimidazole ([¹⁸F]FMISO), is the most used hypoxia-imaging agent in oncology and we have recently reported a fully automated procedure for its synthesis using the Nuclear Interface FDG module and a single neutral alumina column for purification. Using 1-(2′-nitro-1′-imidazolyl)-2-O-tetra-hydropyranyl-3-O-toluenesulfonylpropanediol (NITTP) as the precursor, we have investigated the yield of [¹⁸F]FMISO using different reaction times, temperatures, and the amount of precursor. The overall yield was 48.4 ± 1.2% (n = 3), (without decay correction) obtained using 10 mg NITTP with the radio-fluorination carried out at 145 °C for 3 min followed by acid hydrolysis for 3 min at 125 °C in a total synthesis time of 32 ± 1 min. Increasing the precursor amount to 25 mg did not improve the overall yield under identical reaction conditions, with the decay uncorrected yield being 46.8 ± 1.6% (n = 3), but rather made the production less economical. It was also observed that the yield increased linearly with the amount of NITTP used, from 2.5 to 10 mg and plateaued from 10 to 25 mg. Radio-fluorination efficiency at four different conditions was also compared. It was also observed by radio thin layer chromatography (radio-TLC) that the duration of radio-fluorination of NITTP, not the radio-fluorination temperature favoured the formation of labeled thermally degraded product, but the single neutral alumina column purification was sufficient enough to obtain [¹⁸F]FMISO devoid of any radiochemical as well as cold impurities.     

Structure and Conformation of Individual Molecules upon Adsorption of a Mixture of Benzoporphyrins on Ag(111), Cu(111), and Cu(110) Surfaces

The front cover artwork is provided by the groups of Prof. Dr. Hans-Peter Steinrück and Prof. Dr. Norbert Jux at the Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg. The image shows a mixture of six 2H-tetrakis-(3, 5-di-tert-butyl-phenyl)(x)benzoporphyrins (2H-diTTBP(x)BPs, x = 0, 1, 2-cis, 2-trans, 3, or 4) molecules forming a porous square structure on Ag(111) as observed in scanning tunneling microscopy (STM) at room temperature. Read the full text of the Research Article at 10.1002/cphc.202300355 .     

Opportunities for Mercuric Ion Spectrophotometric Determination based on Reduction of Gold Nanoparticles Aggregation by N-containing Cyclic Molecules

Journal of Analytical Chemistry - Methods for the determination of mercury are described using gold nanoparticles functionalized with nitrogen containing cyclic molecules. Detection methods are...     

Eigenvalue spectra of random matrices for neural networks

The dynamics of neural networks is influenced strongly by the spectrum of eigenvalues of the matrix describing their synaptic connectivity. In large networks, elements of the synaptic connectivity matrix can be chosen randomly from appropriate distributions, making results from random matrix theory highly relevant. Unfortunately, classic results on the eigenvalue spectra of random matrices do not apply to synaptic connectivity matrices because of the constraint that individual neurons are either excitatory or inhibitory. Therefore, we compute eigenvalue spectra of large random matrices with excitatory and inhibitory columns drawn from distributions with different means and equal or different variances.     

The isomeric compounds nimbolide and isonimbolide

Nimbolide [systematic name: (4α,5α,6α,7α,15β,17α)‐7,15:21,23‐diepoxy‐6‐hydroxy‐4,8‐dimethyl‐1‐oxo‐18,24‐dinor‐11,12‐secochola‐2,13,20,22‐tetraene‐4,11‐dicarboxylic acid γ‐lactone methyl ester], C₂₇H₃₀O₇, was isolated from the leaves of Azadirachta indica, and its isomer, isonimbolide [systematic name: (4α,5α,6α,7α,15α)‐7,15:21,23‐diepoxy‐6‐hydroxy‐4,8‐dimethyl‐1‐oxo‐18,24‐dinor‐11,12‐secochola‐2,16,20,22‐tetra­ene‐4,11‐dicarboxylic acid γ‐lactone methyl ester], was prepared from a novel rearrangement reaction of nimbolide, using boron trifluoride etherate and tetra­butyl­ammonium bromide. The reaction conditions are probably responsible for the ether cleavage, double‐bond rearrangement and reformation of the ether linkage. As a result, there are conformational changes in two cyclo­pentane rings and the side‐chain –CH₂COOMe group. In isonimbolide, an (24) hydrogen‐bond motif is observed.     

Sensitivity of in-Plane Strain Measurement to Calibration Parameter for out-of-Plane Specimen Rotations

In practice, out-of-plane motions usually are not avoidable during experiments. Since 2D–DIC measurements are vulnerable to parasitic deformations due to out-of-plane specimen motions, three-dimensional digital image correlation (StereoDIC or 3D–DIC) oftentimes is employed. The StereoDIC method is known to be capable of accurate deformation measurements for specimens subjected to general three-dimensional motions, including out-of-plane rotations and displacements. As a result, there has been limited study of the deformation measurements obtained when using StereoDIC to measure the displacement and strain fields for a specimen subjected only to out-of-plane rotation. To assess the accuracy of strain measurements obtained using stereovision systems and StereoDIC when a specimen undergoes appreciable out of plane rotation, rigid body out-of-plane rotation experiments are performed in the range ?40⁰?≤?θ?≤?40⁰ using a two-camera stereovision system. Results indicate that (a) for what would normally be considered “small angle” calibration processes, the measured normal strain in the foreshortened specimen direction due to specimen rotation increases in a non-linear manner with rotation angle, with measurement errors exceeding ±1400με and (b) for what would normally be considered “large angle” calibration processes, the magnitude of the errors in the strain are reduced to ±300με. To theoretically assess the effect of calibration parameters on the measurements, two separate analyses are performed. First, theoretical strains due to out-of-plane rigid body rotation are determined using a pinhole camera model to project a series of three-dimensional object points into the image plane using large angle calibration parameters and then re-project the corresponding sensor plane coordinates back into the plane using small angle calibration parameters. Secondly, the entire imaging process is also simulated in order to remove experimental error sources and to further validate the theory. Results from both approaches confirmed the same strain error trends as the experimental strain measurements, providing confidence that the source of the errors is the calibration process. Finally, variance based sensitivity analyses show that inaccuracy in the calibrated stereo angle parameter is the most significant factor affecting the accuracy of the measured strain.     

Modal Analysis of a Servo-Hydraulic High Speed Machine and its Application to Dynamic Tensile Testing at an Intermediate Strain Rate

This paper describes the experimental procedure to identify the predominant frequencies of the high speed testing machine by conducting modal analysis. The effects due to the predominant frequencies of the system and loading rate on the magnitude of system ringing and the flow stress were analyzed by using a single degree-of-freedom (SDOF) spring-mass-damper model. The system was then used to study the dynamic tensile behavior of two engineering materials, i.e., polyethylene (PE) fabric-cement composite and Alkaline Resistant (AR) glass fabrics at an intermediate strain rate. The stress oscillations in the response of these materials due to system ringing were addressed. The failure behavior of each material was studied by examining high speed digital camera images of specimens during the test. The validity of the dynamic tensile tests was investigated by examining the condition of dynamic stress equilibrium—a criterion used in split Hopkinson pressure bar (SHPB) tests. The results show that the quantitative criterion for a valid SHPB test is also applicable to dynamic tensile tests of these materials at the intermediate strain rate.     

Directed evolution of cyclic peptides for inhibition of autophagy

In recent decades it has become increasingly clear that induction of autophagy plays an important role in the development of treatment resistance and dormancy in many cancer types. Unfortunately, chloroquine (CQ) and hydroxychloroquine (HCQ), two autophagy inhibitors in clinical trials, suffer from poor pharmacokinetics and high toxicity at therapeutic dosages. This has prompted intense interest in the development of targeted autophagy inhibitors to re-sensitize disease to treatment with minimal impact on normal tissue. We utilized Scanning Unnatural Protease Resistant (SUPR) mRNA display to develop macrocyclic peptides targeting the autophagy protein LC3. The resulting peptides bound LC3A and LC3B—two essential components of the autophagosome maturation machinery—with mid-nanomolar affinities and disrupted protein–protein interactions (PPIs) between LC3 and its binding partners in vitro. The most promising LC3-binding SUPR peptide accessed the cytosol at low micromolar concentrations as measured by chloroalkane penetration assay (CAPA) and inhibited starvation-mediated GFP-LC3 puncta formation in a concentration-dependent manner. LC3-binding SUPR peptides re-sensitized platinum-resistant ovarian cancer cells to cisplatin treatment and triggered accumulation of the adapter protein p62 suggesting decreased autophagic flux through successful disruption of LC3 PPIs in cell culture. In mouse models of metastatic ovarian cancer, treatment with LC3-binding SUPR peptides and carboplatin resulted in almost complete inhibition of tumor growth after four weeks of treatment. These results indicate that SUPR peptide mRNA display can be used to develop cell-penetrating macrocyclic peptides that target and disrupt the autophagic machinery in vitro and in vivo.

SUPR peptide mRNA display was used to evolve a cell-permeable, macrocyclic peptide for autophagy inhibition.