Current Aspects of Radiopharmaceutical Chemistry

Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are in vivo molecular imaging techniques which are widely used in nuclear medicine for the diagnosis and treatment follow-up of many major diseases. They use biomolecules as probes, which are labeled with radionuclides of short half-lives, synthesized prior to the imaging studies. These probes are called radiopharmaceuticals. Their design and development require a rather interdisciplinary process involving many different disciplines of natural and health sciences. In addition to their diagnostic and therapeutic purposes in the field of nuclear medicine, radiopharmaceuticals provide powerful tools for in vivo pharmacology during the process of pre-clinical drug development to identify new drug targets, investigate the pathophysiology of diseases, discover potential drug candidates, and evaluate the pharmacokinetics and pharmacodynamics of drugs in vivo. Furthermore, they allow molecular imaging studies in various small-animal models of disease, including genetically engineered animals. The current collection of articles provides unique examples covering all major aspects in the field

An investigation of the surface finishing action and resulting surfaces produced by the Cascade Finishing process

This paper presents the results of a systematic study of the Cascade Finishing Process with respect to its ability to improve surface finish. Although mainly used to deburr and clean castings and machined parts, the process was able to greatly improve the surface finish under the right operating conditions. Six major topics were investigated: The nature of the surface finish produced, the significance and effects of runtime, vibratory frequency and fixture clearance, the effects of four different media types, the effects of surface orientation, the effects of different initial surface finishes, and the integrity of the surfaces produced, including residual stresses and micro-hardness;Using abrasive media the vibratory action produced directional, matte surfaces with Ra values as fine as.27[mu]m Ra. Surfaces perpendicular to the vibratory motion were found to have undergone a peening action with surfaces having initial roughnesses of 6.7[mu]m Ra being smoothed to 1.5[mu]m under the proper operating conditions. Many profile tracings and micro-photographs of the surfaces produced by the process are included in this paper. Almen strip tests indicate that the peening action observed is less intense than standard shot peening. Run time, vibratory frequency, media type, initial surface roughness and surface orientation were all found to be major factors governing the process. Empirical models and main effect plots resulting from the experiments are also included

Application of Fourier Analysis of Cerebral Glucose Metabolism in Color-Induced Long-Term Potentiation: A Novel Functional PET Spectroscopy (<em>f</em>PETS) Study in Mice

Fourier time-series analysis could be used to segregate changes in the ventral and dorsal streams of the visual system in male and female mice. Color memory processes of long-term potentiation and long-term depression could be identified through spectral analysis. We used small animal positron emission tomography and magnetic resonance imaging (PET/MRI) to measure the accumulation of [18F]fluorodeoxyglucose ([18F]FDG) in the mouse brain during light stimulation with blue and yellow filters compared to darkness condition. The mean standardized uptake values (SUV) of [18F]FDG for each stimulus condition was analyzed using standard Fourier analysis software to derive spectral density estimates for each condition. Spectral peaks were identified as originating from the subcortical region (S-peak) by subcortical long-term potentiation (SLTP) or depression (SLTD), and originating from the cortical region (C-peak) by cortical long-term potentiation (CLTP) or depression (CLTD). Luminance opponency occurred at S-peak by SLTP in the dorsal stream in the left visual cortex in male mice. On the other hand, chromatic opponency occurred by wavelength-differencing at C-peak by CLTP in the cortico-subcortical pathways in the ventral stream in the left visual cortex in male mice. In contrast in female mice, during luminance processing, there was resonance phenomenon at C-peak in the ventral stream in the right visual cortex. Chromatic opponency occurred at S-peak by SLTP in the dorsal stream in the right visual cortex in female mice. Application of Fourier analysis improved spatial and temporal resolutions of conventional fPET/MRI methods. Computation of color processing as a conscious experience has wide range applications in neuroscience and artificial intelligence

Coerced Mechanical Coarsening of Nanoparticle Assemblies

Coarsening is a ubiquitous phenomenon [1-3] that underpins countless processes in nature, including epitaxial growth [1,3,4], the phase separation of alloys, polymers and binary fluids [2], the growth of bubbles in foams5, and pattern formation in biomembranes6. Here we show, in the first real-time experimental study of the evolution of an adsorbed colloidal nanoparticle array, that tapping-mode atomic force microscopy (TM-AFM) can drive the coarsening of Au nanoparticle assemblies on silicon surfaces. Although the growth exponent has a strong dependence on the initial sample morphology, our observations are largely consistent with modified Ostwald ripening processes [7-9]. To date, ripening processes have been exclusively considered to be thermally activated, but we show that nanoparticle assemblies can be mechanically coerced towards equilibrium, representing a new approach to directed coarsening. This strategy enables precise control over the evolution of micro- and nanostructures

The Interplay Between Natural and Accidental Supersymmetry

In this thesis, we will explore the subject of the little hierarchy problem which plagues solutions to the big hierarchy problem of the Standard Model of particle physics. In the first half of this thesis, we study the theoretical framework for a supersymmetric resolution of the little hierarchy problem, known as natural supersymmetry, and argue that regions of the parameter space of this model have been missed by search strategies employed at the large hadron collider, but could be searched for with new search strategies. In the second half of this thesis, we explore the possibility of embedding natural supersymmetry in models of warped extra dimensions in order to UV-complete them by utilizing a mechanism known as accidental supersymmetry. We study the mechanism of accidental supersymmetry in the Randall-Sundrum framework by focusing on a toy model, and argue that accidental supersymmetry is capable solving the little hierarchy problem in that toy model. Finally, as models in the Randall-Sundrum framework themselves require UV completions, we demonstrate that it is possible to realize the mechanism of accidental supersymmetry within the UV-complete framework of type IIB superstring theory

Synthesis and In Vitro Evaluation of 8-Pyridinyl-Substituted Benzo[e]imidazo[2,1-c][1,2,4]triazines as Phosphodiesterase 2A Inhibitors

Phosphodiesterase 2A (PDE2A) is highly expressed in distinct areas of the brain, which are known to be related to neuropsychiatric diseases. The development of suitable PDE2A tracers for Positron Emission Tomography (PET) would permit the in vivo imaging of the PDE2A and evaluation of disease-mediated alterations of its expression. A series of novel fluorinated PDE2A inhibitors on the basis of a Benzoimidazotriazine (BIT) scaffold was prepared leading to a prospective inhibitor for further development of a PDE2A PET imaging agent. BIT derivatives (BIT1–9) were obtained by a seven-step synthesis route, and their inhibitory potency towards PDE2A and selectivity over other PDEs were evaluated. BIT1 demonstrated much higher inhibition than other BIT derivatives (82.9% inhibition of PDE2A at 10 nM). BIT1 displayed an IC50 for PDE2A of 3.33 nM with 16-fold selectivity over PDE10A. This finding revealed that a derivative bearing both a 2-fluoro-pyridin-4-yl and 2-chloro-5-methoxy-phenyl unit at the 8- and 1-position, respectively, appeared to be the most potent inhibitor. In vitro studies of BIT1 using mouse liver microsomes (MLM) disclosed BIT1 as a suitable ligand for 18F-labeling. Nevertheless, future in vivo metabolism studies are required

Newly Synthesized Fluorinated Cinnamylpiperazines Possessing Low In Vitro MAO-B Binding

Herein, we report on the synthesis and pharmacological evaluation of ten novel fluorinated cinnamylpiperazines as potential monoamine oxidase B (MAO-B) ligands. The designed derivatives consist of either cinnamyl or 2-fluorocinnamyl moieties connected to 2-fluoropyridylpiperazines. The three-step synthesis starting from commercially available piperazine afforded the final products in overall yields between 9% and 29%. An in vitro competitive binding assay using l-[3H]Deprenyl as radioligand was developed and the MAO-B binding affinities of the synthesized derivatives were assessed. Docking studies revealed that the compounds 8–17 were stabilized in both MAO-B entrance and substrate cavities, thus resembling the binding pose of l-Deprenyl. Although our results revealed that the novel fluorinated cinnamylpiperazines 8–17 do not possess sufficient MAO-B binding affinity to be eligible as positron emission tomography (PET) agents, the herein developed binding assay and the insights gained within our docking studies will certainly pave the way for further development of MAO-B ligands

Validation of an LC-MS/MS Method to Quantify the New TRPC6 Inhibitor SH045 (Larixyl N-methylcarbamate) and Its Application in an Exploratory Pharmacokinetic Study in Mice

TRPC6 (transient receptor potential cation channels; canonical subfamily C, member 6) is widespread localized in mammalian tissues like kidney and lung and associated with progressive proteinuria and pathophysiological pulmonary alterations, e.g., reperfusion edema or lung fibrosis. However, the understanding of TRPC6 channelopathies is still at the beginning stages. Recently, by chemical diversification of (+)-larixol originating from Larix decidua resin traditionally used for inhalation, its methylcarbamate congener, named SH045, was obtained and identified in functional assays as a highly potent, subtype-selective inhibitor of TRPC6. To pave the way for use of SH045 in animal disease models, this study aimed at developing a capable bioanalytical method and to provide exploratory pharmacokinetic data for this promising derivative. According to international guidelines, a robust and selective LC-MS/MS method based on MRM detection in positive ion mode was established and validated for quantification of SH045 in mice plasma, whereby linearity and accuracy were demonstrated for the range of 2–1600 ng/mL. Applying this method, the plasma concentration time course of SH045 following single intraperitoneal administration (20 mg/kg body weight) revealed a short half-life of 1.3 h. However, the pharmacological profile of SH045 is promising, as five hours after administration, plasma levels still remained sufficiently higher than published low nanomolar IC50 values. Summarizing, the LC-MS/MS method and exploratory pharmacokinetic data provide essential prerequisites for experimental pharmacological TRPC6 modulation and translational treatment of TRPC6 channelopathies