28 research outputs found

    Suppression of Phase Transformation in Nb–H Thin Films below Switchover Thickness

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    Hydrogen uptake in metal–hydrogen (M–H) nanosized systems (e.g., thin films, clusters) is both a fundamental and a technologically relevant topic, which is becoming more important due to the recent developments of hydrogen sensors, purification membranes, and hydrogen storage solutions. It was recently shown that hydrogen (H) absorption in nanosized systems adhered to rigid substrates can lead to ultrahigh mechanical stress in the GPa range. About −10 GPa (compressive) stress were reported for hydrogen loaded niobium (Nb) thin films. Such high stresses can be achieved when conventional stress-release channels are closed, e.g., by reducing the system size. In this paper, we demonstrate that the high stress can be used to strongly modify the system’s thermodynamics. In particular, a complete suppression of the phase transformation is achieved by reducing the film thickness below a switchover value <i>d</i><sub>so</sub>. Combined in situ scanning tunneling microscopy (STM) and in situ X-ray diffraction (XRD) measurements serve to determine the switchover thickness of epitaxial Nb/Al<sub>2</sub>O<sub>3</sub> films in the thickness range from 55 to 5 nm. A switchover thickness <i>d</i><sub>so</sub> = 9 ± 1 nm is found at <i>T</i> = 294 K. This result is supported by complementary methods such as electromotive force (EMF), electrical resistance, and mechanical stress measurements in combination with theoretical modeling

    Synthesis, <sup>18</sup>F‑Radiolabeling, and in Vivo Biodistribution Studies of <i>N</i>‑Fluorohydroxybutyl Isatin Sulfonamides using Positron Emission Tomography

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    The effector caspases-3 and -7 play a central role in programmed type I cell death (apoptosis). Molecular imaging using positron emission tomography (PET) by tracking the activity of executing caspases might allow the detection of the early onset as well as therapy monitoring of various diseases induced by dysregulated apoptosis. Herein, four new fluorinated diastereo- and enantiopure isatin sulfonamide-based potent and selective caspase-3 and -7 inhibitors were prepared by cyclic sulfate ring-opening with fluoride. All fluorohydrins exhibited excellent in vitro affinities (up to IC<sub>50</sub> = 11.8 and 0.951 nM for caspase-3 and -7, respectively), which makes them appropriate PET radiotracer candidates. Therefore, <i>N</i>-(4-[<sup>18</sup>F]­fluoro-3­(<i>R</i>)-hydroxybutyl)- and <i>N</i>-(3­(<i>S</i>)-[<sup>18</sup>F]­fluoro-4-hydroxybutyl)-5-[1-(2­(<i>S</i>)-(methoxymethyl)­pyrrolidinyl)­sulfonyl]­isatin were synthesized in 140 min with 24% and 10% overall radiochemical yields and specific activities of 10–127 GBq/μmol using [<sup>18</sup>F]­fluoride in the presence of Kryptofix and subsequent acidic hydrolysis. In vivo biodistribution studies in wild-type mice using PET/computed tomography imaging proved fast clearance of the tracer after tail vein injection

    Radiolabeled Selective Matrix Metalloproteinase 13 (MMP-13) Inhibitors: (Radio)Syntheses and in Vitro and First in Vivo Evaluation

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    The noninvasive imaging of MMP activity in vivo could have a high impact in basic research as well as in clinical applications. This approach can be established using radiolabeled MMP inhibitors (MMPIs) as tracers for the detection of activated MMPs by means of PET. However, the complexity of diseases associated with dysregulated MMP expression necessitates the imaging of distinct MMPs or MMP subgroups to distinguish their individual role in specific diseases. To this end, selective and potent MMP-13 inhibitors based on a <i>N</i>,<i>N</i>′-bis­(benzyl)­pyrimidine-4,6-dicarboxamide core have been synthesized and successfully radiolabeled with carbon-11, fluorine-18, and gallium-68. Selected radiolabeled candidates were evaluated in vitro and in vivo regarding their pharmacokinetic properties and metabolic stability

    A New Generation of Radiofluorinated Pyrimidine-2,4,6-triones as MMP-Targeted Radiotracers for Positron Emission Tomography

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    Radiolabeled C-5-disubstituted pyrimidine-2,4,6-triones have recently been suggested by our group as a class of potent matrix metalloproteinase (MMP) targeted radiotracers that can noninvasively visualize activated MMPs by means of positron emission tomography (PET). MMPs belong to the zinc- and calcium-dependent endopeptidases which are involved in the proteolytic degradation of components of the extracellular matrix (ECM) but also are capable of processing and releasing bioactive molecules such as growth factors, proteinase inhibitors, and cytokines. Locally increased levels of activated MMPs modulate and contribute to the progression of various diseases, such as cancer, atherosclerosis, stroke, arthritis, and others. Therefore, activated MMPs are suitable biological targets for the specific and noninvasive visualization of aforementioned pathologies in vivo. On the basis of our recent results, we here describe a series of new fluorinated pyrimidine-2,4,6-triones of the second generation with maintained MMP inhibition potencies (IC<sub>50</sub> = 4–605 nM), which are fine-tuned toward more hydrophilic versions, and show the improved biodistribution behavior of one selected radiofluorinated pyrimidine-2,4,6-trione by means of small-animal PET

    Novel Potent Proline-Based Metalloproteinase Inhibitors: Design, (Radio)Synthesis, and First in Vivo Evaluation as Radiotracers for Positron Emission Tomography

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    As dysregulation of matrix metalloproteinase (MMP) activity is associated with a wide range of pathophysiological processes like cancer, atherosclerosis, and arthritis, MMPs represent a valuable target for the development of new therapeutics and diagnostic tools. We herein present the chiral pool syntheses, in vitro evaluation, and SAR studies of a series of d- and l-proline- as well as of (4<i>R</i>)-4-hydroxy-l-proline-derived MMP inhibitors possessing general formula <b>1</b>. Some of the synthesized hydroxamic acids were found to be potent MMP inhibitors with IC<sub>50</sub> values in the nanomolar range, also demonstrating no off-target effects toward the other tested Zn<sup>2+</sup>-dependent metalloproteases (ADAMs and meprins). Utilizing the structure of the (2<i>S</i>,4<i>S</i>)-configured 4-hydroxyproline derivative <b>4</b>, a selective picomolar inhibitor of MMP-13, the radiolabeled counterpart [<sup>18</sup>F]<b>4</b> was successfully synthesized. The radiotracer’s biodistribution in mice as well as its serum stability were evaluated for assessing its potential use as a MMP-13 targeting PET imaging agent

    Synthesis and Evaluation of Fluorinated Fingolimod (FTY720) Analogues for Sphingosine-1-Phosphate Receptor Molecular Imaging by Positron Emission Tomography

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    Sphingosine-1-phosphate (S1P) is a lysophospholipid that evokes a variety of biological responses via stimulation of a set of cognate G-protein coupled receptors (GPCRs): S1P<sub>1</sub>–S1P<sub>5</sub>. S1P and its receptors (S1PRs) play important roles in the immune, cardiovascular, and central nervous systems and have also been implicated in carcinogenesis. Recently, the S1P analogue Fingolimod (FTY720) has been approved for the treatment of patients with relapsing multiple sclerosis. This work presents the synthesis of various fluorinated structural analogues of FTY720, their <i>in vitro</i> and <i>in vivo</i> biological testing, and their development and application as [<sup>18</sup>F]­radiotracers for the study of S1PR biodistribution and imaging in mice using small-animal positron emission tomography (PET)

    Design, (Radio)Synthesis, and in Vitro and in Vivo Evaluation of Highly Selective and Potent Matrix Metalloproteinase 12 (MMP-12) Inhibitors as Radiotracers for Positron Emission Tomography

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    Dysregulated levels of activated matrix metalloproteinases (MMPs) are linked to different pathologies, such as cancer, atherosclerosis, neuroinflammation, and arthritis. Therefore, imaging of MMPs with positron-emission tomography (PET) represents a powerful tool for the diagnosis of MMP-associated diseases. Moreover, to distinguish between the distinct functions and roles of individual MMPs in particular pathophysiological processes, their specific imaging must be realized with radiolabeled tracers, such as fluorine-18-labeled MMP inhibitors (MMPIs). Therefore, fluorinated dibenzofuransulfonamide-based MMPIs showing excellent inhibition of MMP-12 and selectivity for MMP-12 over other MMPs were prepared. MMP-12 is a key enzyme in diseases such as chronic obstructive pulmonary disease (COPD) and atherosclerosis. Because of their promising in vitro properties, three candidates (<b>4</b>, <b>9</b>, and <b>19</b>) were selected from this library, and radiofluorinated analogues (<b>[</b><sup><b>18</b></sup><b>F]­4</b>, <b>[</b><sup><b>18</b></sup><b>F]­9</b>, and <b>[</b><sup><b>18</b></sup><b>F]­19</b>) were successfully synthesized. Initial in vitro serum stability and in vivo biodistribution studies of the radiolabeled MMPIs with PET demonstrated their potential benefit for preferable MMP-12 imaging

    Design, (Radio)Synthesis, and in Vitro and in Vivo Evaluation of Highly Selective and Potent Matrix Metalloproteinase 12 (MMP-12) Inhibitors as Radiotracers for Positron Emission Tomography

    No full text
    Dysregulated levels of activated matrix metalloproteinases (MMPs) are linked to different pathologies, such as cancer, atherosclerosis, neuroinflammation, and arthritis. Therefore, imaging of MMPs with positron-emission tomography (PET) represents a powerful tool for the diagnosis of MMP-associated diseases. Moreover, to distinguish between the distinct functions and roles of individual MMPs in particular pathophysiological processes, their specific imaging must be realized with radiolabeled tracers, such as fluorine-18-labeled MMP inhibitors (MMPIs). Therefore, fluorinated dibenzofuransulfonamide-based MMPIs showing excellent inhibition of MMP-12 and selectivity for MMP-12 over other MMPs were prepared. MMP-12 is a key enzyme in diseases such as chronic obstructive pulmonary disease (COPD) and atherosclerosis. Because of their promising in vitro properties, three candidates (<b>4</b>, <b>9</b>, and <b>19</b>) were selected from this library, and radiofluorinated analogues (<b>[</b><sup><b>18</b></sup><b>F]­4</b>, <b>[</b><sup><b>18</b></sup><b>F]­9</b>, and <b>[</b><sup><b>18</b></sup><b>F]­19</b>) were successfully synthesized. Initial in vitro serum stability and in vivo biodistribution studies of the radiolabeled MMPIs with PET demonstrated their potential benefit for preferable MMP-12 imaging

    Early Assessment of the Efficacy of Temozolomide Chemotherapy in Experimental Glioblastoma Using [<sup>18</sup>F]FLT-PET Imaging

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    <div><p></p><p>Addition of temozolomide (TMZ) to radiation therapy is the standard treatment for patients with glioblastoma (GBM). However, there is uncertainty regarding the effectiveness of TMZ. Considering the rapid evolution of the disease, methods to assess TMZ efficacy early during treatment would be of great benefit. Our aim was to monitor early effects of TMZ in a mouse model of GBM using positron emission tomography (PET) with 3′-deoxy-3′-[<sup>18</sup>F]fluorothymidine ([<sup>18</sup>F]FLT).</p><p>Methods</p><p>Human glioma cells sensitive to TMZ (Gli36dEGFR-1) were treated with sub-lethal doses of TMZ to obtain cells with lower sensitivity to TMZ (Gli36dEGFR-2), as measured by growth and clonogenic assays. Gli36dEGFR-1 and Gli36dEGFR-2 cells were subcutaneously (s.c.) or intracranially (i.c.) xenografted into nude mice. Mice were treated for 7 days with daily injection of 25 or 50 mg/kg TMZ. Treatment efficacy was measured using [<sup>18</sup>F]FLT-PET before treatment and after 2 days. Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) were used to determine tumor volumes before treatment and after 7 days.</p><p>Results</p><p>A significant difference was observed between TMZ and DMSO treated tumors in terms of variations of [<sup>18</sup>F]FLT T/B ratio as soon as day 2 in the i.c. as well as in the s.c. mouse model. Variations of [<sup>18</sup>F]FLT T/B uptake ratio between days 0 and 2 correlated with variations of tumor size between days 0 and 7 (s.c. model: n<sub>tumor</sub> = 17 in n<sub>mice</sub> = 11, <i>P</i><0.01; i.c. model: n<sub>tumor/mice</sub> = 9, <i>P</i><0.01).</p><p>Conclusions</p><p>Our results indicate that [<sup>18</sup>F]FLT-PET may be useful for an early evaluation of the response of GBM to TMZ chemotherapy in patients with glioma.</p></div

    Inhibition of melanoma cell proliferation <i>in vitro</i>.

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    <p>[<sup>3</sup>H]thymidine proliferation assay demonstrating effects of purified mouse IgG on HMW-MAA expressing melanoma cells. 518A2 or M14 cells were incubated with increasing concentrations of purified IgG from mice immunized with 15/3/6-KLH conjugate or KLH for 72 h and pulsed with [<sup>3</sup>H]thymidine. Data are presented as percentage of inhibition of proliferation compared to untreated cells. Percentage of inhibition was calculated as follows: 100−(cpm (treated)/cpm (untreated)×100). Values represent the mean of three independent experiments.</p
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