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Biomass-based materials have emerged as a promising alternative to the conventional graphite anode in Li-ion batteries due to their renewability, low cost, and environmental friendliness. Therefore, a facile synthesis method for porous hard carbons based on cellulose acetate microspheres and bead cellulose is used, and their application as anode materials in Li-ion batteries is discussed. The resulting porous carbons exhibit promising electrochemical characteristics, including a reversible capacity of about 300â mAh g-1 at 0.1â C (37â mA g-1) after 50 cycles, and stable capacities up to 210â mAh g-1 over 1000 cycles at 1â C (372â mA g-1) in half-cells for cellulose acetate microspheres carbonised at 1200 °C. Moreover, at 60 °C cellulose-derived carbons show higher specific capacities than graphite (300â mAh g-1 vs 240â mAh g-1 at 1â C after 500 cycles), indicating their potential for use in high-temperature applications. The different charge storage mechanisms of the prepared hard carbon materials and graphite are observed. While capacity of graphite is mainly controlled by the Faradaic redox process, the cellulose-derived carbons combine Faradaic intercalation and capacitive charge adsorption.
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Thin films of cellulose ferulate were designed to study the formation of dehydrogenation polymers (DHPs) on anchor groups of the surface. Trimethylsilyl (TMS) cellulose ferulate with degree of substitution values of 0.35 (ferulate) and 2.53 (TMS) was synthesized by sophisticated polysaccharide chemistry applying the Mitsunobu reaction. The biopolymer derivative was spin-coated into thin films to yield ferulate moieties on a smooth cellulose surface. Dehydrogenative polymerization of coniferyl alcohol was performed in a Quartz crystal microbalance with a dissipation monitoring device in the presence of H2O2 and adsorbed horseradish peroxidase. The amount of DHP formed on the surface was found to be independent of the base layer thickness from 14 to 75 nm. Pyrolysis-GC-MS measurements of the DHP revealed ß-O-4 and ß-5 linkages. Mimicking lignification of plant cell walls on highly defined model films enables reproducible investigations of structure-property relationships.
Assuntos
Celulose , Lignina , Celulose/química , Peroxidase do Rábano Silvestre/química , Peróxido de Hidrogênio/química , Lignina/química , PolimerizaçãoRESUMO
PURPOSES: We present the first in-human brain PET imaging data of the new α4ß2 nicotinic acetylcholine receptor (nAChR)-targeting radioligand (+)-[18F]Flubatine. Aims were to develop a kinetic modeling-based approach to quantify (+)-[18F]Flubatine and compare the data of healthy controls (HCs) and patients with Alzheimer's disease (AD); to investigate the partial volume effect (PVE) on regional (+)-[18F]Flubatine binding; and whether (+)-[18F]Flubatine binding and cognitive test data respective ß-amyloid radiotracer accumulation were correlated. METHODS: We examined 11 HCs and 9 mild AD patients. All subjects underwent neuropsychological testing and [11C]PiB PET/MRI examination. (+)-[18F]Flubatine PET data were evaluated using full kinetic modeling and regional as well as voxel-based analyses. RESULTS: With 270-min p.i., the unchanged parent compound amounted to 97 ± 2%. Adequate fits of the time-activity curves were obtained with the 1 tissue compartment model (1TCM). (+)-[18F]Flubatine distribution volume (binding) was significantly reduced in bilateral mesial temporal cortex in AD patients compared with HCs (right 10.6 ± 1.1 vs 11.6 ± 1.4, p = 0.049; left 11.0 ± 1.1 vs 12.2 ± 1.8, p = 0.046; one-sided t tests each). PVE correction increased not only (+)-[18F]Flubatine binding of approximately 15% but also standard deviation of 0.4-70%. Cognitive test data and (+)-[18F]Flubatine binding were significantly correlated in the left anterior cingulate, right posterior cingulate, and right parietal cortex (r > 0.5, p < 0.05 each). In AD patients, (+)-[18F]Flubatine binding and [11C]PiB standardized uptake value ratios were negatively correlated in several regions; whereas in HCs, a positive correlation between cortical (+)-[18F]Flubatine binding and [11C]PiB accumulation in the white matter was found. No adverse event related to (+)-[18F]Flubatine occurred. CONCLUSION: (+)-[18F]Flubatine is a safe and stable PET ligand. Full kinetic modeling can be realized by 1TCM without metabolite correction. (+)-[18F]Flubatine binding affinity was high enough to detect group differences. Of interest, correlation between white matter ß-amyloid PET uptake and (+)-[18F]Flubatine binding indicated an association between white matter integrity and availability of α4ß2 nAChRs. Overall, (+)-[18F]Flubatine showed favorable characteristics and has therefore the potential to serve as α4ß2 nAChR-targeting PET ligand in further clinical trials.
Assuntos
Doença de Alzheimer , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides , Compostos de Anilina , Benzamidas , Encéfalo/diagnóstico por imagem , Compostos Bicíclicos Heterocíclicos com Pontes , Humanos , Ligantes , Neuroimagem , Tomografia por Emissão de Pósitrons , Receptores NicotínicosRESUMO
The σ2 receptor (transmembrane protein 97), which is involved in cholesterol homeostasis, is of high relevance for neoplastic processes. The upregulated expression of σ2 receptors in cancer cells and tissue in combination with the antiproliferative potency of σ2 receptor ligands motivates the research in the field of σ2 receptors for the diagnosis and therapy of different types of cancer. Starting from the well described 2-(4-(1H-indol-1-yl)butyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline class of compounds, we synthesized a novel series of fluorinated derivatives bearing the F-atom at the aromatic indole/azaindole subunit. RM273 (2-[4-(6-fluoro-1H-pyrrolo[2,3-b]pyridin-1-yl)butyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline) was selected for labelling with 18F and evaluation regarding detection of σ2 receptors in the brain by positron emission tomography. Initial metabolism and biodistribution studies of [18F]RM273 in healthy mice revealed promising penetration of the radioligand into the brain. Preliminary in vitro autoradiography on brain cryosections of an orthotopic rat glioblastoma model proved the potential of the radioligand to detect the upregulation of σ2 receptors in glioblastoma cells compared to healthy brain tissue. The results indicate that the herein developed σ2 receptor ligand [18F]RM273 has potential to assess by non-invasive molecular imaging the correlation between the availability of σ2 receptors and properties of brain tumors such as tumor proliferation or resistance towards particular therapies.
Assuntos
Encéfalo/metabolismo , Radioisótopos de Flúor/química , Radioisótopos de Flúor/metabolismo , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/metabolismo , Receptores sigma/metabolismo , Animais , Feminino , Humanos , Ligantes , Masculino , Camundongos , Neoplasias/metabolismo , Ratos , Ratos Endogâmicos F344 , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/metabolismoRESUMO
The adenosine A2A receptor (A2AR) represents a potential therapeutic target for neurodegenerative diseases. Aiming at the development of a positron emission tomography (PET) radiotracer to monitor changes of receptor density and/or occupancy during the A2AR-tailored therapy, we designed a library of fluorinated analogs based on a recently published lead compound (PPY). Among those, the highly affine 4-fluorobenzyl derivate (PPY1; Ki(hA2AR) = 5.3 nM) and the 2-fluorobenzyl derivate (PPY2; Ki(hA2AR) = 2.1 nM) were chosen for 18F-labeling via an alcohol-enhanced copper-mediated procedure starting from the corresponding boronic acid pinacol ester precursors. Investigations of the metabolic stability of [18F]PPY1 and [18F]PPY2 in CD-1 mice by radio-HPLC analysis revealed parent fractions of more than 76% of total activity in the brain. Specific binding of [18F]PPY2 on mice brain slices was demonstrated by in vitro autoradiography. In vivo PET/magnetic resonance imaging (MRI) studies in CD-1 mice revealed a reasonable high initial brain uptake for both radiotracers, followed by a fast clearance.
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Encéfalo/diagnóstico por imagem , Radioisótopos de Flúor/química , Hidrocarbonetos Fluorados/química , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/química , Receptor A2A de Adenosina/metabolismo , Adenosina/metabolismo , Antagonistas do Receptor A2 de Adenosina/química , Animais , Autorradiografia , Encéfalo/metabolismo , Cromatografia Líquida de Alta Pressão , Cricetinae , Hidrocarbonetos Fluorados/síntese química , Imageamento por Ressonância Magnética , Camundongos , Simulação de Acoplamento Molecular , Relação Estrutura-AtividadeRESUMO
Gaucher disease (GD) is a lysosomal storage disorder that responds well to enzyme replacement therapy (ERT). Certain laboratory parameters, including blood concentration of glucosylsphingosine (Lyso-Gb1), the lyso-derivate of the common glycolipid glucocerebroside, correlate with clinical improvement and are therefore considered candidate-monitoring biomarkers. Whether they can indicate a reduction or loss of treatment efficiency, however, has not been systematically addressed for obvious reasons. We established and validated measurement of Lyso-Gb1 from dried blood spots (DBSs) by mass spectrometry. We then characterized the assay's longitudinal performance in 19 stably ERT-treated GD patients by dense monitoring over a 3-year period. The observed level of fluctuation was accounted for in the subsequent development of a unifying data normalization concept. The resulting approach was eventually applied to data from Lyso-Gb1 measurements after an involuntary treatment break for all 19 patients. It enabled separation of the "under treatment" versus "not under treatment" conditions with high sensitivity and specificity. We conclude that Lyso-Gb1 determination from DBSs indicates treatment issues already at an early stage before clinical consequences arise. In addition to its previously shown diagnostic utility, Lyso-Gb1 thereby qualifies as a monitoring biomarker in GD patients.
Assuntos
Biomarcadores/sangue , Teste em Amostras de Sangue Seco/métodos , Terapia de Reposição de Enzimas/métodos , Doença de Gaucher/patologia , Glucosilceramidase/administração & dosagem , Psicosina/análogos & derivados , Adolescente , Adulto , Idoso , Criança , Estudos de Coortes , Feminino , Seguimentos , Doença de Gaucher/sangue , Doença de Gaucher/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Psicosina/sangue , Adulto JovemRESUMO
Steeping of cellulosic materials in aqueous solution of NaOH is a common pre-treatment in several industrial processes for production of cellulose-based products, including viscose fibers. This study investigated whether the span of commonly applied process settings has the potential for process optimization regarding purity, yield, and degree of transformation to alkali cellulose. A hardwood kraft dissolving pulp was extracted with 17-20 wt% aq. NaOH at 40-50 °C. The regenerated residue of the pulp was characterized regarding its chemical composition, molecular structure, and cellulose conformation. Yield was shown to be favored primarily by low temperature and secondly by high alkali concentration. Purity of xylan developed inversely. Both purity of xylan and yield varied over the applied span of settings to an extent which makes case-adapted process optimization meaningful. Decreasing the steeping temperature by 2 °C increased xylan content in the residue with 0.13%-units over the whole span of applied alkali concentrations, while yield increased by 0.15%-units when extracting with 17 wt% aq. NaOH, and by 0.20%-units when extracting with 20 wt%. Moreover, the yield-favoring conditions resulted in a narrower molecular weight distribution. The degree of transformation via alkali cellulose to cellulose II, as determined with Raman spectroscopy, was found to be high at all extraction settings applied.
Assuntos
Álcalis/química , Celulose/química , Madeira/química , Hidrólise , Ciência dos Materiais , Peso Molecular , Temperatura , Xilanos/análise , Xilanos/químicaRESUMO
Due to their chemical structure, conventional flame retardants are often toxic, barely biodegradable and consequently neither healthy nor environmentally friendly. Their use is therefore increasingly limited by regulations. For this reason, research on innovative flame retardants based on sustainable materials is the main focus of this work. Wheat starch, wheat protein, xylan and tannin were modified with phosphate salts in molten urea. The functionalization leads to the incorporation of phosphates (up to 48 wt.%) and nitrogen (up to 22 wt.%). The derivatives were applied on wood fibers and tested as flame retardants. The results indicate that these modified biopolymers can provide the same flame-retardant performances as commercial compounds currently used in the wood fiber industry. Besides, the flame retardancy smoldering effects may also be reduced compared to unmodified wood fibers depending on the used biopolymer. These results show that different biopolymers modified in phosphate/urea systems are a serious alternative to conventional flame retardants.
Assuntos
Retardadores de Chama/síntese química , Organofosfatos/química , Proteínas de Plantas/química , Amido/química , Taninos/química , Triticum/química , Ureia/química , Madeira/química , Xilanos/químicaRESUMO
Biopolymer-based flame retardants (FR) are a promising approach to ensure adequate protection against fire while minimizing health and environmental risks. Only a few, however, are suitable for industrial purposes because of their poor flame retardancy, complex synthesis pathway, expensive cleaning procedures, and inappropriate application properties. In the present work, wheat starch was modified using a common phosphate/urea reaction system and tested as flame retardant additive for wood fibers. The results indicate that starch derivatives from phosphate/urea systems can reach fire protection efficiencies similar to those of commercial flame retardants currently used in the wood fiber industry. The functionalization leads to the incorporation of fire protective phosphates (up to 38 wt.%) and nitrogen groups (up to 8.3 wt.%). The lowest levels of burning in fire tests were measured with soluble additives at a phosphate content of 3.5 wt.%. Smoldering effects could be significantly reduced compared to unmodified wood fibers. The industrial processing of a starch-based flame retardant on wood insulating materials exhibits the fundamental applicability of flame retardants. These results demonstrate that starch modified from phosphate/urea-systems is a serious alternative to traditional flame retardants.
Assuntos
Retardadores de Chama/análise , Fósforo/química , Amido/química , Triticum/química , Madeira/química , Teste de MateriaisRESUMO
Glioblastoma multiforme (GBM) is the most devastating primary brain tumour characterised by infiltrative growth and resistance to therapies. According to recent research, the sigma-1 receptor (sig1R), an endoplasmic reticulum chaperone protein, is involved in signaling pathways assumed to control the proliferation of cancer cells and thus could serve as candidate for molecular characterisation of GBM. To test this hypothesis, we used the clinically applied sig1R-ligand (S)-(-)-[18F]fluspidine in imaging studies in an orthotopic mouse model of GBM (U87-MG) as well as in human GBM tissue. A tumour-specific overexpression of sig1R in the U87-MG model was revealed in vitro by autoradiography. The binding parameters demonstrated target-selective binding according to identical KD values in the tumour area and the contralateral side, but a higher density of sig1R in the tumour. Different kinetic profiles were observed in both areas, with a slower washout in the tumour tissue compared to the contralateral side. The translational relevance of sig1R imaging in oncology is reflected by the autoradiographic detection of tumour-specific expression of sig1R in samples obtained from patients with glioblastoma. Thus, the herein presented data support further research on sig1R in neuro-oncology.
Assuntos
Benzofuranos/metabolismo , Neoplasias Encefálicas/diagnóstico por imagem , Glioblastoma/diagnóstico por imagem , Imagem Molecular/métodos , Piperidinas/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Receptores sigma/metabolismo , Animais , Autorradiografia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Radioisótopos de Flúor , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Imageamento por Ressonância Magnética , Camundongos , Camundongos Knockout , Camundongos Nus , Compostos Radiofarmacêuticos , Receptores sigma/genética , Transplante Heterólogo , Receptor Sigma-1RESUMO
Monocarboxylate transporters 1-4 (MCT1-4) are involved in several metabolism-related diseases, especially cancer, providing the chance to be considered as relevant targets for diagnosis and therapy. [18F]FACH was recently developed and showed very promising preclinical results as a potential positron emission tomography (PET) radiotracer for imaging of MCTs. Given that [18F]FACH did not show high blood-brain barrier permeability, the current work is aimed to investigate whether more lipophilic analogs of FACH could improve brain uptake for imaging of gliomas, while retaining binding to MCTs. The 2-fluoropyridinyl-substituted analogs 1 and 2 were synthesized and their MCT1 inhibition was estimated by [14C]lactate uptake assay on rat brain endothelial-4 (RBE4) cells. While compounds 1 and 2 showed lower MCT1 inhibitory potencies than FACH (IC50 = 11 nM) by factors of 11 and 25, respectively, 1 (IC50 = 118 nM) could still be a suitable PET candidate. Therefore, 1 was selected for radiosynthesis of [18F]1 and subsequent biological evaluation for imaging of the MCT expression in mouse brain. Regarding lipophilicity, the experimental log D7.4 result for [18F]1 agrees pretty well with its predicted value. In vivo and in vitro studies revealed high uptake of the new radiotracer in kidney and other peripheral MCT-expressing organs together with significant reduction by using specific MCT1 inhibitor α-cyano-4-hydroxycinnamic acid. Despite a higher lipophilicity of [18F]1 compared to [18F]FACH, the in vivo brain uptake of [18F]1 was in a similar range, which is reflected by calculated BBB permeabilities as well through similar transport rates by MCTs on RBE4 cells. Further investigation is needed to clarify the MCT-mediated transport mechanism of these radiotracers in brain.
Assuntos
Encéfalo/diagnóstico por imagem , Transportadores de Ácidos Monocarboxílicos/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Piridinas/síntese química , Compostos Radiofarmacêuticos/síntese química , Simportadores/metabolismo , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Encéfalo/citologia , Encéfalo/metabolismo , Linhagem Celular , Ácidos Cumáricos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Feminino , Radioisótopos de Flúor , Ligantes , Camundongos , Transportadores de Ácidos Monocarboxílicos/antagonistas & inibidores , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Piridinas/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Simportadores/antagonistas & inibidoresRESUMO
Reported here for the first time is the alkaline periodate oxidation of lignocelluloses for the selective isolation of cellulose nanocrystals (CNCs). With the high concentrations as a potassium salt at pHâ 10, periodate ions predominantly exist as dimeric orthoperiodate ions (H2 I2 O104- ). With reduced oxidizing activity in alkaline solutions, dimeric orthoperiodate ions preferentially oxidized non-ordered cellulose regions. The alkaline surroundings promoted the degradation of these oxidized cellulose chains by ß-alkoxy fragmentation and generated CNCs. The obtained CNCs were uniform in size and generally contained carboxy groups. Furthermore, the reaction solution could be reused after regeneration of the periodate with ozone gas. This method allows direct production of CNCs from diverse sources, in particular lignocellulosic raw materials including sawdust (European beech and Scots pine), flax, and kenaf, in addition to microcrystalline cellulose and pulp.
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In early Alzheimer's dementia, there is a need for PET biomarkers of disease progression with close associations to cognitive dysfunction that may aid to predict further cognitive decline and neurodegeneration. Amyloid biomarkers are not suitable for that purpose. The α4ß2 nicotinic acetylcholine receptors (α4ß2-nAChRs) are widely abundant in the human brain. As neuromodulators they play an important role in cognitive functions such as attention, learning and memory. Post-mortem studies reported lower expression of α4ß2-nAChRs in more advanced Alzheimer's dementia. However, there is ongoing controversy whether α4ß2-nAChRs are reduced in early Alzheimer's dementia. Therefore, using the recently developed α4ß2-nAChR-specific radioligand (-)-18F-flubatine and PET, we aimed to quantify the α4ß2-nAChR availability and its relationship to specific cognitive dysfunction in mild Alzheimer's dementia. Fourteen non-smoking patients with mild Alzheimer's dementia, drug-naïve for cholinesterase therapy, were compared with 15 non-smoking healthy controls matched for age, sex and education by applying (-)-18F-flubatine PET together with a neuropsychological test battery. The one-tissue compartment model and Logan plot method with arterial input function were used for kinetic analysis to obtain the total distribution volume (VT) as the primary, and the specific binding part of the distribution volume (VS) as the secondary quantitative outcome measure of α4ß2-nAChR availability. VS was determined by using a pseudo-reference region. Correlations between VT within relevant brain regions and Z-scores of five cognitive functions (episodic memory, executive function/working memory, attention, language, visuospatial function) were calculated. VT (and VS) were applied for between-group comparisons. Volume of interest and statistical parametric mapping analyses were carried out. Analyses revealed that in patients with mild Alzheimer's dementia compared to healthy controls, there was significantly lower VT, especially within the hippocampus, fronto-temporal cortices, and basal forebrain, which was similar to comparisons of VS. VT decline in Alzheimer's dementia was associated with distinct domains of impaired cognitive functioning, especially episodic memory and executive function/working memory. Using (-)-18F-flubatine PET in patients with mild Alzheimer's dementia, we show for the first time a cholinergic α4ß2-nAChR deficiency mainly present within the basal forebrain-cortical and septohippocampal cholinergic projections and a relationship between lower α4ß2-nAChR availability and impairment of distinct cognitive domains, notably episodic memory and executive function/working memory. This shows the potential of (-)-18F-flubatine as PET biomarker of cholinergic α4ß2-nAChR dysfunction and specific cognitive decline. Thus, if validated by longitudinal PET studies, (-)-18F-flubatine might become a PET biomarker of progression of neurodegeneration in Alzheimer's dementia.
Assuntos
Doença de Alzheimer/complicações , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/metabolismo , Receptores Nicotínicos/metabolismo , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Atenção/fisiologia , Benzamidas/farmacocinética , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Transtornos Cognitivos/diagnóstico por imagem , Estudos de Coortes , Escolaridade , Função Executiva , Feminino , Humanos , Masculino , Memória de Curto Prazo/fisiologia , Pessoa de Meia-Idade , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons , Fatores SexuaisRESUMO
Monocarboxylate transporters 1 and 4 (MCT1 and MCT4) are involved in tumor development and progression. Their expression levels are related to clinical disease prognosis. Accordingly, both MCTs are promising drug targets for treatment of a variety of human cancers. The noninvasive imaging of these MCTs in cancers is regarded to be advantageous for assessing MCT-mediated effects on chemotherapy and radiosensitization using specific MCT inhibitors. Herein, we describe a method for the radiosynthesis of [18 F]FACH ((E)-2-cyano-3-{4-[(3-[18 F]fluoropropyl)(propyl)amino]-2-methoxyphenyl}acrylic acid), as a novel radiolabeled MCT1/4 inhibitor for imaging with PET. A fluorinated analog of α-cyano-4-hydroxycinnamic acid (FACH) was synthesized, and the inhibition of MCT1 and MCT4 was measured via an L-[14 C]lactate uptake assay. Radiolabeling was performed by a two-step protocol comprising the radiosynthesis of the intermediate (E)/(Z)-[18 F]tert-Bu-FACH (tert-butyl (E)/(Z)-2-cyano-3-{4-[(3-[18 F]fluoropropyl)(propyl)amino]-2-methoxyphenyl}acrylate) followed by deprotection of the tert-butyl group. The radiofluorination was successfully implemented using either K[18 F]F-K2.2.2 -carbonate or [18 F]TBAF. The final deprotected product [18 F]FACH was only obtained when [18 F]tert-Bu-FACH was formed by the latter procedure. After optimization of the deprotection reaction, [18 F]FACH was obtained in high radiochemical yields (39.6 ± 8.3%, end of bombardment (EOB) and radiochemical purity (greater than 98%).
Assuntos
Acrilatos/síntese química , Acrilatos/farmacologia , Radioisótopos de Flúor/química , Transportadores de Ácidos Monocarboxílicos/antagonistas & inibidores , Proteínas Musculares/antagonistas & inibidores , Simportadores/antagonistas & inibidores , Acrilatos/química , Animais , Linhagem Celular Tumoral , Técnicas de Química Sintética , Humanos , Marcação por Isótopo , Camundongos , RadioquímicaRESUMO
This work is focused on the identification and investigation of the catalytically relevant key iron species in a photocatalytic proton reduction system described by Beller and co-workers. The system is driven by visible light and consists of the low-cost [Fe3 (CO)12 ] as catalyst precursor, electron-poor phosphines P(R)3 as co-catalysts, and a standard iridium-based photosensitizer dissolved in a mixture of THF, water, and the sacrificial reagent triethylamine. The catalytic reaction system was investigated by operando continuous-flow FTIR spectroscopy coupled with H2 gas volumetry, as well as by X-ray absorption spectroscopy, NMR spectroscopy, DFT calculations, and cyclic voltammetry. Several iron carbonyl species were identified, all of which emerge throughout the catalytic process. Depending on the applied P(R)3 , the iron carbonyl species were finally converted into [Fe2 (CO)6 (µ-CO){µ-P(R)2 }]- . This involves a P-C cleavage reaction. The requirements of P(R)3 and the necessary reaction conditions are specified. [Fe2 (CO)6 (µ-CO){µ-P(R)2 }]- represents a self-assembling, sulfur-free [FeFe]-hydrogenase active-site mimic and shows good catalytic activity if the substituent R is electron poor. Deactivation mechanisms have also been investigated, for example, the decomposition of the photosensitizer or processes observed in the case of excessive amounts of P(R)3 . [Fe2 (CO)6 (µ-CO){µ-P(R)2 }]- has potential for future applications.
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Both (+)-[18F]flubatine and its enantiomer (-)-[18F]flubatine are radioligands for the neuroimaging of α4ß2 nicotinic acetylcholine receptors (nAChRs) by positron emission tomography (PET). In a clinical study in patients with early Alzheimer's disease, (+)-[18F]flubatine ((+)-[18F]1) was examined regarding its metabolic fate, in particular by identification of degradation products detected in plasma and urine. The investigations included an in vivo study of (+)-flubatine ((+)-1) in pigs and structural elucidation of formed metabolites by LC-MS/MS. Incubations of (+)-1 and (+)-[18F]1 with human liver microsomes were performed to generate in vitro metabolites, as well as radiometabolites, which enabled an assignment of their structures by comparison of LC-MS/MS and radio-HPLC data. Plasma and urine samples taken after administration of (+)-[18F]1 in humans were examined by radio-HPLC and, on the basis of results obtained in vitro and in vivo, formed radiometabolites were identified.
Assuntos
Benzamidas/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Neuroimagem , Tomografia por Emissão de Pósitrons , Receptores Nicotínicos/química , Animais , Benzamidas/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Cromatografia Líquida , Humanos , Metaboloma/genética , Receptores Nicotínicos/isolamento & purificação , Suínos/sangue , Suínos/urina , Espectrometria de Massas em TandemRESUMO
Sigma-1 receptors (Sig1R) are highly expressed in various human cancer cells and hence imaging of this target with positron emission tomography (PET) can contribute to a better understanding of tumor pathophysiology and support the development of antineoplastic drugs. Two Sig1R-specific radiolabeled enantiomers (S)-(-)- and (R)-(+)-[18F]fluspidine were investigated in several tumor cell lines including melanoma, squamous cell/epidermoid carcinoma, prostate carcinoma, and glioblastoma. Dynamic PET scans were performed in mice to investigate the suitability of both radiotracers for tumor imaging. The Sig1R expression in the respective tumors was confirmed by Western blot. Rather low radiotracer uptake was found in heterotopically (subcutaneously) implanted tumors. Therefore, a brain tumor model (U87-MG) with orthotopic implantation was chosen to investigate the suitability of the two Sig1R radiotracers for brain tumor imaging. High tumor uptake as well as a favorable tumor-to-background ratio was found. These results suggest that Sig1R PET imaging of brain tumors with [18F]fluspidine could be possible. Further studies with this tumor model will be performed to confirm specific binding and the integrity of the blood-brain barrier (BBB).
Assuntos
Benzofuranos/farmacologia , Neoplasias Encefálicas/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Piperidinas/farmacologia , Receptores sigma/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos Nus , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X , Receptor Sigma-1RESUMO
Cyclic nucleotide phosphodiesterase 10A (PDE10A) regulates the level of the second messengers cAMP and cGMP in particular in brain regions assumed to be associated with neurodegenerative and psychiatric diseases. A better understanding of the pathophysiological role of the expression of PDE10A could be obtained by quantitative imaging of the enzyme by positron emission tomography (PET). Thus, in this study we developed, radiolabeled, and evaluated a new PDE10A radioligand, 8-bromo-1-(6-[18 F]fluoropyridin-3-yl)-3,4-dimethylimidazo[1,5-a]quinoxaline ([18 F]AQ28A). [18 F]AQ28A was radiolabeled by both nucleophilic bromo-to-fluoro or nitro-to-fluoro exchange using K[18 F]F-K2.2.2 -carbonate complex with different yields. Using the superior nitro precursor, we developed an automated synthesis on a Tracerlab FX F-N module and obtained [18 F]AQ28A with high radiochemical yields (33 ± 6%) and specific activities (96-145 GBq·µmol-1 ) for further evaluation. Initially, we investigated the binding of [18 F]AQ28A to the brain of different species by autoradiography and observed the highest density of binding sites in striatum, the brain region with the highest PDE10A expression. Subsequent dynamic PET studies in mice revealed a region-specific accumulation of [18 F]AQ28A in this region, which could be blocked by preinjection of the selective PDE10A ligand MP-10. In conclusion, the data suggest [18 F]AQ28A is a suitable candidate for imaging of PDE10A in rodent brain by PET.
Assuntos
Radioisótopos de Flúor/química , Imidazóis/síntese química , Diester Fosfórico Hidrolases/metabolismo , Quinoxalinas/síntese química , Compostos Radiofarmacêuticos/síntese química , Animais , Encéfalo/diagnóstico por imagem , Feminino , Imidazóis/farmacocinética , Ligantes , Camundongos , Tomografia por Emissão de Pósitrons , Ligação Proteica , Quinoxalinas/farmacocinética , Compostos Radiofarmacêuticos/efeitos adversos , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Ratos Sprague-Dawley , Suínos , Distribuição TecidualRESUMO
For the first time, structurally defined manganese pincer complexes catalyze the dehydrogenation of aqueous methanol to hydrogen and carbon dioxide, which is a transformation of interest with regard to the implementation of a hydrogen and methanol economy. Excellent long-term stability was demonstrated for the Mn-PNPiPr catalyst, as a turnover of more than 20 000 was reached. In addition to methanol, other important hydrogen carriers were also successfully dehydrogenated.
RESUMO
Hydrogenations constitute fundamental processes in organic chemistry and allow for atom-efficient and clean functional group transformations. In fact, the selective reduction of nitriles, ketones, and aldehydes with molecular hydrogen permits access to a green synthesis of valuable amines and alcohols. Despite more than a century of developments in homogeneous and heterogeneous catalysis, efforts toward the creation of new useful and broadly applicable catalyst systems are ongoing. Recently, Earth-abundant metals have attracted significant interest in this area. In the present study, we describe for the first time specific molecular-defined manganese complexes that allow for the hydrogenation of various polar functional groups. Under optimal conditions, we achieve good functional group tolerance, and industrially important substrates, e.g., for the flavor and fragrance industry, are selectively reduced.