1,723,626 research outputs found
Does the melanin-concentrating hormone antagonist SNAP-7941 deserve 3As?
No full textMelanin-concentrating hormone (MCH) is orexigenic (stimulates food intake). Two receptors for MCH have been identified in humans, MCH1-R and MCH2-R. SNAP-7941 is a small molecule MCH1-R antagonist. SNAP-7941 inhibits MCH-induced food intake in rats. SNAP-7941 alone reduced weight gain in young growing rats and in mature rats fed a high-fat diet. Preliminary testing with SNAP-7941 in animal models of depression and anxiety shows it has antidepressant and anxiolytic effects. SNAP-7941 should undergo further development as an anorectic, antidepressant and anxiolytic
Enzymatische Metabolisierung des MCHR-1 Antagonisten SNAP-7941 zur SNAP-Säure und Auswertung durch Hochleistungsflüssigkeitschromatographie (HPLC)
No full textDas Melanin-Concentrating-Hormon (MCH)-System wirkt auf Ingestion, Energiehomöostase und Schlafverhalten, es wird deswegen mit Erkrankungen wie Adipositas und Depressionen in Verbindung gebracht. Zur Visualisierung und Quantifizierung des Melanin-Concentrating-Hormon Rezeptors 1 (MCH-R1) und zur Berechnung der Dosisanpassung des MCH-R1 Antagonisten wurde der PET- Tracer [11C]SNAP-7941 entwickelt. Für die Synthese des Tracers wird die synthetisch aufwändig herzustellende Vorläufersubstanz (Präcursor) SNAP-Säure benötigt. Da die Synthese von SNAP-7941 einfach und in einer guten Ausbeute zu bewerkstelligen ist, war primäres Ziel dieser Arbeit, mit Hilfe von Enzymen den Präcursor SNAP-Säure aus SNAP-7941 herzustellen.
Bei der Arbeit mit Enzymen ist es essentiell, diese auf ihre Aktivität zu überprüfen. Deshalb war die Etablierung von Protease- und Lipaseaktivitätsassays am AKH Wien ein weiteres Ziel dieser Arbeit.
Die Metabolisierung von SNAP-7941 zur SNAP-Säure konnte mit Hilfe der verwendeten Enzyme nicht bewerkstelligt werden.
Jedoch konnten sowohl der Protease- als auch der Lipaseaktivitätsassay am AKH Wien erfolgreich etabliert werden.The melanin concentrating hormone (MCH)-System affects ingestion energy homeostasis and sleeping behaviour. Therefore, it is associated with obesity and depression. For visualisation and quantification of melanin concentrating hormone-receptor 1 (MCH-R1) and for scaling the dose of MCH-R1 antagonists the PET tracer [11C]SNAP-7941 was developed. For the synthesis of [11C]SNAP- 7941 the precursor SNAP-acid is needed. In difference to SNAP-acid, SNAP- 7941 is easily synthesised in a high yield. For that reason, the main aim of this thesis was to produce SNAP-acid through enzymatic cleaving of SNAP-7941.
While working with enzymes it is essential to verify their activity. Therefore, an other aim of this work was to establish assays to verify the activity of proteases and lipases.
The metabolisation of SNAP-7941 to SNAP-acid was not achieved with the chosen enzymes.
However, it was possible to establish the assays to verify the activity of proteases and lipases in the AKH Wien
In vivo evaluation of radiotracers targeting the melanin-concentrating hormone receptor 1: [11C]SNAP-7941 and [18F]FE@SNAP reveal specific uptake in the ventricular system
No full textThe MCHR1 is involved in the regulation of energy homeostasis and changes of the expression are linked to a variety of associated diseases, such as diabetes and adiposity. The study aimed at the in vitro and in vivo evaluation of [11C]SNAP-7941 and [18F]FE@SNAP as potential PET-tracers for the MCHR1. Competitive binding studies with non-radioactive derivatives and small-animal PET/CT and MRI brain studies were performed under baseline conditions and tracer displacement with the unlabelled MCHR1 antagonist (±)-SNAP-7941. Binding studies evinced high binding affinity of the non-radioactive derivatives. Small-animal imaging of [11C]SNAP-7941 and [18F]FE@SNAP evinced high tracer uptake in MCHR1-rich regions of the ventricular system. Quantitative analysis depicted a significant tracer reduction after displacement with (±)-SNAP-7941. Due to the high binding affinity of the non-labelled derivatives and the high specific tracer uptake of [11C]SNAP-7941 and [18F]FE@SNAP, there is strong evidence that both radiotracers may serve as highly suitable agents for specific MCHR1 imaging.© The Author(s) 201
Investigation of binding of the two MCHR1 ligands SNAP-7941 and FE@SNAP on brown adipose tissue
No full textDas hypothalamische Neuropeptid Melanin-konzentrierendes Hormon (MCH) spielt eine wichtige Rolle für die Aufrechterhaltung der Energiehomeostase und des Körpergewichts. Zwei PET-Tracer sind vor kurzem entwickelt worden, welche am MCHR1 – der Rezeptor für MCH – binden, [11C]SNAP-7941 und [18F]FE@SNAP. [18F]FE@SNAP zeigte eine spezifische Aufnahme in braunem Fettgewebe von wachen, nicht-anästhesierten Ratten, welche durch die Applikation von SNAP-7941 signifikant reduziert wurde. Die MCHR1 Expression in braunem Fettgewebe ist aber in der Literatur noch nicht beschrieben. Gegenteiliges wurde in µPET Studien bei anästhesierten Ratten beobachtet: Die Applikation einer pharmakologischen Dosis von SNAP-7941 (15 mg/kg Körpergewicht) führte zu einer gesteigerten [18F]FE@SNAP-Anreicherung im braunen Fettgewebe. Weiters konnte SNAP-7941 die Aufnahme von [18F]FDG in braunem Fettgewebe von anästhetisierten Ratten steigern. Dies war ähnlich einer Aktivierung von braunem Fettgewebe durch β3-Adrenozeptor (ADRB3) Agonisten. Der ADRB3 wird hauptsächlich im Fettgewebe exprimiert, wo er für die Lipolyse und in braunem Fettgewebe auch für die Thermogenese unerlässlich ist.
Die Hypothese war, dass die zwei MCHR1 Liganden an ADRB3 in braunem Fettgewebe binden. Die Affinität von SNAP-7941 und FE@SNAP zu ADRB3 ist mittels kompetitiven Bindungsstudien (Filtrationsmethode) mit Membranen, die ADRB3 exprimieren, und mit [3H]-CGP-12177 als Radioligand bestimmt worden. Zusätzlich sind Echt-Zeit-Zellbindungsstudien mit CHO-K1 Zellen, die ADRB3 exprimieren, und mit [125I]-(-)-Iodocyanopindolol als Radioligand durchgeführt worden. Außerdem wurden Bindungsstudien mit den PET-Tracern [11C]SNAP-7941 and [18F]FE@SNAP vorgenommen. Das zweite Ziel war, die Interaktion von [11C]SNAP-7941 und braunen Fettgewebszellen zu charakterisieren sowie den Effekt von den bekannten ADRB3 Liganden und MCHR1 Liganden SNAP-7941 und FE@SNAP auf die Aufnahme von [18F]FDG im braunen Fettgewebe zu untersuchen. Murine braune Präadipozyten sind in braune Adipozyten differenziert worden und mit Oil Red O gefärbt worden. Es wurden Echt-Zeit-Zellbindungsstudien, die LigandTracer® Experimente, sowie konventionelle Radioligand-Bindungsstudien ("well plate assays") durchgeführt.
SNAP-7941 (Ki = 14.5 ± 0.3 µM) und FE@SNAP (Ki = 65.1 ± 2.9 µM) zeigten eine mittlere Affinität für den ADRB3. Kompetitive LigandTracer® Experimente zeigten, dass FE@SNAP (35µM) und SNAP-7941 (20µM) in jenem Konzentrationsbereich eine Verdrängung vom [125I]CYP verursachen, was auf eine Interaktion mit dem ADRB3 hindeutet. Die Anreicherung von [11C]SNAP-7941 in CHO-K1-ADRB3 Zellen erfolgte konzentrationsabhängig, konnte aber mittels ADRB3 Agonisten Carazolol oder CL 316243 nicht verdrängt werden. Interessanterweise wurde durch Carazolol (2 µM) eine verstärkte [18F]FE@SNAP-Akkumulation in dieser Zelllinie verursacht, wobei CL 316243 keinen Effekt hatte. Im Gegensatz zu Präadipozyten wurde [18F]FDG von differenzierten Adipozyten stark und linear aufgenommen. Durch konventionelle Radioligand-Bindungsstudien konnte eine um 35% gesteigerte [18F]FDG-Aufnahme in braune Fettzellen beobachtet werden, welche durch den ADRB3 Agonist CL 316243 ausgelöst wurde. Die MCHR1 Liganden SNAP-7941 und FE@SNAP wiesen hingegen ein anderes Verhalten als in vivo auf. Die Aufnahme von [18F]FDG wurde in den in vitro Experimenten signifikant reduziert (um 30% im Falle von SNAP-7941 und um 26% bei FE@SNAP). In vitro wurde [11C]SNAP-7941 von den differenzierten braunen Fettzellen akkumuliert, wobei diese teilweise verdrängbar war. In LigandTracer® Experimenten konnte durch 20 µM SNAP-7941 nur eine gerinfügige Verdrängung von [11C]SNAP-7941 Bindung erzielt werden. Die konventionellen Radioligand-Bindungsstudien zeigten eine 25%ige Reduktion der [11C]SNAP-7941-Akkumulation, wenn mit SNAP-7941 (2 oder 20 µM) vorbehandelt wurde. Die ADRB3 Liganden CL 316243 und Propranolol (2 µM) haben die Bindung bzw. die Aufnahme von [11C]SNAP-7941 um ungefähr 10% reduziert, was bedeutet, dass nur ein kleiner Teil der [11C]SNAP-7941 Bindung ADRB3 vermittelt ist.
Die mittlere Affinität von SNAP-7941 und FE@SNAP zu ADRB3, die in µM-Bereich liegt, kann die Anreicherung von [11C]SNAP-7941 und [18F]FE@SNAP in braunem Fettgewebe in vivo nicht erklären, da in µPET Experimenten lediglich pM-Konzentrationen der PET-Tracer appliziert werden. Vermutlich liegen hier neben der ADRB3 Bindung auch andere Prozesse wie eine nicht-spezifische Anreicherung im Fettgewebe sowie eine passive Diffusion vor. Anhand der Affinität von SNAP-7941 und FE@SNAP zu ADRB3 deutet der Effekt der pharmakologischen (µM) Dosis auf die Aufnahme von [18F]FDG jedoch auf einen ADRB3-vermittelten Effekt hin. SNAP-7941 hat allerdings einen gegenteiligen Effekt bezüglich [18F]FDG Aufnahme in differenzierte braune Fettzellen in vitro im Vergleich zu in vivo und hat sich auch anders als der ADRB3 Agonist CL 316243 verhalten.Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide playing a key role in energy homeostasis and body weight. Two PET tracers targeting MCHR1, the receptor for this peptide, have recently been developed, [11C]SNAP-7941 and [18F]FE@SNAP. Specific uptake of [18F]FE@SNAP into brown adipose tissue (BAT) of conscious freely moving rats was observed after blocking with a pharmacological dose of SNAP-7941 (15 mg/kg BW), although the expression of MCHR1 in BAT has not been described yet. However, contradictory observations were made in µPET studies: a trend towards uptake enhancement of [18F]FE@SNAP into BAT of anaesthetized rats after displacement with SNAP-7941 was observed. Moreover, administration of SNAP-7941 led to an increased uptake of [18F]FDG into BAT of anaesthetized rats, suggestive of activating BAT in a similar way as it was described for beta3-adrenergic receptor (ADRB3) agonists. ADRB3 is expressed primarily in adipose tissue, where it is essential for lipolysis and in BAT for thermogenesis.
The hypothesis was, that these two MCHR1 ligands bind to ADRB3 in BAT and the affinity of SNAP-7941 and FE@SNAP for ADRB3 was determined. Competitive binding studies using the filtration method with membranes expressing hADRB3 and [3H]-CGP-12177 as radioligand and real-time whole cell-binding studies using LigandTracer® Technology with CHO-K1 cells stably expressing hADRB3 and [125I]-(-)-Iodocyanopindolol as well as [11C]SNAP-7941 and [18F]FE@SNAP were performed.
The second aim was to characterize the interaction of [11C]SNAP-7941 with brown adipocytes and to elicit the effect of the two MCHR1 ligands as well as known ADRB3 ligands on the uptake of [18F]FDG into BAT. Murine brown preadipocytes were differentiated into mature brown adipocytes, stained with Oil Red O and real-time binding LigandTracer® experiments and well plate radioligand binding assays were performed.
The affinities of the two MCHR1 ligands for ADRB3 were in two-digit µM-range. SNAP-7941 was more affine (Ki = 14.5 ± 0.3 µM) than FE@SNAP (Ki = 65.1 ± 2.9 µM). In real-time whole cell-binding studies, similar concentrations (20 µM SNAP-7941, 35 µM FE@SNAP) led to displacement of [125I]CYP. [11C]SNAP-7941 accumulated in concentration-dependent manner to CHO-K1-ADRB3 cells and could not be displaced from the cells with ADRB3 agonists (carazolol, CL 316243). Interestingly, 2 µM carazolol led to an increase in accumulation of [18F]FE@SNAP to the cell line, while CL 316243 had no effect. [18F]FDG was linearly taken up to the mature brown adipocytes in contrast to undifferentiated preadipocytes. In well plate assays, ADRB3 agonist CL 316243 increased the uptake of [18F]FDG into brown adipocytes (35% increase). MCHR1 ligands SNAP-7941 and FE@SNAP however behaved differently than in vivo and in 20 µM concentration decreased [18F]FDG uptake significantly (30% and 26% decrease, respectively). [11C]SNAP-7941 was accumulated in murine brown adipocytes in vitro and this was partly reversible. 20 µM SNAP-7941 displaced its radiolabeled analogue only slightly in LigandTracer® experiment, in pre-blocking well plate experiment the accumulation was reduced by about 25% and there was no significant difference between 2 and 20 µM SNAP-7941. 2 µM of the ADRB3 ligands CL 316243 and propranolol reduced the accumulation by approximately 10% in the well plate assay, which is in agreement with the low affinity of SNAP-7941 and FE@SNAP for ADRB3.
The affinities of SNAP-7941 and FE@SNAP in µM-range do not explain the specific accumulation of [18F]FE@SNAP into BAT in vivo, PET tracers are applied in pM-concentrations in µPET experiments. The accumulation of potential MCHR1 PET tracers in BAT can partly be caused by binding to ADRB3 in brown adipocytes, but there is probably an extensive non-specific binding or at least partial passive diffusion into brown fat cells. Taking into account the affinity of SNAP-7941 and FE@SNAP to ADRB3, the effect of a pharmacological (µM) dose of SNAP-7941 on [18F]FDG uptake could be via ADRB3. However, SNAP-7941 had a directly opposite effect on [18F]FDG uptake in mature brown adipocytes in vitro compared to in vivo in anaesthetized rats and acted differently than ADRB3 agonist CL 316243
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
In vivo evaluation of radiotracers targeting the melanin-concentrating hormone receptor 1: [11C]SNAP-7941 and [18F]FE@SNAP reveal specific uptake in the ventricular system
No full textAbstractThe MCHR1 is involved in the regulation of energy homeostasis and changes of the expression are linked to a variety of associated diseases, such as diabetes and adiposity. The study aimed at the in vitro and in vivo evaluation of [11C]SNAP-7941 and [18F]FE@SNAP as potential PET-tracers for the MCHR1. Competitive binding studies with non-radioactive derivatives and small-animal PET/CT and MRI brain studies were performed under baseline conditions and tracer displacement with the unlabelled MCHR1 antagonist (±)-SNAP-7941. Binding studies evinced high binding affinity of the non-radioactive derivatives. Small-animal imaging of [11C]SNAP-7941 and [18F]FE@SNAP evinced high tracer uptake in MCHR1-rich regions of the ventricular system. Quantitative analysis depicted a significant tracer reduction after displacement with (±)-SNAP-7941. Due to the high binding affinity of the non-labelled derivatives and the high specific tracer uptake of [11C]SNAP-7941 and [18F]FE@SNAP, there is strong evidence that both radiotracers may serve as highly suitable agents for specific MCHR1 imaging.</jats:p
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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