Albeda Research

Copenhagen, Denmark

Albeda Research

Copenhagen, Denmark
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Chiavazza E.,University of Turin | Viale A.,University of Turin | Karlsson M.,Albeda Research | Aime S.,University of Turin
Contrast Media and Molecular Imaging | Year: 2013

The synthesis, NMR properties and preliminary polarization tests on protonated and perdeuterated forms of α-trimethylglutamine (NMe3Gln), α-trimethylglutamate (NMe3Glu) and ε-trimethyllysine (NMe3Lys) are reported. The 15N-permethylated, perdeuterated amino acids display very long 15N-T1 values, ranging between 190 and 330 s, are well polarized by the dynamic nuclear polarization (DNP) procedure, yielding good polarization levels (10%), and appear to be well tolerated by cells and mice. The obtained results make perdeuterated amino acids excellent candidates for innovative DNP 15N-MRI applications such as perfusion or targeting studies. Copyright © 2013 John Wiley & Sons, Ltd. 15N-permethylated, perdeuterated amino acids display very long-T1 values for the (CD3)3 15N resonances thus representing particularly suitable substrates for applications such as perfusion or targeting studies. © 2013 John Wiley & Sons, Ltd.

Allouche-Arnon H.,Hebrew University of Jerusalem | Allouche-Arnon H.,BrainWatch Ltd | Lerche M.H.,Albeda Research | Karlsson M.,Albeda Research | And 3 more authors.
Contrast Media and Molecular Imaging | Year: 2011

The promising dynamic nuclear polarization (DNP) for hyperpolarized 13C-MRI/MRS of real-time metabolism in vivo is challenged by the limited number of agents with the required physical and biological properties. The physical requirement of a liquid-state T 1 of tens of seconds is mostly found for 13C-carbons in small molecules that have no direct protons attached, i.e. carbonyl, carboxyl and certain quaternary carbons. Unfortunately, such carbon positions do not exist in a large number of metabolic agents, and chemical shift dispersion often limits detection of their chemical evolution. We have previously shown that direct deuteration of protonated carbon positions significantly prolongs the 13C T 1 in the liquid state and provides potential 13C-labeled agents with differential chemical shift with respect to metabolism. The Choline Molecular Probe [1,1,2,2-D 4, 2- 13C]choline chloride (CMP2) has recently been introduced as a means of studying choline metabolism in a hyperpolarized state. Here, the biophysical properties of CMP2 were characterized and compared with those of [1- 13C]pyruvate to evaluate the impact of molecular probe deuteration. The CMP2 solid-state polarization build-up time constant (30min) and polarization level (24%) were comparable to those of [1- 13C]pyruvate. Both compounds' liquid state T 1 increased with temperature. The high-field T 1 of CMP2 compared favorably with [1- 13C]pyruvate. Thus, a deuterated agent demonstrated physical properties comparable to a hyperpolarized compound of already proven value, whereas both showed chemical shift dispersion that allowed monitoring of their metabolism. It is expected that the use of deuterated carbon-13 positions as reporting hyperpolarized nuclei will substantially expand the library of agents for DNP-MR. © 2011 John Wiley & Sons, Ltd.

Jensen P.R.,Technical University of Denmark | Jensen P.R.,Albeda Research | Meier S.,Technical University of Denmark
Analyst | Year: 2016

The influx of exogenous substrates into cellular reaction cascades on the seconds time scale is directly observable by NMR spectroscopy when using nuclear spin polarization enhancement. Conventional NMR assignment spectra for the identification of reaction intermediates are not applicable in these experiments due to the non-equilibrium nature of the nuclear spin polarization enhancement. We show that ambiguities in the intracellular identification of transient reaction intermediates can be resolved by experimental schemes using site-specific isotope labelling, optimised referencing and response to external perturbations. © The Royal Society of Chemistry 2016.

Meier S.,Carlsberg Laboratory | Karlsson M.,Albeda Research | Jensen P.R.,Albeda Research | Lerche M.H.,Albeda Research | Duus J.O.,Carlsberg Laboratory
Molecular BioSystems | Year: 2011

Central carbon metabolism of living Saccharomyces cerevisiae is visualized by DNP-NMR. Experiments are conducted as real time assays that detect metabolic bottlenecks, pathway use, reversibility of reactions and reaction mechanisms in vivo with subsecond time resolution. © 2011 The Royal Society of Chemistry.

Karlsson M.,Albeda Research | Jensen P.R.,Albeda Research | Duus J.O.,Carlsberg Laboratory | Meier S.,Carlsberg Laboratory | Lerche M.H.,Albeda Research
Applied Magnetic Resonance | Year: 2012

Dissolution dynamic nuclear polarization (DNP) provides a broadly applicable and rather simple means of developing probes for the real-time molecular imaging of cellular functions in vivo. The development of novel dissolution DNP substrate formulations is only rewarding for substrates that yield detectable metabolism within few minutes. In addition, in vivo preparations usually require amorphous samples at molar substrate concentrations for an efficient and reproducible DNP step with sufficient material. The composition ranges of novel substrate preparations need to be established experimentally owing to the solute's impact on vitrification behavior. Here, we describe simple rationales employed in the development of novel substrate preparations for dissolution DNP-magnetic resonance. Solution state substrate polarizations between 10 and 40 % have been obtained for ~40 metabolic substrates in highly concentrated preparations that yield physiologically tolerable solutions with sufficient T 1 for in vivo nuclear magnetic resonance. Substrate metabolism is observed for novel in vivo substrates such as 3-hydroxybutyrate and aspartate. © 2012 Springer-Verlag.

Lerche M.H.,Albeda Research | Meier S.,Carlsberg Laboratory | Jensen P.R.,Albeda Research | Hustvedt S.O.,General Electric | And 3 more authors.
NMR in Biomedicine | Year: 2011

Analytical platforms for the fast detection, identification and quantification of circulating drugs with a narrow therapeutic range are vital in clinical pharmacology. As a result of low drug concentrations, analytical tools need to provide high sensitivity and specificity. Dynamic nuclear polarization-NMR (DNP-NMR) in the form of the hyperpolarization-dissolution method should afford the sensitivity and spectral resolution for the direct detection and quantification of numerous isotopically labeled circulating drugs and their metabolites in single liquid-state NMR transients. This study explores the capability of quantitative in vitro DNP-NMR to assay drug metabolites in blood plasma. The lower limit of detection for the anti-epileptic drug 13C-carbamazepine and its pharmacologically active metabolite 13C-carbamazepine-10,11-epoxide is 0.08μg/mL in rabbit blood plasma analyzed by single-scan 13C DNP-NMR. An internal standard is used for the accurate quantification of drug and metabolite. Comparison of quantitative DNP-NMR data with an established analytical method (liquid chromatography-mass spectrometry) yields a Pearson correlation coefficient r of 0.99. Notably, all DNP-NMR determinations were performed without analyte derivatization or sample purification other than plasma protein precipitation. Quantitative DNP-NMR is an emerging methodology which requires little sample preparation and yields quantitative data with high sensitivity for therapeutic drug monitoring. This study demonstrates that quantitative in vitro dynamic nuclear polarization-NMR (DNP-NMR) provides high sensitivity and accuracy for the assay of circulating drugs and their metabolites. The lower limit of detection for 13C-carbamazepine and its metabolite 13C-carbamazepine-10,11-epoxide is 0.08μg/mL in rabbit blood plasma analyzed by single-scan 13C DNP-NMR. Copyright © 2010 John Wiley & Sons, Ltd.

Jensen P.R.,Albeda Research | Karlsson M.,Albeda Research | Lerche M.H.,Albeda Research | Meier S.,Carlsberg Laboratory
Chemistry - A European Journal | Year: 2013

Uptake and upshot in vivo: Straightforward methods that permit the real-time observation of organic acid influx, intracellular acidification, and concomitant effects on cellular-reaction networks are crucial for improved bioprocess monitoring and control (see scheme). Herein, dynamic nuclear polarization (DNP) NMR is used to observe acetate influx, ensuing intracellular acidification and the metabolic consequences on alcoholic fermentation and glycolysis in living cells. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Jensen P.R.,Technical University of Denmark | Jensen P.R.,Albeda Research | Meier S.,Technical University of Denmark
Chemical Communications | Year: 2016

Organic phosphate metabolites contain functional groups with pKa values near the physiologic pH range, yielding pH-dependent 13C chemical shift changes of adjacent quaternary carbon sites. When formed in defined cellular compartments from exogenous hyperpolarised 13C substrates, metabolites can thus yield localised pH values and correlations of organelle pH and catalytic activity. © The Royal Society of Chemistry 2016.

Meier S.,Carlsberg Laboratory | Jensen P.R.,Albeda Research | Duus J.O.,Carlsberg Laboratory
FEBS Letters | Year: 2011

The direct tracking of cellular reactions in vivo has been facilitated with recent technologies that strongly enhance NMR signals in substrates of interest. This methodology can be used to assay intracellular reactions that occur within seconds to few minutes, as the NMR signal enhancement typically fades on this time scale. Here, we show that the enhancement of 13C nuclear spin polarization in deuterated glucose allows to directly follow the flux of glucose signal through rather extended reaction networks of central carbon metabolism in living Escherichia coli. Alterations in central carbon metabolism depending on the growth phase or upon chemical perturbations are visualized with minimal data processing by instantaneous observation of cellular reactions. © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Meier S.,Carlsberg Laboratory | Solodovnikova N.,Carlsberg Laboratory | Jensen P.R.,Albeda Research | Wendland J.,Carlsberg Laboratory
ChemBioChem | Year: 2012

Detecting the molecular targets of xenobiotic substances in vivo poses a considerable analytical challenge. Here, we describe the use of an NMR-based tracer methodology for the instantaneous in vivo observation of sulfur(IV) action on cellular metabolism. Specifically, we find that glycolytic flux is directed towards sulfite adducts of dihydroxyacetone phosphate and pyruvate as off-pathway intermediates that obstruct glycolytic flux. In particular, the pyruvate-sulfite association hinders the formation of downstream metabolites. The apparent in vivo association constant of pyruvate and sulfite agrees with the apparent inhibition constant of CO2 formation, thus supporting the importance of pyruvate interception in disturbing central metabolism and inhibiting NAD regeneration. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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