Christina Hultsch

Technische Universität München, München, Bavaria, Germany

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Publications (15)38.96 Total impact

  • Frank Wuest · Christina Hultsch · Mathias Berndt · Ralf Bergmann
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    ABSTRACT: The study describes the use of [(18)F]FDG as (18)F building block for the direct labelling of various aminooxy-functionalised peptides via chemoselective oxime formation.
    No preview · Article · Aug 2009 · Bioorganic & medicinal chemistry letters
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    ABSTRACT: Oxime formation between an aminooxy-functionalized peptide and an (18)F-labelled aldehyde has recently been introduced as a powerful method for the rapid one-step chemoselective synthesis of radiofluorinated peptides. Here, the potential of using routinely produced and thus readily available [(18)F]fluorodeoxyglucose ([(18)F]FDG) as the aldehydic prosthetic group was investigated using an aminooxyacetyl-conjugated cyclic RGD peptide (cyclo(RGDfK(Aoa-(Boc)) as a model peptide. The use of [(18)F]FDG from routine production ([(18)F]FDGTUM) containing an excess of D: -glucose did not allow the radiosynthesis of [(18)F]FDG-RGD in activities >37 MBq in reasonable yield, rendering the direct use of clinical grade [(18)F]FDG for the routine clinical synthesis of (18)F-labelled peptides impossible. Using no-carrier-added (n.c.a.) [(18)F]FDG obtained via HPLC separation of [(18)F]FDGTUM from excess glucose, however, afforded [(18)F]FDG-RGD in yields of 56-93% (decay corrected) and activities up to 37 MBq. Suitable reaction conditions were 20 min at 120 degrees C and pH 2.5, and a peptide concentration of 5 mM. In a preliminary in vivo biodistribution study in M21 melanoma-bearing nude mice, [(18)F]FDG-RGD showed increased tumour accumulation compared to the "gold standard" [(18)F]galacto-RGD (2.18 vs 1.49 %iD/g, respectively, at 120 min after injection), but also slightly increased uptake in non-target organs, leading to comparable tumour/organ ratios for both compounds. These data demonstrate that chemoselective (18)F-labelling of aminooxy-functionalized peptides using n.c.a. [(18)F]FDG represents a radiofluorination/glycosylation strategy that allows preparation of (18)F-labelled peptides in high yield with suitable pharmacokinetics. As soon as the necessary n.c.a. preparation of [(18)F]FDG prior to reaction with the Aoa-peptide can be implemented in a fully automated [(18)F]FDG-synthesis, [(18)F]fluoroglucosylation of peptides may represent a promising alternative to currently used chemoselective one-step (18)F-labelling protocols.
    No preview · Article · Apr 2009 · European Journal of Nuclear Medicine
  • C. Hultsch · R. Bergmann · M. Berndt · F. Wuest

    No preview · Article · Jan 2009 · Journal of Labelled Compounds and Radiopharmaceuticals
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    ABSTRACT: Unsaturated α-, β- and γ-amino acids have been investigated as substrates for the reductive Meerwein arylation. Radical reactions of this type have been shown to be a valuable tool for the fast and efficient introduction of the 4-[18F]fluorophenyl group into precursor molecules allowing short-time syntheses of potential PET radiotracers, which would be more difficult to access by other methods.
    No preview · Article · Dec 2008 · Tetrahedron
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    ABSTRACT: The increasing demand for radiopharmaceuticals to be provided reproducibly and flexibly with high frequency for clinical application and animal imaging would be better met by improved or even new strategies for automated tracer production. Radiosynthesis in microfluidic systems, i.e. narrow tubing with a diameter of approximately 50-500 microm, holds promise for providing the means for repetitive multidose and multitracer production. In this study, the performance of a conceptually simple microfluidic device integrated into a fully automated synthesis procedure for in-capillary radiosynthesis (ICR) of clinical grade [(18)F]FDG was evaluated. The instrumental set-up consisted of pumps for reagent and solvent delivery into small mixing chambers, micro-fluidic capillaries, in-process radioactivity monitoring, solid-phase extraction and on-column deprotection of the (18)F-labelled intermediate followed by on-line formulation of [(18)F]FDG. In-capillary(18)F-fluorination of 2.1 micromol 1,3,4,6-tetra-O-acetyl-2-O-trifluoromethanesulphonyl-beta-D-mannopyranose (TATM; precursor for [(18)F]FDG) in acetonitrile (MeCN) at a flow rate of 0.3 ml/min within 40 s and subsequent on-line hydrolysis of the intermediate by treatment with 0.3 M NaOH for 1 min at 40 degrees C resulted in a radiochemical yield of 88 +/- 4% within <7 min. Reproducibility, robustness and suitability as a fast and efficient radiopharmaceutical research tool for (18)F-fluorination was demonstrated by eight independent, sequentially performed ICRs which provided identical tracer quality (radiochemical purity >97%, MeCN <5 microg/ml) and similar absolute yields (approximately 1.4 GBq). The described ICR process is a simple and efficient alternative to classic radiotracer production systems and provides a comparatively cheap instrumental methodology for the repetitive production of [(18)F]FDG with remarkably high efficiency and high yield under fully automated conditions. Although the results concerning the levels of activity need to be confirmed after installation of the equipment in a suitable GMP hot-cell environment, we expect the instrumental design to allow up-scaling without major difficulties or fundamental restrictions. Furthermore, we are convinced that similar or nearly identical procedures, and thus instrumentation, will allow ICR of other (18)F-labelled radiopharmaceuticals.
    No preview · Article · Dec 2008 · European Journal of Nuclear Medicine
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    ABSTRACT: In this study, we report on the radical [18F]fluoroarylation of different olefins using 4-[18F]fluorobenzenediazonium ions to provide a new route to radiopharmaceuticals containing a deactivated, 4-[18F]fluoro substituted phenyl group. This new methodology was shown to be well suited for the synthesis of 18F-labelled stilbenes. Stilbene 7 is now accessible within 80min in 30–45% overall radiochemical yield starting from [18F]fluoride.
    Preview · Article · Mar 2008 · Tetrahedron Letters
  • Christina Hultsch · Mathias Berndt · Ralf Bergmann · Frank Wuest
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    ABSTRACT: Three methods for (18)F-labeling of dimeric and tetrameric neurotensin(8-13) derivatives were evaluated with respect to the labeling yield and the required peptide amounts. Labeling using N-succinimidyl-4-[(18)F]fluorobenzoate ([(18)F]SFB) gave low radiochemical yield for the dimeric peptides. Coupling of the tetramer with [(18)F]SFB was not successful. High yields were obtained for labeling of the aminooxy-functionalized neurotensin(8-13) dimer using 4-[(18)F]fluorobenzaldehyde ([(18)F]FBA) whilst coupling of the corresponding tetramer gave only low yields. Labeling of sulfydryl-functionalized neurotensin(8-13) derivatives using the maleinimide 4-[(18)F]fluorobenzaldehyde-O-[6-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-hexyl]-oxime ([(18)F]FBAM) resulted in high radiochemical yields for both, the dimer and the tetramer. Therefore, [(18)F]FBAM seems to be the most suitable (18)F-labeling agent for multivalent neurotensin(8-13) derivatives.
    No preview · Article · Aug 2007 · Applied Radiation and Isotopes
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    ABSTRACT: Amadori products are formed in the early stage of the so-called Maillard reaction between reducing sugars and amino acids or proteins. Such nonenzymatic glycosylation may occur during the heating or storage of foods, but also under physiological conditions. N-epsilon-fructoselysine is formed via this reaction between the epsilon-amino group of peptide-bound lysine and glucose. Despite the fact that, in certain heated foods, up to 50% of lysyl moieties may be modified to such lysine derivatives, up to now, very little is known about the metabolic fate of alimentary administered Amadori compounds. In the present study, N-succinimidyl-4-[18F]fluorobenzoate was used to modify N-epsilon-fructoselysine at the alpha-amino group of the lysyl moiety. The in vitro stability of the resulting 4-[18F]fluorobenzoylated derivative was tested in different tissue homogenates. Furthermore, the 4-[18F]fluorobenzoylated N-epsilon-fructoselysine was used in positron emission tomography studies, as well as in studies concerning biodistribution and catabolism. The results show that the 4-[18F]fluorobenzoylated N-epsilon-fructoselysine is phosphorylated in vitro, as well as in vivo. This phosphorylation is caused by fructosamine 3-kinases and occurs in vivo, particularly in the kidneys. Despite the action of these enzymes, it was shown that a large part of the intravenously applied radiolabeled N-epsilon-fructoselysine was excreted nearly unchanged in the urine. Therefore, it was concluded that the predominant part of peptide-bound lysine that was fructosylated during food processing is not available for nutrition.
    No preview · Article · Nov 2006 · Nuclear Medicine and Biology
  • Christina Hultsch · Beate Pawelke · Ralf Bergmann · Frank Wuest
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    ABSTRACT: Neurotensin(8-13) is a hexapeptide with subnanomolar affinity to the neurotensin receptor 1 which is expressed with high incidence in several human tumor entities. Thus, radiolabeled neurotensin(8-13) might be used for tumor targeting. However, its application is limited by insufficient metabolic stability. The present study aims at improving metabolic stability by the synthesis of multimeric neurotensin(8-13) derivatives rather than commonly employed chemical modifications of the peptide itself. Thus, different dimeric and tetrameric peptides carrying C- or N-terminal attached neurotensin(8-13) moieties have been synthesized and their binding affinity toward the neurotensin receptor has been determined. The results demonstrate that branched compounds containing neurotensin(8-13) attached via its C-terminus only show low receptor affinities, whilst derivatives with neurotensin(8-13) attached via the N-terminus show IC50 values in the nanomolar range. Moreover, within the multimeric neurotensin(8-13) derivatives with neurotensin(8-13) attached via the N-terminus an increasing number of branching units lead to higher binding affinities toward the neurotensin receptor.
    No preview · Article · Oct 2006 · Bioorganic & Medicinal Chemistry
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    ABSTRACT: Neurotensin(8-13) analogs containing a glycine or 5-aminovaleroyl spacer were labeled with fluorescein through formation of an N-terminal thiourea function. The receptor binding was measured in HT-29 cell cultures and showed a substantial decrease in affinity, especially for the metabolically stabilized [MeArg(9), Tle(11)] analog. Using fluorescence microscopy, the internalization of the fluorescent neurotensin analogs into HT-29 cells was observed. Copyright (c) 2006 European Peptide Society and John Wiley & Sons, Ltd.
    No preview · Article · Aug 2006 · Journal of Peptide Science
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    ABSTRACT: I. E. Markó [Université catholique de Louvain, Belgium]—Novel Orthoesters in Organic Synthesis. S. J. Harwood [GlaxoSmithKline, UK]—The Synthesis of Stable Labelled Ketamine. Th. Moenius, R. Salter, B. Wietfeld, P. Burtscher, C. Zueger [Novartis, Switzerland]—C-13, C-14, N-15 Labelling of the 4-Cyanobenzyl bromide – A Versatile Labelling Building Block. J. Clayden [University of Manchester, UK]—Synthesis and Stereocontrol with Lithiated Amides. R. Salter, K. Bordeaux, P. Burtscher, Y. Metz, Th. Moenius, I. Rodriguez, R. Ruetsch, R. Voges, C. Zueger [Novartis, Switzerland]—Isotopic Labelling of STI571 and its Metabolites in the Development of Gleevec®. J. M. Gardiner, W. Stimpson, N. Panchal [University of Manchester, UK], J. Herbert, G. J. Ellames [Sanofi-Aventis, UK]—Synthesis of Labelled Carbohydrates. M. Beller [Rostock University, Germany]—Homogeneous Catalysis – A Powerful Tool for the Synthesis of Pharmaceuticals. J. Kozempel, J. Kadeřávek, L. Lešetický, O. Lebeda [University of Prague, Czech]—Preparation of Ortho-radiohalogenated Phenylazides and Triazenes, Versatile Building Blocks for Indirect Labelling. K. Wähälä, P. Kiuru, E. Leppälä, M. Pohjoispää, K. Parikka, B. Raffaelli [University of Helsinki, Finland]—Controlled Polydeuteration of Estrogenic Compounds. J. M. Herbert [Sanofi-Aventis, UK]—Catalyst Stability in Iridium-mediated Isotope Exchange. C. G. M. Janssen, W.L.M. Verluyten, M. Vliegen [Johnson & Johnson Pharmaceutical, Belgium]—Pd/C Catalysed Hydrogenolytic H/T Exchange in Solvents, Effects on Solvents and Product in a Bromine-tritium Exchange Reaction. P. Mäding, F. Füchtner, R. Bergmann, J. Pietzsch, C. Hultsch, F. Wüst [Forschungszentrum Rossendorf, Germany]—A New Module-Assisted Synthesis of the Versatile, Bifunctional Labelling Agent [18F]SFB: From Radiochemistry to Applications. M. Scheunemann, J. Vercouillie, St. Fischer, J. Steinbach [Institut für Interdisziplinäre Isotopenforschung Leipzig, Germany], D. Sorger, U. Großmann, O. Sabri, R. Schliebs [University Leipzig, Germany]—Syntheses and First Biological Evaluation of 18F Labelled Bicyclic Analogues of Vesamicol as Potential VAChT Imaging Agents.
    No preview · Article · Feb 2006 · Journal of Labelled Compounds and Radiopharmaceuticals
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    ABSTRACT: The human organism is exposed to numerous processes that generate reactive oxygen species (ROS). ROS may directly or indirectly cause oxidative modification and damage of proteins. Protein oxidation is regarded as a crucial event in the pathogenesis of various diseases ranging from rheumatoid arthritis to Alzheimer's disease and atherosclerosis. As a representative example, oxidation of low density lipoprotein (LDL) is regarded as a crucial event in atherogenesis. Data concerning the role of circulating oxidized LDL (oxLDL) in the development and outcome of diseases are scarce. One reason for this is the shortage of methods for direct assessment of the metabolic fate of circulating oxLDL in vivo. We present an improved methodology based on the radiolabelling of apoB-100 of native LDL (nLDL) and oxLDL, respectively, with the positron emitter fluorine-18 ((18)F) by conjugation with N-succinimidyl-4-[(18)F]fluorobenzoate ([(18)F]SFB). Radiolabelling of both nLDL and oxLDL using [(18)F]SFB causes neither additional oxidative structural modifications of LDL lipids and proteins nor alteration of their biological activity and functionality, respectively, in vitro. The method was further evaluated with respect to the radiopharmacological properties of both [(18)F]fluorobenzoylated nLDL and oxLDL by biodistribution studies in male Wistar rats. The metabolic fate of [(18)F]fluorobenzoylated nLDL and oxLDL in rats in vivo was further delineated by dynamic positron emission tomography (PET) using a dedicated small animal tomograph (spatial resolution of 2 mm). From this study we conclude that the use of [(18)F]FB-labelled LDL particles is an attractive alternative to, e.g., LDL iodination methods, and is of value to characterize and to discriminate the kinetics and the metabolic fate of nLDL and oxLDL in small animals in vivo.
    Full-text · Article · Jan 2006 · Amino Acids
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    ABSTRACT: Isopeptide bonds between the epsilon-amino group of lysine and the gamma-carboxamide group of glutamine are formed during strong heating of pure proteins or, more important, by enzymatic reaction mediated by transglutaminases. Despite the wide use of a microbial transglutaminase in food biotechnology, up to now little is known about the metabolic fate of the isopeptide N(epsilon)-(gamma-glutamyl)-L-lysine. In the present study, N-succinimidyl-4-[(18)F]fluorobenzoate was used to modify N(epsilon)-(gamma-glutamyl)-L-lysine at each of its two alpha-amino groups, resulting in the 4-[(18)F]fluorobenzoylated derivatives, for which biodistribution, catabolism, and elimination were investigated in male Wistar rats. A significant different biochemical behavior of the two labelled isopeptides was observed in terms of in vitro stability, in vivo metabolism as well as biodistribution. The results suggest that the metabolic fate of isopeptides is likely to be dependent on how they are reabsorbed - free or peptide bound.
    Full-text · Article · Jan 2006 · Amino Acids
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    ABSTRACT: Oxidative modification of low-density lipoprotein (LDL) is regarded as a crucial event in atherogenesis. Assessing the metabolic fate of oxidized LDL (oxLDL) in vivo with radiotracer techniques is hindered by the lack of suitable sensitive and specific radiolabeling methods. We evaluated an improved methodology based on the radiolabeling of native LDL (nLDL) and oxLDL with the positron emitter fluorine-18 ((18)F) by conjugation with N-succinimidyl-4-[(18)F]fluorobenzoate ([(18)F]SFB). We investigated whether radiolabeling of LDL induces adverse structural modifications. Results suggest that radiolabeling of both nLDL and oxLDL using [(18)F]SFB causes neither additional oxidative structural modifications of LDL lipids and proteins nor alteration of their biological activity and functionality, respectively. Thus, radiolabeling of LDL using [(18)F]SFB could prove to be a promising approach for studying the kinetics of oxLDL in vivo.
    No preview · Article · Dec 2004 · Nuclear Medicine and Biology
  • F Wüst · C Hultsch · R Bergmann · B Johannsen · T Henle
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    ABSTRACT: The isopeptide N(epsilon)-(gamma-glutamyl)-L-lysine 4 was labelled with 18F via N-succinimidyl-4-[18F]fluorobenzoate ([18F]SFB). A modified approach for the convenient synthesis of [18F]SFB was used, and [18F]SFB could be obtained in decay-corrected radiochemical yields of 44-53% (n = 20) and radiochemical purity >95% within 40 min after EOB. For labelling N(epsilon)-(gamma-glutamyl)-L-lysine with [18F]SFB the effects of isopeptide concentration, temperature, and pH were studied to determine the optimum reaction conditions. The coupling reaction was shown to be temperature and pH independent while being strongly affected by the isopeptide concentration. Using the optimized labelling conditions, in a typical experiment 1.3GBq of [18F]SFB could be converted into 447MBq (46%, decay-corrected) of [18F]fluorobenzoylated isopeptide within 45 min, including HPLC purification.
    No preview · Article · Jul 2003 · Applied Radiation and Isotopes

Publication Stats

279 Citations
38.96 Total Impact Points


  • 2008-2009
    • Technische Universität München
      • Nuklearmedizinische Klinik und Poliklinik
      München, Bavaria, Germany
  • 2004-2009
    • Helmholtz-Zentrum Dresden-Rossendorf
      • • Institute of Radiopharmacy
      • • PET Center
      Dresden, Saxony, Germany
  • 2003
    • Technische Universität Dresden
      • Food Chemistry
      Dresden, Saxony, Germany