Ulrike Bauder-Wuest

Publications (3)16.24 Total impact

• Article: 68Ga-complex lipophilicity and the targeting property of a urea-based PSMA inhibitor for PET imaging.

  Matthias Eder, Martin Schäfer, Ulrike Bauder-Wüst, William-Edmund Hull, Carmen Wängler, Walter Mier, Uwe Haberkorn, Michael Eisenhut
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  ABSTRACT: Urea-based inhibitors of the prostate-specific membrane antigen (PSMA) represent low-molecular-weight pepidomimetics showing the ability to image PSMA-expressing prostate tumors. The highly efficient, acyclic Ga(III) chelator N,N'-bis [2-hydroxy-5-(carboxyethyl)benzyl] ethylenediamine-N,N'- diacetic acid (HBED-CC) was introduced as a lipophilic side chain into the hydrophilic pharmacophore Glu-NH-CO-NH-Lys which was found favorable to interact with the PSMA "active binding site". This report describes the syntheses, in vitro binding analyses, and biodistribution data of the radiogallium labeled PSMA inhibitor Glu-NH-CO-NH-Lys(Ahx)-HBED-CC in comparison to the corresponding DOTA conjugate. The binding properties were analyzed using competitive cell binding and enzyme-based assays followed by internalization experiments. Compared to the DOTA-conjugate, the HBED-CC derivative showed reduced unspecific binding and considerable higher specific internalization in LNCaP cells. The (68)Ga complex of the HBED-CC ligand exhibited higher specificity for PSMA expressing tumor cells resulting in improved in vivo properties. (68)Ga labeled Glu-NH-CO-NH-Lys(Ahx)-HBED-CC showed fast blood and organ clearances, low liver accumulation, and high specific uptake in PSMA expressing organs and tumor. It could be demonstrated that the PET-imaging property of a urea-based PSMA inhibitor could significantly be improved with HBED-CC.
  Bioconjugate Chemistry 02/2012; 23(4):688-97. · 4.93 Impact Factor
• Article: Zn(II)-bis(cyclen) complexes and the imaging of apoptosis/necrosis.

  Dorte Oltmanns, Sabine Zitzmann-Kolbe, Andre Mueller, Ulrike Bauder-Wuest, Martin Schaefer, Matthias Eder, Uwe Haberkorn, Michael Eisenhut
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  ABSTRACT: In vivo cell-death imaging is still a challenging issue. Until now, only (99m)Tc-labeled HYNIC-rh-annexin A5 has been extensively studied in clinical trials. In the ongoing search for an alternative imaging agent, we synthesized a series of fluorescent zinc-cyclen complexes as annexin A5 mimics and studied structural variations on the uptake behavior of cells undergoing apoptosis/necrosis. The number of cyclen chelators was varied and the spacer separating cyclen from the central scaffold was modified. Five zinc-cyclen complexes were labeled with fluorescein for flow cytometric studies and one was labeled with (18)F for in vivo applications. Jurkat cells were treated with staurosporine to induce apoptosis/necrosis, incubated with the fluorescein-labeled zinc complexes and analyzed them by flow cytometry. Fluorescent annexin A5 and propidium iodide were applied as reference dyes. Flow cytometry revealed greater accumulation of zinc-cyclen complexes in staurosporine treated cells. The uptake was contingent on the presence of zinc and the fluorescence intensity was dependent on the number of zinc-cyclen groups. Confocal laser scanning microscopy showed the {bis[Zn(cyclen)]}(4+) complex distributed throughout the cytosol different to annexin A5. Owing to the structural similarity of the bis-cyclen ligands with CXCR4 binding bis-cyclam derivatives the zinc-cyclen complex uptake was challenged with the meta derivative of AMD3100. Lack of uptake depletion in staurosporine treated cells ruled out measurable CXCR4 interaction. PET imaging using the (18)F labeled zinc-cyclen complex revealed significantly higher uptake in an irradiated Dunning R3327-AT1 prostate tumor as compared to the contralateral control tumor. PET imaging of a HelaMatu tumor model additionally showed an increased uptake after taxol treatment. It could be demonstrated that the fluorescent zinc-cyclen complexes offer potential as new agents for flow cytometry and microscopic imaging of cell death. In addition, the (18)F labeled analogue holds promise for in vivo applications providing informations about cell death after radiation therapy and cytostatic drug treatment.
  Bioconjugate Chemistry 12/2011; 22(12):2611-24. · 4.93 Impact Factor
• Article: 131I-labeled peptides as caspase substrates for apoptosis imaging.

  Claudia Bauer, Ulrike Bauder-Wuest, Walter Mier, Uwe Haberkorn, Michael Eisenhut
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  ABSTRACT: Nonivasive assessment of programmed cell death is currently an attractive research topic for the follow-up of tumor therapy and myocardial infarction. Apoptosis imaging with (99m)Tc-HYNIC-annexin V (HYNIC is hydrazinonicotinamide) is based on the binding of the tracer to externalized phosphatidylserine residues. Concurrently with the externalization of phosphatidylserine, a series of caspases are activated after the onset of apoptosis. These enzymes were chosen as an alternative target for apoptosis imaging. Ten radiolabeled peptides containing the DEVDG sequence, selective for downstream caspases such as caspase-3, were synthesized and evaluated for their uptake kinetics using an apoptosis test system. The molecular requirement of the peptides for being accepted as caspase substrate was studied using a competitive enzyme assay and matrix-assisted laser desorption/ionization mass spectrometry. Within this series of peptides, radioiodinated Tat(49-57)-yDEVDG-NH(2) (7) and Tat(57-49)-yDEVDG-NH(2) (8) were favorably taken up by apoptotic cells (12.54% +/- 1.18% and 12.63% +/- 1.17% after 10-min incubation, respectively) as compared with the controls (7.50% +/- 0.92% and 8.04% +/- 0.28%). The enhanced uptake is interpreted as the interaction of the labeled peptide or fragment with activated caspases. Proof of caspase substrate specificity of peptide 7 and YDEVDG-NH(2) (2) was substantiated. The former peptide was shown to have a stronger competition with the fluorescent Z-DEVD-R110 for caspase-3 than peptide 2. In addition, mass spectrometry revealed only fragmentation for peptide 7. It could be demonstrated that peptides consisting of DEVDG and Tat sequence are caspase substrates with enhanced uptake and retention in apoptotic cells. Current efforts are focused on alternative radioisotopes that include radiometal complexes to further improve these characteristics.
  Journal of Nuclear Medicine 07/2005; 46(6):1066-74. · 6.38 Impact Factor