Björn Wängler

Universität Mannheim, Mannheim, Baden-Württemberg, Germany

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Publications (82)289.05 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Modern imaging techniques that can provide functional information on tumor vascularization, metabolic activity, or cellularity have seen significant improvements over the past decade. However, most of these techniques are currently not broadly utilized neither in clinical trials nor in clinical routine, although there is a large agreement on the fact that conventional approaches for therapy response assessment such as Response Evaluation Criteria in Solid Tumors or World Health Organization criteria-that exclusively focus on the change in tumor size-are of less value for response assessment in modern thoracic oncology. The aim of this article comprises two parts: a short review of the most promising state-of-the-art imaging techniques that have the potential to play a larger role in thoracic oncology within the near future followed by a meeting report including recommendations of an interdisciplinary expert panel that discussed the potential of the different techniques during the Dresden 2013 Post World Congress of Lung Cancer (WCLC) - International Association for the Study of Lung Cancer (IASLC) meeting. It is intended to provide a comprehensive summary about ongoing trends and future perspectives on functional imaging in thoracic oncology.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 02/2015; 10(2):237-49. DOI:10.1097/JTO.0000000000000412 · 5.80 Impact Factor
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    ABSTRACT: Hintergrund Gastrointestinale Stromatumoren (GIST) sind die häufigste mesenchymale Neoplasie des Gastrointestinaltraktes. Sie unterscheiden sich hinsichtlich Tumorbiologie, Behandlungsstrategie und insbesondere Indikationsstellung zum chirurgischen Vorgehen in wesentlichen Aspekten von gastrointestinalen Karzinomen. Jeder an der Behandlung von GIST beteiligte Chirurg sollte mit diesen Aspekten vertraut sein. Ziel der Arbeit In dieser Arbeit wird der Stellenwert der Positronenemissionstomographie (PET) in der chirurgischen Behandlung von Patienten mit GIST diskutiert und ein Ausblick auf die Entwicklung von auf GIST maßgeschneiderten molekularen Tracern gegeben. Ergebnisse In verschiedenen klinischen Szenarien ist die PET eine wertvolle Hilfe für die Therapieplanung und insbesondere chirurgische Indikationsstellung in der multimodalen Behandlung von GIST. Hervorzuheben sind das Primärstaging, das Monitoring unter neoadjuvanter Therapie sowie das Staging und die Verlaufskontrolle in der metastasierten Situation. Der routinemäßig eingesetzte Tracer ist 18F-FDG, der zuverlässig den Metabolismus von GIST-Läsionen abbildet. Verglichen mit Computertomographie/Magnetresonanztomographie erlaubt das 18F-FDG-PET häufig eine frühere und genauere Responsebeurteilung. GIST-spezifische molekulare Tracer, die eine direkte Prognose zum Therapieansprechen und frühzeitige Informationen zur Resistenzentwicklung liefern könnten, befinden sich in der präklinischen Entwicklung. Hier sind aber noch pharmakokinetische und immunologische Hürden zu überwinden. Fernziel ist die Entwicklung von „theranostics“, also Substanzen, die zugleich diagnostische und therapeutische Zwecke erfüllen. Diskussion In der multimodalen Therapie von GIST und der Indikationsstellung zum chirurgischen Vorgehen hat die PET einen festen Stellenwert.
    coloproctology 01/2015; DOI:10.1007/s00053-015-0525-6
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    ABSTRACT: The aim of this study is to non-invasively assess early, irradiation-induced normal tissue alterations via metabolic imaging with 3'-deoxy-3'-[(18) F]fluorothymidine ([(18) F]FLT).
    Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging 06/2014; 16(6). DOI:10.1007/s11307-014-0755-y · 2.87 Impact Factor
  • Annual meeting of the Society of Nuclear Medicine and Molecular Imaging (SNMMI) , St. Louis MI, USA; 06/2014
  • Gabriel Fischer, Björn Wängler, Carmen Wängler
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    ABSTRACT: Dendritic structures, being highly homogeneous and symmetric, represent ideal scaffolds for the multimerization of bioactive molecules and thus enable the synthesis of compounds of high valency which are e.g., applicable in radiolabeled form as multivalent radiotracers for in vivo imaging. As the commonly applied solution phase synthesis of dendritic scaffolds is cumbersome and time-consuming, a synthesis strategy was developed that allows for the efficient assembly of acid amide bond-based highly modular dendrons on solid support via standard Fmoc solid phase peptide synthesis protocols. The obtained dendritic structures comprised up to 16 maleimide functionalities and were derivatized on solid support with the chelating agent DOTA. The functionalized dendrons furthermore could be efficiently reacted with structurally variable model thiol-bearing bioactive molecules via click chemistry and finally radiolabeled with 68Ga. Thus, this solid phase-assisted dendron synthesis approach enables the fast and straightforward assembly of bioactive multivalent constructs for example applicable as radiotracers for in vivo imaging with Positron Emission Tomography (PET).
    Molecules 06/2014; 19(6):6952-74. DOI:10.3390/molecules19066952 · 2.10 Impact Factor
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    M Pretze, C Wängler, B Wängler
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    ABSTRACT: For many years, the main application of [18F]F-DOPA has been the PET imaging of neuropsychiatric diseases, movement disorders, and brain malignancies. Recent findings however point to very favorable results of this tracer for the imaging of other malignant diseases such as neuroendocrine tumors, pheochromocytoma, and pancreatic adenocarcinoma expanding its application spectrum. With the application of this tracer in neuroendocrine tumor imaging, improved radiosyntheses have been developed. Among these, the no-carrier-added nucleophilic introduction of fluorine-18, especially, has gained increasing attention as it gives [18F]F-DOPA in higher specific activities and shorter reaction times by less intricate synthesis protocols. The nucleophilic syntheses which were developed recently are able to provide [18F]F-DOPA by automated syntheses in very high specific activities, radiochemical yields, and enantiomeric purities. This review summarizes the developments in the field of [18F]F-DOPA syntheses using electrophilic synthesis pathways as well as recent developments of nucleophilic syntheses of [18F]F-DOPA and compares the different synthesis strategies regarding the accessibility and applicability of the products for human in vivo PET tumor imaging.
    BioMed Research International 05/2014; 2014:674063. DOI:10.1155/2014/674063 · 2.71 Impact Factor
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    ABSTRACT: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the digestive tract. The GIST differ substantially from gastrointestinal carcinomas regarding tumor biology, treatment strategies and indications for surgery. Every surgeon involved in the treatment of GIST should be acquainted with these aspects. The aims of this article are to discuss the value of positron emission tomography (PET) in the surgical treatment of patients with GIST and to provide an outlook on the development of molecular tracers specifically tailored for GIST. PET is an invaluable decision aid in the multimodal therapy of GIST and particularly for deciding on surgical indications. Specific scenarios in which PET is used are primary staging monitoring during neoadjuvant therapy and staging and response assessment in the metastatic setting. The routinely used tracer is 18F-fluorodeoxyglucose (18F-FDG) and uptake reliably correlates with the metabolism of GIST lesions. Compared to computed tomography and magnetic resonance imaging (CT/MRI), 18F-FDG-PET often allows a more timely and accurate response assessment. GIST-specific molecular tracers, which could provide a direct prognosis regarding response and development of resistance to treatment, are currently in preclinical development. However, pharmacokinetic and immunological issues still need to be resolved. A distant aim is the development of "theranostics", i.e. substances which serve both diagnostic and therapeutic purposes. PET has an established value in the multimodal treatment of GIST and is particularly useful for deciding on surgical indications.
    Der Chirurg 05/2014; DOI:10.1007/s00104-013-2670-1 · 0.52 Impact Factor
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    ABSTRACT: Water soluble 3nm maleimide-terminated PEGylated gold nanoparticles (maleimide-AuNP) were synthesized in both partially hydrolyzed and non-hydrolyzed forms. Both of these maleimide-AuNPs, when reacted with the silicon-fluorine prosthetic group [18F]SiFA-SH, resulted in radiolabelled AuNPs. These NPs were readily purified with high radiochemical yields (RCY) of 60-80% via size exclusion chromatography. Preliminary small animal positron emission tomography (PET) in healthy rats gave information about the pathway of excretion and the stability of the radioactive label in vivo. The partially hydrolyzed [18F]SiFA-maleimide-AuNPs showed uptake in the brain region of interest (ROI) (> 0.13 % ID/g) which was confirmed by ex vivo examination of the thoroughly perfused rat brain. The multiple maleimide end groups on the AuNP surface also allowed for the simultaneous incorporation of [18F]SiFA-SH and a bioactive peptide (cysteine-modified octreotate, cys-TATE, which can bind to somatostatin receptor subtypes 2 and 5) in a proof of concept study. The well-defined Michael addition reaction between various thiol containing molecules and the multi-functionalized maleimide-AuNPs thus offers an opportunity to develop a new bio-conjugation platform for new diagnostics as well as therapeutics.
    Bioconjugate Chemistry 05/2014; 25(6). DOI:10.1021/bc5001593 · 4.82 Impact Factor
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    ABSTRACT: To determine if the conjugation of a small receptor ligand to a peptidic carrier potentially facilitating the transport across the BBB by "Molecular Trojan Horse" transcytosis is feasible, we synthesized several transport peptide-fallypride-fusion molecules as model systems and determined their binding affinities to the hD2 receptor. Although being affected by conjugation, the binding affinities were found to be still in the nM range (between 1.5nM and 64.2nM). In addition, a homology modeling of the receptor and docking studies for the most potent compounds were performed elucidating the binding modes of the fusion molecules and the structure elements contributing to the observed high receptor binding. Furthermore, no interaction of the hybrid compounds and P-gp, the main excretory transporter of the BBB, were found. From these results it can be inferred that the approach to deliver small neuroreceptor ligands across the BBB by transport peptide carriers is feasible.
    Journal of Medicinal Chemistry 04/2014; 57(10). DOI:10.1021/jm5004123 · 5.48 Impact Factor
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    ABSTRACT: Molecular imaging-and especially positron emission tomography (PET)-has gained increasing importance for diagnosis of various diseases and thus experiences an increasing dissemination. Therefore, there is also a growing demand for highly affine PET tracers specifically accumulating and visualizing target structures in the human body. Beyond the development of agents suitable for PET alone, recent tendencies aim at the synthesis of bimodal imaging probes applicable in PET as well as optical imaging (OI), as this combination of modalities can provide clinical advantages. PET, due to the high tissue penetration of the γ-radiation emitted by PET nuclides, allows a quantitative imaging able to identify and visualize tumors and metastases in the whole body. OI on the contrary visualizes photons exhibiting only a limited tissue penetration but enables the identification of tumor margins and infected lymph nodes during surgery without bearing a radiation burden for the surgeon. Thus, there is an emerging interest in bimodal agents for PET and OI in order to exploit the potential of both imaging techniques for the imaging and treatment of tumor diseases. This short review summarizes the available hybrid probes developed for dual PET and OI and discusses future directions for hybrid agent development.
    04/2014; 2014:153741. DOI:10.1155/2014/153741
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    ABSTRACT: The application of microfluidics to the synthesis of Positron Emission Tomography (PET) tracers has been explored for more than a decade. Microfluidic benefits such as superior temperature control have been successfully applied to PET tracer synthesis. However, the design of a compact microfluidic platform capable of executing a complete PET tracer synthesis workflow while maintaining a line of sight towards commercialization remains a significant challenge. This study takes an integral system design approach to tackle commercialization challenges such as material to process compatibility with a path towards cost effective lab-on-chip mass manufacturing from the start. It integrates all functional elements required for a simple PET tracer synthesis into one compact radiochemistry platform. For the lab-on-chip this includes the integration of on-chip valves, on-chip solid phase extraction (SPE), on-chip reactors and a reversible fluid interface while maintaining compatibility with all process chemicals, temperatures and chip mass manufacturing techniques. For the radiochemistry device it includes an automated chip-machine interface enabling one-move connection of all valve actuators and fluid connectors. A vial-based reagent supply as well as methods to transfer reagents efficiently from the vials to the chip has been integrated. After validation of all those functional elements, the microfluidic platform is exemplarily employed for the automated synthesis of a Gastrin-releasing peptide receptor (GRPR) binding PEGylated Bombesin BN(7-14)-derivative ([18F]PESIN) based PET tracer.
    Lab on a Chip 04/2014; 14(14). DOI:10.1039/C4LC00076E · 5.75 Impact Factor
  • 52. Jahrestagung der Deutschen Gesellschaft für Nuklearmedizin, Hannover, Deutschland; 03/2014
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    ABSTRACT: Gastrin-releasing-peptide (GRP)-receptors and αvβ3-integrins are widely discussed as potential target structures for oncological imaging with positron emission tomography (PET). Favored by the over-expression of receptors on the surface of tumor cells good imaging characteristics can be achieved with highly specific radiolabeled receptor ligands. PEGylated Bombesin (PESIN) derivatives as specific GRP receptor ligands and RGD peptides as specific αvβ3 binders were synthesized and tagged with a Silicon-Fluorine-Acceptor (SiFA) moiety. The SiFA synthon allows for a fast and highly efficient isotopic exchange reaction at room temperature giving the [18F]fluoride labeled peptides in up to 62% radiochemical yields (d.c.) and ≥99% radiochemical purity. Using nanomolar quantities of precursor high specific activities of up to 60 GBq µmol-1 were obtained. To compensate the high lipophilicity of the SiFA moiety various hydrophilic structure modifications were introduced leading to significantly reduced logD values. Competitive displacement experiments with the PESIN derivatives showed a 32 to 6 nM affinity to the GRP receptor on PC3 cells, and with the RGD peptides a 7 to 3 µM affinity to the αvβ3 integrins on U87MG cells could be achieved. All derivatives proved to be stable in human plasma over at least 120 min. Small animal PET measurements and biodistribution studies revealed an enhanced and specific accumulation of the RGD peptide 18F-SiFA-LysMe3-γ-carboxy-D-Glu-RGD (17) in the tumor tissue of U87MG tumor-bearing mice of 5.3% ID/g whereas the PESIN derivatives showed a high liver uptake and an only low accumulation in the tumor tissue of PC3 xenografts. These results demonstrate that the reduction of the overall lipophilicity of SiFA tagged RGD peptides is a promising approach for the generation of novel potent 18F-labeled imaging agents which can be efficiently radiolabeled in a total synthesis time of less than 20 minutes.
    Bioconjugate Chemistry 03/2014; 25(4). DOI:10.1021/bc400588e · 4.82 Impact Factor
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    ABSTRACT: Recently, silicon fluoride building blocks (SiFA) have emerged as valuable and promising tools to overcome challenges in the labeling of peptides and proteins for positron emission tomography (PET). Herein, we report a fully automated synthesis of N-succinimidyl 3-(di-tert-butyl[(18)F]fluorosilyl)benzoate ([(18)F]SiFB) by a commercially available Scintomics Hot Box 3 synthesis module, to be used as a prosthetic group for peptide and protein labeling. The drying of K2.2.2./K (18)F complex was performed according to the Munich method modified by our group (avoiding azeotropic drying) using oxalic acid to neutralize the base from the (18)F(-) containing QMA eluent. This K2.2.2./K (18)F complex was then used for SiFA (18)F-(19)F isotopic exchange followed by a fast purification by a solid-phase-extraction (SPE) to afford [(18)F]SiFB with an average preparative radiochemical yield (RCY) of 24±1% (non-decay corrected (NDC)) within a synthesis time of 30min. The [(18)F]SiFB produced by automated synthesis was then used for the (18)F-labeling of rat serum albumin (RSA) as a proof of applicability.
    Applied radiation and isotopes: including data, instrumentation and methods for use in agriculture, industry and medicine 02/2014; 89C:146-150. DOI:10.1016/j.apradiso.2014.02.017 · 1.06 Impact Factor
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    ABSTRACT: The gastrin releasing peptide receptor (GRPR), being overexpressed on several tumor types, represents a promising target for specific non-invasive in vivo tumor imaging using Positron Emission Tomography. Many of the radiolabeled bombesin analogs being applied in tumor imaging however suffer from shortcomings such as limited in vivo stability and poor tumor to background ratios. These obstacles can be overcome by peptide multimerization as this approach results in constructs comprising several copies of the same peptide, thus retaining the ability to specifically bind to the target structure even if one peptide is cleaved. Furthermore, peptide multimers can result in increased binding avidities to the target which can result in higher absolute tumor uptakes and also tumor to background levels. We therefore synthesized monomers and multimers of the peptide PESIN on dendrimer scaffolds comprising linkers of different lengths. The monomers/multimers were functionalized with the chelator NODAGA, efficiently radiolabeled with 68Ga and evaluated in vitro regarding their GRPR binding affinity. The results show that shorter distances between the peptides moieties result in substantially higher binding affinities/avidities of the monovalent/multivalent PESIN ligands to the GRPR. Furthermore, the bivalent ligands gave the best results in terms of binding avidity, achieving a 2.5-fold increase in avidity compared to the respective monomer. Moreover, the most potent bivalent ligand showed an about 2-fold higher absolute tumor uptake and twice as high tumor-to-background ratios than the monomeric reference DOTA-PESIN in an initial animal PET study in tumor-bearing mice. Thus, besides high avidities, also multivalency positively influences the in vivo pharmacokinetics of peptide multimers.
    Bioconjugate Chemistry 02/2014; 25(3). DOI:10.1021/bc4004662 · 4.82 Impact Factor
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    ABSTRACT: Background. Over the recent years, radiopharmaceutical chemistry has experienced a wide variety of innovative pushes towards finding both novel and unconventional radiochemical methods to introduce fluorine-18 into radiotracers for positron emission tomography (PET). These "nonclassical" labeling methodologies based on silicon-, boron-, and aluminium-(18)F chemistry deviate from commonplace bonding of an [(18)F]fluorine atom ((18)F) to either an aliphatic or aromatic carbon atom. One method in particular, the silicon-fluoride-acceptor isotopic exchange (SiFA-IE) approach, invalidates a dogma in radiochemistry that has been widely accepted for many years: the inability to obtain radiopharmaceuticals of high specific activity (SA) via simple IE. Methodology. The most advantageous feature of IE labeling in general is that labeling precursor and labeled radiotracer are chemically identical, eliminating the need to separate the radiotracer from its precursor. SiFA-IE chemistry proceeds in dipolar aprotic solvents at room temperature and below, entirely avoiding the formation of radioactive side products during the IE. Scope of Review. A great plethora of different SiFA species have been reported in the literature ranging from small prosthetic groups and other compounds of low molecular weight to labeled peptides and most recently affibody molecules. Conclusions. The literature over the last years (from 2006 to 2014) shows unambiguously that SiFA-IE and other silicon-based fluoride acceptor strategies relying on (18)F(-) leaving group substitutions have the potential to become a valuable addition to radiochemistry.
    BioMed Research International 01/2014; 2014:454503. DOI:10.1155/2014/454503 · 2.71 Impact Factor
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    ABSTRACT: Purpose:To evaluate diagnostic performance of gallium 68-tetraazacyclododecane tetraacetic acid-octreotate ((68)Ga-DOTATATE) in detection of recurrent neuroendocrine tumors (NETs).Materials and Methods:Approval was waived by the local ethics committee for this retrospective study. Between 2007 and 2011, 63 patients (mean age, 58 years) were examined with (68)Ga-DOTATATE positron emission tomography (PET)/computed tomography (CT) after primary NET curative resection. Reasons for PET/CT were regular follow-up examinations (n = 30), increased plasma levels of tumor markers (n = 27), or clinical suspicion of recurrence (n = 6). Final diagnosis was determined with histopathologic verification (n = 25) or clinical follow-up (n = 38). PET/CT scans were evaluated in consensus by two readers without blinding to clinical information and independently by two readers with blinding. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated.Results:Final diagnosis of NET recurrence was determined in 29 patients. In three other patients, tumors of nonneuroendocrine origin were diagnosed. (68)Ga-DOTATATE PET/CT helped identify NET recurrence in 26 of 29 patients (sensitivity, 90% ) and exclude presence of recurrent NET in 28 of 34 patients (specificity, 82% ). PET/CT provided false-positive and false-negative results in six and three patients (PPV, 81% [26 of 32]; NPV, 90% [28 of 31]; accuracy, 86% [54 of 63]). In gastroenteropancreatic NET (n = 45), sensitivity was 94% (17 of 18); specificity was 89% (24 of 27); PPV was 85% (17 of 20); NPV was 96% (24 of 25); and accuracy was 91% (41 of 45). Two blinded readers achieved sensitivity of 79% (23 of 29) and 76% (22 of 29); specificity of 85% (29 of 34) and 94% (32 of 34) (κ = 0.80); and accuracy of 83% and 86%.Conclusion:(68)Ga-DOTATATE PET/CT is accurate in detection of recurrent NET. Blinded PET/CT review markedly decreased sensitivity, underlining importance of considering clinical parameters in NET recurrence. Present results must be further validated to substantiate use of (68)Ga-DOTATATE PET/CT in routine follow-up after curative resection of NET.© RSNA, 2013Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13122501/-/DC1.
    Radiology 09/2013; 270(2). DOI:10.1148/radiol.13122501 · 6.21 Impact Factor
  • 21. Jahrestagung der Arbeitsgemeinschaft Radiochemie / Radiopharmazie, Pamhagen, Österreich; 09/2013
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    ABSTRACT: The development of brain imaging agents for positron emission tomography and other in vivo imaging modalities mostly relies on small compounds of low MW as a result of the restricted transport of larger molecules, such as peptides and proteins, across the blood-brain barrier. Besides passive transport, only a few active carrier mechanisms, such as glucose transporters and amino acid transporters, have so far been exploited to mediate the accumulation of imaging probes in the brain. An important question for the future is whether some of the abundant active carrier systems located at the blood-brain barrier can be used to shuttle potential, but non-crossing, imaging agents into the brain. What are the biological and chemical constrictions toward such bioconjugates and is it worthwhile to persue such a delivery strategy?
    Future medicinal chemistry 09/2013; 5(14):1621-34. DOI:10.4155/fmc.13.128 · 4.00 Impact Factor

Publication Stats

945 Citations
289.05 Total Impact Points

Institutions

  • 2012–2014
    • Universität Mannheim
      Mannheim, Baden-Württemberg, Germany
  • 2008–2014
    • Universität Heidelberg
      • Institute of Clinical Radiology
      Heidelburg, Baden-Württemberg, Germany
    • German Cancer Research Center
      Heidelburg, Baden-Württemberg, Germany
  • 2009–2013
    • Ludwig-Maximilians-University of Munich
      • Department of Nuclear Medicine
      München, Bavaria, Germany
    • Technische Universität München
      München, Bavaria, Germany
    • Technische Universität Dortmund
      • Chair of Inorganic Chemistry
      Dortmund, North Rhine-Westphalia, Germany
  • 2007–2012
    • McGill University
      • McConnell Brain Imaging Centre
      Montréal, Quebec, Canada
  • 2002–2006
    • Johannes Gutenberg-Universität Mainz
      • • Klinik und Poliklinik für Nuklearmedizin
      • • Institute for Nuclear Chemistry
      Mainz, Rhineland-Palatinate, Germany