DOCSLIB.ORG

Design and Synthesis of FVIII- and Upar-Selective Ligands and Cross- Linked Polymers As Media for NMR-Spectroscopy

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Design and Synthesis of FVIII- and Upar-Selective Ligands and Cross- Linked Polymers As Media for NMR-Spectroscopy Technische Universität München Department Chemie Lehrstuhl II für Organische Chemie Design and Synthesis of FVIII- and uPAR-Selective Ligands and Cross- Linked Polymers as Media for NMR-Spectroscopy Sebastian Knör Vollständiger Abdruck der von der Fakultät für Chemie der Technischen Universität München zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften genehmigten Dissertation. Vorsitzender: Univ.-Prof. Dr. K. Köhler Prüfer der Dissertation: 1. Univ.-Prof. Dr. H. Kessler 2. Univ.-Prof. Dr. A. Türler 3. Priv.-Doz. Dr. Viktor Magdolen Die Dissertation wurde am 23.05.2007 bei der Technischen Universität München eingereicht und durch die Fakultät für Chemie am 05.07.2007 angenommen. Die vorliegende Arbeit wurde am Lehrstuhl II für Organische Chemie der Technischen Universität München in der Zeit von Oktober 2002 bis Mai 2007 unter der Leitung von Prof. Dr. Horst Kessler angefertigt. Meiner Frau gewidmet Σ’αγαπώ πολύ Publier dans un petit journal ne veut pas dire petit résultat. Ce qui compte c'est que les gens l'essayent pour dire que ça marche!! In einem kleinen Journal zu publizieren heißt nicht, kleine Ergebnisse zu haben. Was zählt ist, dass die Leute es ausprobieren um zu sagen: Es geht! (Abdellah Benhida, Univ. Leuven) DANKSAGUNG Meinem Doktorvater, Herrn Professor Dr. Horst Kessler, danke ich besonders für die vielen interessanten Themen, die ich bearbeiten durfte. Insbesondere bedanke ich mich für die uneingeschränkte Unterstützung in jeder Hinsicht, für den großen wissenschaftlichen Freiraum, der mir gewährt wurde, sowie für die zahlreichen fruchtbaren und hilfreichen Diskussionen. Für die ausgezeichnete Zusammenarbeit auf dem Gebiet der Faktor VIII Liganden möchte ich mich ganz herzlich bei • Dr. Alexey Khrenov und Prof. Dr. Evgueni Saenko, • Dr. Charlotte Hauser, • Dr. Abdellah Benhida und Prof Dr. Jean-Marie Saint-Remy, • Dr. Rainer Schwaab und Prof. Dr. Johannes Oldenburg sowie • Dr. Nathalie Beaufort und PD. Dr. Viktor Magdolen bedanken. Mit ihrer Hilfe habe ich viel über die Biologie des Faktor VIII und die Schwierigkeiten in der Behandlung der Hämophilie gelernt. Ihr großartiger Einsatz hat maßgebliche zum Erfolg des Projektes beigetragen. Für die hervorragende Zusammenarbeit auf dem Gebieten des Tumor-Imaging und der Tumor-Therapy und bedanke ich mich bei: • Dr. Sumito Sato, PD Dr. Viktor Magdolen und Prof. Dr. Manfred Schmitt, • Dr. Christof Seidl und Prof. Dr. Reingard Senekowitsch-Schmidtke sowie • Dr. Thorsten Poethko, Dr. Margret Schottelius und Prof. Dr. Hans-Jürgen Wester Ohne Ihren unermüdlichen Eifer wäre ein Gelingen dieser Projekte nicht möglich gewesen. Burghard Cordes und Helmut Krause bin ich für zahlreiche analytische Messungen und Maria Kranawetter für das HPLC-Trennen unzähliger Verbindungen zu großem Dank verpflichtet. Mona Wolff danke ich für das Ausführen zahlreicher Synthesen, die Organisation unseres Chemikalienhaushaltes und ihre immer hilfreichen Antworten auf Fragen wie: „Wo ist…?“, „Haben wir…?“, usw. Alexander Frenzel und Rainer Haeßner danke ich für die Hilfe bei allen Computerproblemen, wie „Internet geht nicht!“ und Evelyn Bruckmaier für die vielen netten Worte und Aufmunterun- gen. Der gesamten NMR-Gruppe, insbesondere Rainer Haeßner, Gerd Gemmecker, Burkhard Luy, Peter Kaden, Grit Kummerlöwe und Andreas Enthart für die Einführung in das Messen von NMR-Spektren und die sofortige Hilfe bei allen kleinen und großen Problemen. Allen derzeitigen und ehemaligen Mitgliedern des Arbeitskreises danke ich für das gute Klima und die nette Atmosphäre, insbesondere Burkhardt Laufer, Timo Huber, Jayanter Chatterjee, Eric Biron, Grit Kummerlöwe, Enrique Mann, Armin Modlinger, Axel Meyer, Dominik Heckmann, Andreas Frank, Jörg Auernheimer, Martin Sukopp, Ulrich Hersel, Florian Manzenrieder, Florian Opperer, Lukas Doedens, Peter Kaden, Andreas Enthart und Oliver Demmer. Mein weiterer Dank gilt: • Burkhardt Laufer, Jayanter Chatterjee, Timo Huber, Dominik Heckmann und Grit Kummerlöwe für das Korrekturlesen dieser Arbeit. • Philipp Gradicsky für zwei Jahre als studentische Hilfskraft im Labor – jederzeit zur Stelle • Meinen zahlreichen Forschungsstudenten und Chemielaboranten-Azubis für ihre selbständige Mitarbeit in meinen Forschungsprojekten und die Hilfe im Labor, insbesondere Burkhardt Laufer, Philipp Gradicsky, Bianca Ludwig, Bastian Sauerer, Robert Jäger und Helge Menz. • Axel Meyer, Jörg Auernhaimer, Armin Modlinger, Thorsten Arndt, Dominik Heckmann, Burkhardt Laufer, Timo Huber und Eric Biron für anregende Diskussionen und Hilfestellung jeder Art. Großer Dank gebührt all meinen Förderern, Lehrer und Tutoren in Schul- und Studienzeiten, ohne deren Einsatz diese Ausbildung nicht möglich gewesen wäre. Insbesondere bedanke ich mich bei meinem Chemielehrer Herrn Franz Hetzer, der seine Begeisterung für die Chemie auf mich hat überspringen lassen, sowie bei Professor Dr. Wolfgang Steglich und Professor Dr. Paul Knochel für Ihren großen Einsatz als Hochschullehrer und die intensive und zeitaufwändige Förderung während meines Studiums. Meinen Eltern, danke ich für die großzügige Unterstützung während der meiner gesamten Ausbildung. Ganz besonderer Dank gilt meiner Frau, für die Erduldung der vielen Entbehrungen während meiner Ausbildung, die tolle Verpflegung, die uneingeschränkte Unterstüt- zung in allen Zeiten und alles andere, wofür man einem Menschen sonst noch danken kann. Publications Parts of this work have already been published or are in preparation: Publications S. Knör, A. Khrenov, B. Laufer, E. L. Saenko, C. A. E. Hauser, H. Kessler. Develop- ment of a peptidomimetic ligand for efficient isolation and purification of factor VIII via affinity chromatography. Journal of Medicinal Chemistry, submitted. S. Knör, A. Khrenov, B. Laufer, A. Benhida, R. Schwaab, J. Oldenburg, N. Beaufort, V. Magdolen, J.-M. Saint-Remy, E. L. Saenko, C. A. E. Hauser, H. Kessler. Efficient FVIII affinity purification using a small synthetic ligand. Journal of Thrombosis and Haemostasis, submitted. S. Knör, S. Sato, T. Huber, A. Morgenstern, F. Bruchertseifer, M. Schmitt, H. Kessler, R. Senekowitsch-Schmidtk, V. Magdolen, C. Seidl. Development and evaluation of peptidic ligands targeting tumour-associated urokinase plasminogen activator receptor (uPAR) for use in α-emitter therapy of disseminated ovarian cancer. European Journal of Nuclear Medicine and Molecular Imaging, submitted. S. Knör, A. Modlinger, T. Poethko, M. Schottelius, H.J. Wester, H. Kessler. Synthe- sis of novel DOTA-derivatives for chemoselective attachment to polyfunctionalized compounds. Chemistry — A European Journal 2007, in press. S. Knör, B. Laufer, H. Kessler. Efficient enantioselective synthesis of condensed and aromatic ring-substituted tyrosine derivatives. Journal of Organic Chemistry 2006, 71, 5625-5630. B. Luy, K. Kobzar, S. Knör, J. Furrer, D. Heckmann, H. Kessler. Orientational properties of stretched polystyrene gels in organic solvents and the suppression of their residual 1H NMR signals. Journal of the American Chemical Society 2005, 127, 6459-6465. J. C. Freudenberger, S. Knör, K. Kobzar, D. Heckmann, T. Paululat, B. Luy. Stretched poly(vinyl acetate) gels as NMR alignment media fort he measurement of residual dipolar dipolar couplings in polar organic solvents. Angewandte Chemie International Edition 2005, 44, 423-426. Patents S. Knör, H. Kessler, C. A. E. Hauser, A. Khrenov, E. L. Saenko. Small peptidic and peptidomimetic affinity ligands for Factor VIII and Factor VIII-like proteins. International patent application PCT/EP2006/011786. H. Kessler, C. A. E. Hauser, A. Khrenov, S. Knör, E. L. Saenko. Minimized affinity ligands for Factor VIII and Factor VIII-like proteins. European patent application No. 04 013 852.6. S. Knör, A. Modlinger, H.-J. Wester, H. Kessler. Novel DOTA-derivatives for chemoselective attachment to polyfunctionalized compounds. Great Britain patent application No. 06 245 87.2. Abstracts S. Knör, B. Laufer, A. Khrenov, A. Benhida, S. Grailly, J.-M. Saint-Remy, E. L. Saenko, C. A. E. Hauser and H. Kessler. Factor VIII affinity purification using small ligands. Hämostaseologie 2007, 1, A 65. H. Kessler, B. Luy, K. Kobzar, J. C. Freudenberger, S. Knör, D. Heckmann, J. Klages. RDC as a new NMR-parameter for peptides. Biopolymers 2005, 80, 500. S. Knör, D. Heckmann, L. Marinelli, E. L. Saenko, C. A. E. Hauser and H. Kessler. Linear and cyclic peptides as affinity ligands in Factor VIII purification. Peptides 2004, Proceedings of the 28th European Peptide Symposium, Prague, Czech Republic & Journal of Peptide Science 2004, 10(S2), 272. — Table of Contents — SYNOPSIS 1 CHAPTER 1: DEVELOPMENT OF SMALL MOLECULE LIGANDS FOR AFFINITY PURIFICATION OF FACTOR VIII 9 1.1 Background 9 1.1.1 Blood coagulation and fibrinolysis 10 1.1.1.1 The intrinsic pathway 10 1.1.1.2 The extrinsic pathway 12 1.1.1.3 The common pathway and clot formation 14 1.1.1.4 Temporal and spatial control of clot formation 15 1.1.1.5 Fibrinolysis 17 1.1.2 Hemophilia 18 1.1.2.1 Bleeding disorders: A general overview 18 1.1.2.2 Hemophilia A – The Royal disease 19 1.1.2.3 Treatment of hemophilia A 21 1.1.3 FVIII structure and mechanism of cofactor action 22 1.1.4 FVIII production and purification 26 1.1.5 General synthetic aspects: Solid-phase peptide synthesis 27 1.2 Systematic lead optimization and minimization: From an octa- peptide to an unnatural dipeptide 31 1.2.1 Preliminary studies. Development of the binding assay and selection of the lead structure 31 1.2.2 Optimization of the lead octapeptide EYHSWEYC (3) 32 1.2.3
Load more

Recommended publications
  • Targeting Somatostatin Receptors: Preclinical Evaluation of Novel 18F-Fluoroethyltriazole-Tyr3-Octreotate Analogs for PET
    Journal of Nuclear Medicine, published on August 18, 2011 as doi:10.2967/jnumed.111.088906 Targeting Somatostatin Receptors: Preclinical Evaluation of Novel 18F-Fluoroethyltriazole-Tyr3-Octreotate Analogs for PET Julius Leyton1, Lisa Iddon2, Meg Perumal1, Bard Indrevoll3, Matthias Glaser2, Edward Robins2, Andrew J.T. George4, Alan Cuthbertson3, Sajinder K. Luthra2, and Eric O. Aboagye1 1Comprehensive Cancer Imaging Center at Imperial College, Faculty of Medicine, Imperial College London, London, United Kingdom; 2MDx Discovery (part of GE Healthcare) at Hammersmith Imanet Ltd., Hammersmith Hospital, London, United Kingdom; 3GE Healthcare AS, Oslo, Norway; and 4Section of Immunobiology, Faculty of Medicine, Imperial College London, London, United Kingdom Key Words: somatostatin receptor; octreotide; 18F-fluoroethyl- The incidence and prevalence of gastroenteropancreatic triazole-Tyr3-octreotate; positron emission tomography; and neuroendocrine tumors has been increasing over the past 3 neuroendocrine decades. Because of high densities of somatostatin receptors J Nucl Med 2011; 52:1–8 (sstr)—mainly sstr-2—on the cell surface of these tumors, 111In- DOI: 10.2967/jnumed.111.088906 diethylenetriaminepentaacetic acid-octreotide scintigraphy has become an important part of clinical management. 18F-radio- labeled analogs with suitable pharmacokinetics would permit PET with more rapid clinical protocols. Methods: We compared the affinity in vitro and tissue pharmacokinetics by PET of 5 structurally related 19F/18F-fluoroethyltriazole-Tyr3-octreotate The incidence and prevalence of gastroenteropancreatic (FET-TOCA) analogs: FET-G-polyethylene glycol (PEG)-TOCA, neuroendocrine tumors (GEP-NETs) has increased signifi- FETE-PEG-TOCA, FET-G-TOCA, FETE-TOCA, and FET-bAG- cantly over the past 3 decades (1). The most common site TOCA to the recently described 18F-aluminum fluoride NOTA- of primary GEP-NETs is the gastrointestinal tract (60%).
    [Show full text]
  • Alshaer Danah Mahdi 2020.Pdf (14.70Mb)
    Synthesis and physiochemical characterization of new siderophore- inspired peptide-chelators with 1- hydroxypridine-2-one (1,2-HOPO) Thesis Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy by Danah Mahdi AlShaer 2020 Supervisor: Prof. Beatriz Garcia de la Torre Co-supervisor: Prof. Fernando Albericio Synthesis and physiochemical characterization of new siderophore-inspired peptide• chelators with 1-hydrnxypridine-2-one (1,2-JB[OPO) 217078895 Danah Mahdi AllSlh.aer A thesis submitted to the School of Health Sciences, College of Health Sciences, University of KwaZulu-Natal, Westville, for the degree of Doctor of Philosophy by research in Pharmaceutical Chemistry. This is the thesis in which the chapters are written as a set of discrete research publications that have followed each journal's format with an overall introduction and final summary. These chapters have been published in internationally recognized, peer-reviewed journals. This is to certify that the contents of this thesis are the original research work of Mrs Danah Mahdi AllSllnaer, carried out under our supervision at the Peptide Sciences Laboratory, Westville campus, University of KwaZulu-Natal, Durban, South Africa. Supervisor: --"-:I-----::... Date: gth December 2020 Date: 8th December 2020 As the candidate's supervisors we agree to the submission of this thesis Table of Contents Abstract……………..…………………………………………………………………..……1 Declaration 1: Plagiarism.……………………………………………………….…………..2 Declaration 2: Publications ….………………………………………………….…...….…..3 Acknowledgment………………………………………..………………...…………….…..5 Aim and objectives……….….……………………………………………………………...6 Chapter 1: (Introduction) Hydroxamate Siderophores: Natural Occurrence, Chemical Synthesis, Iron Binding Affinity and Use as Trojan Horses Against ………..……….. 7 Reprint………………………………………………………………………………………8 Chapter 2: Solid-phase synthesis of peptides containing 1-Hydroxypyridine-2-one (1,2-HOPO) …………………………………………………….……………………….
    [Show full text]
  • Somatostatin Analogues in the Treatment of Neuroendocrine Tumors: Past, Present and Future
    International Journal of Molecular Sciences Review Somatostatin Analogues in the Treatment of Neuroendocrine Tumors: Past, Present and Future Anna Kathrin Stueven 1, Antonin Kayser 1, Christoph Wetz 2, Holger Amthauer 2, Alexander Wree 1, Frank Tacke 1, Bertram Wiedenmann 1, Christoph Roderburg 1,* and Henning Jann 1 1 Charité, Campus Virchow Klinikum and Charité, Campus Mitte, Department of Hepatology and Gastroenterology, Universitätsmedizin Berlin, 10117 Berlin, Germany; [email protected] (A.K.S.); [email protected] (A.K.); [email protected] (A.W.); [email protected] (F.T.); [email protected] (B.W.); [email protected] (H.J.) 2 Charité, Campus Virchow Klinikum and Charité, Campus Mitte, Department of Nuclear Medicine, Universitätsmedizin Berlin, 10117 Berlin, Germany; [email protected] (C.W.); [email protected] (H.A.) * Correspondence: [email protected]; Tel.: +49-30-450-553022 Received: 3 May 2019; Accepted: 19 June 2019; Published: 22 June 2019 Abstract: In recent decades, the incidence of neuroendocrine tumors (NETs) has steadily increased. Due to the slow-growing nature of these tumors and the lack of early symptoms, most cases are diagnosed at advanced stages, when curative treatment options are no longer available. Prognosis and survival of patients with NETs are determined by the location of the primary lesion, biochemical functional status, differentiation, initial staging, and response to treatment. Somatostatin analogue (SSA) therapy has been a mainstay of antisecretory therapy in functioning neuroendocrine tumors, which cause various clinical symptoms depending on hormonal hypersecretion. Beyond symptomatic management, recent research demonstrates that SSAs exert antiproliferative effects and inhibit tumor growth via the somatostatin receptor 2 (SSTR2).
    [Show full text]
  • Tanibirumab (CUI C3490677) Add to Cart
    5/17/2018 NCI Metathesaurus Contains Exact Match Begins With Name Code Property Relationship Source ALL Advanced Search NCIm Version: 201706 Version 2.8 (using LexEVS 6.5) Home | NCIt Hierarchy | Sources | Help Suggest changes to this concept Tanibirumab (CUI C3490677) Add to Cart Table of Contents Terms & Properties Synonym Details Relationships By Source Terms & Properties Concept Unique Identifier (CUI): C3490677 NCI Thesaurus Code: C102877 (see NCI Thesaurus info) Semantic Type: Immunologic Factor Semantic Type: Amino Acid, Peptide, or Protein Semantic Type: Pharmacologic Substance NCIt Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor tyrosine kinase expressed by endothelial cells, while VEGF is overexpressed in many tumors and is correlated to tumor progression. PDQ Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor
    [Show full text]
  • Downloaded from Bioscientifica.Com at 09/23/2021 09:50:19AM Via Free Access
    5 181 S W J Lamberts and Octreotide 181:5 R173–R183 Review L J Hofland ANNIVERSARY REVIEW Octreotide, 40 years later Correspondence should be addressed Steven W J Lamberts and Leo J Hofland to S W J Lamberts Division of Endocrinology, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands Email [email protected] Abstract Octreotide remains 40 years after its development a drug, which is commonly used in the treatment of acromegaly and GEP-NETs. Very little innovation that competes with this drug occurred over this period. This review discusses several aspects of 40 years of clinical use of octreotide, including the application of radiolabeled forms of the peptide. European Journal of Endocrinology (2019) 181, R173–R183 Introduction A peptide inhibiting the release of growth hormone initial enthusiasm for its clinical use. From 1978 on, a (GH) was accidentally detected in the hypothalamus of number of drug companies started programs to synthesize rats during studies of the distribution of GH-releasing long-acting somatostatin analogs. factor (1). This peptide, called somatostatin, is a peptide Octreotide (SMS 201-995) was one of the first hormone that plays an inhibitory role in the regulation biologically stable somatostatin analogs to be synthesized of multiple physiological functions, including pituitary, (8): it has a much longer half-life in the human circulation European Journal of Endocrinology pancreatic and gastrointestinal hormone secretion (2, 3). than somatostatin and binds with a high affinity to Somatostatin exerts its biological effects by interaction SST2 (9). The structure of natural somatostatin and with specific somatostatin receptors (SSTs) expressed on octreotide is shown in Fig.
    [Show full text]
  • Multi-Discipline Review(S)
    CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 210828Orig1s000 MULTI-DISCIPLINE REVIEW Summary Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review NDA/BLA Multi-Disciplinary Review and Evaluation (NDA 210828) 505(b)(2) (Ga-68-DOTATOC) NDA/BLA Multi-Disciplinary Review and Evaluation Application Type NME & 505 (b)(2) Application Number(s) NDA 210828 Priority or Standard Standard Submit Date(s) May 23, 2018 Received Date(s) May 23, 2018 PDUFA Goal Date August 23, 2019 Division/Office Office of Drug Evaluation IV/Division of Medical Imaging Products (DMIP/ODEIV) Review Completion Date TBD Established/Proper Name Ga-68-DOTATOC injection (Proposed) Trade Name Not applicable Pharmacologic Class Radioactive diagnostic agent Code name IC2000 Applicant University of Iowa Health Care/P.E.T. Imaging Center Dosage Form Injection: Clear, colorless solution containing 18.5 to 148 MBq/mL (0.5 to 4 mCi/mL) of Ga-68-DOTATOC injection at end of synthesis (EOS) (approximately 14 mL volume) in a 30 mL multiple-dose vial. Applicant proposed Dosing For adults: 148 MBq (4 mCi); for pediatric patients: 1.59 Regimen MBq/kg (0.043 mCi/kg) with a range of 11.1 MBq (0.3 mCi) to 111 MBq (3 mCi) Applicant Proposed For localization of somatostatin receptor positive (b) (4) Indication(s)/Population(s) neuroendocrine tumors (NETs) in (b) (4) adult and pediatric patients. Applicant Proposed Indicated for use with positron emission tomography (PET) for SNOMED CT Indication localization of somatostatin receptor positive neuroendocrine (b) (4) Disease Term for Each tumors (NETs) in adult and pediatric (b) (4) Proposed Indication patients.
    [Show full text]
  • Overview of Results of Peptide Receptor Radionuclide Therapy with 3 Radiolabeled Somatostatin Analogs
    Overview of Results of Peptide Receptor Radionuclide Therapy with 3 Radiolabeled Somatostatin Analogs Dik J. Kwekkeboom, MD1; Jan Mueller-Brand, MD2; Giovanni Paganelli, MD3; Lowell B. Anthony, MD4; Stanislas Pauwels, MD5; Larry K. Kvols, MD6; Thomas M. O’Dorisio, MD7; Roelf Valkema, MD1; Lisa Bodei, MD3; Marco Chinol, PhD3; Helmut R. Maecke, PhD2; and Eric P. Krenning, MD1 1Department of Nuclear Medicine, Erasmus Medical Center, University Hospital Rotterdam, Rotterdam, The Netherlands; 2Department of Nuclear Medicine, University Hospital Basel, Basel, Switzerland; 3Department of Nuclear Medicine, European Institute of Oncology, Milan, Italy; 4Division of Hematology and Oncology, Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana; 5Department of Nuclear Medicine, Universitaire Catholique Louvain, Brussels, Belgium; 6Lee Moffitt Cancer Center, University of South Florida, Tampa, Florida; and 7Division of Endocrinology, Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa Key Words: somatostatin; somatostatin receptor; radionuclide A new treatment modality for inoperable or metastasized gas- therapy; gastroenteropancreatic tumors troenteropancreatic tumors is the use of radiolabeled soma- J Nucl Med 2005; 46:62S–66S tostatin analogs. Initial studies with high doses of [111In-diethyl- enetriaminepentaacetic acid (DTPA)0]octreotide in patients with metastasized neuroendocrine tumors were encouraging, al- though partial remissions were uncommon. Another radiola- beled somatostatin analog that is used for peptide receptor Neuroendocrine gastroenteropancreatic (GEP) tumors, radionuclide therapy (PRRT) is [90Y-1,4,7,10-tetraazacyclodode- which comprise pancreatic islet cell tumors, nonfunctioning -cane-N,NЈ,NЉ,Nٞ-tetraacetic acid (DOTA)0,Tyr3]octreotide. Vari- neuroendocrine pancreatic tumors, and carcinoids, are usu ous phase 1 and phase 2 PRRT trials have been performed with ally slow growing.
    [Show full text]
  • Use of DOTATATE PET/CT Scan in the Diagnosis and Staging Of
    WJOESWJOES DOTATATE10.5005/jp-journals-10002-1231 PET/CT in Thymic Carcinoid CASE REPORT Use of DOTATATE PET/CT Scan in the Diagnosis and Staging of Thymic Atypical Carcinoid Tumor in a Patient with Secondary ACTH-dependent Cushing Syndrome: Look Twice and Cut Once 1John Agzarian, 2Hisham Quandeel, 3Irina Bancos, 4Geoffrey B Johnson, 5Stephen C Scharf, 6Geoffrey B Thompson 7Joanne Yi, 8Xiaotun Zhang, 9K Robert Shen ABSTRACT Keywords: DOTATATE, Mediastinal, Positron emission tomog- raphy, Thymic carcinoid. Neuroendocrine thymic tumors represent the least common type of primary thymic tumor with a prevalence of 2 to 5%. We How to cite this article: Agzarian J, Quandeel H, Bancos I, present a case of locally advanced thymic atypical carcinoid Johnson GB, Scharf SC, Thompson GB, Yi J, Zhang X, Shen KR. tumor diagnosed incidentally while investigating progressive Use of DOTATATE PET/CT Scan in the Diagnosis and Staging of Thymic Atypical Carcinoid Tumor in a Patient with Second- Cushing syndrome. Computed tomography (CT) scan demon- ary ACTH-dependent Cushing Syndrome: Look Twice and Cut strated a large 2.9 cm exophytic thyroid nodule and a 2.0 cm Once. World J Endoc Surg 2018;10(2):127-133. anterior mediastinal mass. Biopsy of the thyroid nodule demon- strated benign thyroid tissue, and octreotide scan revealed avid Source of support: Nil uptake in the right thyroid lobe with minimal uptake in the thymic Conflict of interest: None tumor. 68Gallium-1,4,7,10-tetraazacyclododecane-N,N′,N″N′″- tetraacetic acid-D-Phe1,Tyr 3-octreotate (Ga-68 DOTATATE) positron emission tomography (PET)/CT scan showed intense INTRODUCTION uptake in the thyroid gland followed by a moderate amount of activity in the anterior mediastinal mass.
    [Show full text]
  • Selected Cases 2018
    25-28 October 2018 Regnum Carya Hotel, Antalya - Turkey SELECTED CASES www.endobridge.org 2018 STEERING COMMITTEE Susan Mandel President, ES Dolores Shoback Chair, Scientific & Educational Programs Committee, ES Aart J Van Der Lely President, ESE Jens Bollerslev Immediate Past Chair, Education Committee, ESE Camilla Schalin-Jäntti Chair, Education Committee, ESE Sevim Gullu President, SEMT Sadi Gundogdu Past President, SEMT Bulent O. Yildiz Founder & President, EndoBridge® Dilek Yazici Scientific Secreteriat, EndoBridge® Ozlem Celik Scientific Secreteriat, EndoBridge® 2 25 - 28 October, 2018 Antalya - Turkey 2018 SCIENTIFIC PROGRAM Friday, 26 October 2018 08.40 - 09.00 Welcome and Introduction to EndoBridge 2018 MAIN HALL Chairs: Sadi Gündoğdu, Aj van der Lely 09.00 - 09.30 Difficult cases with anterior pituitary tumors: Beyond the guidelines - Jens Otto Jorgensen 09.30 - 10.00 Radiological examination of the sellar region - Jean-François Bonneville 10.00 - 10.30 Evaluation and management of hypophysitis - Niki Karavitaki 10.30 - 11.00 Fluid and electrolyte balance following pituitary surgery - Alper Gürlek 11.00 - 11.20 Coffee Break 11.20 - 12.50 Interactive Case Discussion Sessions HALL A Pituitary - Niki Karavitaki, Züleyha Karaca HALL B Adrenal - Richard Auchus, Serkan Yener HALL C Neuroendocrine tumors- Camilla Schalin-Jäntti, Djuro Macut HALL D Male Reproductive Endocrinology - Dimitrios Goulis, Özlem Üstay Tarçın 12.50 - 14.00 Lunch 14.00 - 15.30 Interactive Case Discussion Sessions HALL A Pituitary - Jens Otto Jorgensen, Jean-François
    [Show full text]
  • Assessment Report
    13 October 2016 EMA/734748/2016 Committee for Medicinal Products for Human Use (CHMP) Assessment report SomaKit TOC International non-proprietary name: edotreotide Procedure No. EMEA/H/C/004140/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. 30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5520 Send a question via our website www.ema.europa.eu/contact An agency of the European Union Table of contents 1. Background information on the procedure .............................................. 6 1.1. Submission of the dossier ..................................................................................... 6 1.2. Steps taken for the assessment of the product ........................................................ 7 2. Scientific discussion ................................................................................ 8 2.1. Problem statement ............................................................................................... 8 2.1.1. Disease or condition .......................................................................................... 8 2.1.2. Epidemiology .................................................................................................... 8 2.1.3. Biologic features ............................................................................................... 9 2.1.4. Clinical presentation .......................................................................................
    [Show full text]
  • Comparison of the Therapeutic Response to Treatment with a 177-Lutetium Labeled Somatostatin Receptor
    Journal of Nuclear Medicine, published on October 29, 2015 as doi:10.2967/jnumed.115.167007 Comparison of the therapeutic response to treatment with a 177-lutetium labeled somatostatin receptor agonist and antagonist in preclinical models Simone U. Dalm1, Julie Nonnekens1,2, Gabriela N. Doeswijk1, Erik de Blois1, Dik C. van Gent2, Mark W. Konijnenberg1 and Marion de Jong1 1Department of Nuclear Medicine & Radiology, Erasmus MC, Rotterdam, The Netherlands 2Department of Genetics, Erasmus MC, Rotterdam, The Netherlands Corresponding author: Simone U. Dalm (PhD student) Room: Na620 P.O box 2040 3000 CA Rotterdam, the Netherlands +31-107041033 [email protected] Word count: 4999 Running title: Therapy with SSTR agonist vs. antagonist ABSTRACT Peptide receptor scintigraphy (PRS) and peptide receptor radionuclide therapy (PRRT) using radiolabeled somatostatin receptor (SSTR) agonists are successfully used in the clinic for imaging and treatment of neuroendocrine tumors. Contrary to the paradigm that internalization and the resulting accumulation of radiotracers in cells is necessary for efficient tumor targeting, recent studies have demonstrated superiority of radiolabeled SSTR antagonists for imaging purposes, despite little to no internalization in cells. However, studies comparing the therapeutic anti-tumor effects of radiolabeled SSTR agonists versus antagonists are lacking. The aim of this study was to directly compare the therapeutic effect of 177Lu-DOTA-octreotate, an SSTR agonist, and 177Lu-DOTA-JR11, an SSTR antagonist. Methods: We analyzed radiotracer uptake (both membrane-bound and internalized fractions) and the produced DNA double strand breaks, by determining the number of p53 binding protein 1 (53BP1) foci, after incubating SSTR2 positive cells with 177Lu-DTPA, 177Lu-DOTA-octreotate or 177Lu-DOTA-JR11.
    [Show full text]
  • [177Lu-DOTA0,Tyr3]Octreotate in Patients with Gastroenteropancreatic and Bronchial Neuroendocrine Tumors
    Author Manuscript Published OnlineFirst on April 20, 2017; DOI: 10.1158/1078-0432.CCR-16-2743 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Title: Long-term efficacy, survival and safety of [177Lu-DOTA0,Tyr3]octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors Authors: Tessa Brabander1, Wouter A van der Zwan1, Jaap JM Teunissen1, Boen LR Kam1, Richard A Feelders2, Wouter W de Herder2, Casper HJ van Eijck3, Gaston JH Franssen3, Eric P Krenning1, Dik J Kwekkeboom1† 1Department of Radiology & Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands 2Department of Internal Medicine, Erasmus Medical Center, ENETS Center of Excellence, Rotterdam, The Netherlands 3Department of Surgery, Erasmus Medical Center, Rotterdam, The Netherlands Corresponding author: Tessa Brabander, [email protected] Department of Radiology & Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. ‘s-Gravendijkwal 230 3015 CE Rotterdam Tel: +31107040321 Fax: +31107033737 Running head: Efficacy, survival and toxicity after 177Lu-DOTATATE. Keywords: Neuroendocrine tumors; Peptide receptor radionuclide therapy (PRRT), 177Lu-DOTATATE, toxicity. Conflict of Interest: DJ Kwekkeboom and EP Krenning are stockholders of Advanced Accelerators Applications, Geneva, France. 1 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 20, 2017; DOI: 10.1158/1078-0432.CCR-16-2743 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. TRANSLATIONAL RELEVANCE Peptide receptor radionuclide therapy (PRRT) with [177Lu-DOTA0,Tyr3]octreotate is a therapeutic option for metastasized or inoperable gastroenteropancreatic and bronchial neuroendocrine tumors that present the somatostatin receptors on their surface.
    [Show full text]