Specific PET-Ligands for Selected 5-Htand GABA A-Receptor Subtypes

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Specific PET-Ligands for Selected 5-Htand GABA A-Receptor Subtypes Specific PET-ligands for Selected 5-HT and GABAA-Receptor Subtypes PET-Liganden mit Spezifität für definierte 5-HT und GABAA-Rezeptor-Subtypen Dissertation zur Erlangung des Grades „Doktor der Naturwissenschaften“ am Fachbereich Biologie der Fabian Debus geb. am 19.09.1976 in Frankfurt am Main Mainz, im März 2008 Erklärung Hiermit versichere ich, dass ich die vorliegende Dissertation eigenständig verfasst und keine anderen als die angegebenen Hilfsmittel verwendet habe. Die Dissertation habe ich weder als Arbeit für eine staatliche oder andere wissenschaftliche Prüfung eingereicht noch ist sie oder ein Teil dieser als Dissertation bei einer anderen Fakultät oder einem anderem Fachbereich eingereicht worden. Mainz, im März 2008 II Dekan: 1. Berichterstatter: 2. Berichterstatter: Tag der mündlichen Prüfung: 28.05.2008 III Danksagung Eine solche Schrift kann niemals als Ergebnis der Arbeit eines Einzelnen, sondern sollte immer als Resultat der Arbeit einer großen Anzahl von fleißigen Menschen betrachtet werden, die dabei mitgeholfen haben, dass aus einer Idee ein gelungenes Projekt wurde. Bei meinen beiden Betreuern, Prof. Dr. H. L. und Prof. Dr. F. R., möchte ich mich für das spannende und abwechslungsreiche Thema bedanken. Außerdem für Ihr Vertrauen und Ihre Diskussionsbereitschaft. Insbesondere Herrn Prof. Dr. H. L. möchte ich für seine Unterstützung und seine vorbildliche Betreuung danken. Ich hätte mir keinen besseren Doktorvater wünschen können und bin sehr dankbar für alles, was ich in diesen drei Jahren in seiner Arbeitsgruppe lernen durfte. Besonderer Dank gebührt der gesamten Arbeitsgruppe für Ihre herzliche Gemeinschaft und das produktive Miteinander. Im Einzelnen gebührt Frau R. Dank für das Licht im Dunkel der Bürokratie. Frau B. D. danke ich für ihre hervorragende Arbeit und Unterstützung im Umgang mit den Versuchstieren bei den in vivo Bindungsversuchen sowie den PET-Untersuchungen sowie allgemein für ihre ständige Hilfsbereitschaft, Dr. I. B. für seine kompetente Hilfe bei molekularbiologischen Fragen und seine Diskussionsbereitschaft sowie Dr. H. R. für seine hervorragende Unterstützung bei allen elektrophysiologischen Themen und sein stets offenes Ohr. Ich möchte mich bei Prof. Dr. C. H. und allen Mitarbeitern seiner Arbeitsgruppe für ihre Diskussionsbereitschaft und Hilfsbereitschaft bedanken. Insbesondere Dr. U. S. möchte ich für seine Unterstützung und wertvollen Tipps im Bereich Versuchstiere danken. Von unschätzbarem Wert war die exzellente Arbeit von Dipl. Chemiker M. H. und Dipl. Chemikerin T. C., beide Mitarbeiter der Arbeitsgruppe von Prof. Dr. F. R., ohne die diese Arbeit nicht durchführbar gewesen wäre. Ein ebenso großes Dankeschön geht jedoch an die gesamte Arbeitsgruppe R., insbesondere an Dr. M. P., der nicht Müde wurde mit Rat und Tat dabei zu sein, wann immer Not am Mann war. Ich bedanke mich ganz herzlich bei Prof. Dr. H. L. für die Verleihung des Stipendiums sowie die hervorragende und engagierte Leitung des DFG-Graduiertenkollegs „Entwicklungsabhängige und krankheitsinduzierte Modifikationen im Nervensystem“ der Universität Mainz, seine Diskussionsbereitschaft, sein Vertrauen und seine Unterstützung. Eine große Bereicherung und Hilfe waren auch alle Kooperationspartner, insbesondere mein Aufenthalt bei der Arbeitsgruppe von Prof. Dr. E.K., sowie der Arbeitsgruppe von Prof. Dr. G. K., und dort besonders M. P.. Allen danke ich für die schöne Zeit und die Gastfreundschaft während der Aufenthalte sowie für die anregenden Diskussionen und Tipps im Bereich Autoradiographie und PET. Last but not least ein herzliches Dankeschön an alle Lektoren, die es auf sich genommen haben die Arbeit zu lesen und zu korrigieren. IV 1 TABLE OF CONTENTS 1 TABLE OF CONTENTS 1 TABLE OF CONTENTS ......................................................................................V 1.1 Table Index: .......................................................................................................VII 1.2 Figure Index......................................................................................................VIII 2 INTRODUCTION ...............................................................................................12 2.1 Positron Emission Tomography .........................................................................12 2.1.1 Small Animal Positron Emission Tomography ...................................................13 2.1.2 PET - Ligands ....................................................................................................13 2.1.3 PET Modeling ....................................................................................................14 2.2 The GABAergic System .....................................................................................16 2.2.1 The GABAA Receptor.........................................................................................17 2.2.2 The α5 Subunit ..................................................................................................19 2.3 The Serotonergic System ..................................................................................20 2.3.1 5-HT Receptors..................................................................................................22 2.3.2 The 5-HT2A Receptor .........................................................................................23 2.4 PET and Pharmacology of the GABAA and 5-HT2A Receptors ..........................24 2.4.1 Receptor Binding Studies ..................................................................................24 2.4.2 Drug Occupancy ................................................................................................26 2.4.3 Measurement of Changes in Neurotransmitter Release....................................26 2.4.4 Drug Interaction with a Task Assignment ..........................................................27 2.5 GABAA Receptor α5-Subunit and 5-HT2A Receptor and their Role in Learning and Memory ........................................................................................27 2.6 GABAA Receptor α5-Subunit and 5-HT2A Receptor and their Role in Schizophrenia and Alzheimer’s Disease............................................................28 2.7 Aims of this Work ...............................................................................................30 3 MATERIALS AND METHODS ..........................................................................31 3.1 Materials, Buffers, Media, Software and Hardware ...........................................31 3.1.1 Chemicals ..........................................................................................................31 3.1.2 Animals ..............................................................................................................31 3.2 Chemistry...........................................................................................................31 3.2.1 [18F]MHMZ .........................................................................................................31 3.2.2 TC Compounds..................................................................................................32 3.3 Bacteria..............................................................................................................33 3.3.1 Cloning Vector ...................................................................................................33 3.3.2 Competent Bacteria ...........................................................................................33 3.3.3 Bacteria Transformation.....................................................................................33 3.4 Plasmid Maxi Preparation ..................................................................................34 3.4.1 Culture for Plasmid Maxi Purification .................................................................34 V 1 TABLE OF CONTENTS 3.4.2 CsCl density gradient method............................................................................34 ® 3.4.3 Quiagen HiSpeed Plasmid Purification Maxi Kit...............................................35 TM 3.4.4 Promega PureYield Plasmid Maxiprep System..............................................36 3.5 Restriction Analysis of Bacteria Plasmid DNA ...................................................36 3.5.1 Determination of DNA Concentration.................................................................36 3.5.2 Restriction Enzyme Digest.................................................................................36 3.5.3 Agarose Gel Electrophoresis .............................................................................37 3.6 Cell Culture ........................................................................................................38 3.6.1 Maintenance Culture..........................................................................................38 3.6.2 Plating Out of Cells for Binding Assays .............................................................38 3.6.3 Plating Out of Cells for Electrophysiology..........................................................38 3.6.4 Transfection for Binding Assay ..........................................................................39 3.6.5 Transfection for Electrophysiology.....................................................................40 3.6.6 Cell Harvesting...................................................................................................40 3.6.7 Transfection Control...........................................................................................41
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