[123I]-ADAM Und [99Mtc]-TRODAT-1: Szintigraphische in Vivo Darstellung

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[123I]-ADAM Und [99Mtc]-TRODAT-1: Szintigraphische in Vivo Darstellung Aus der Klinik und Poliklinik für Nuklearmedizin der Ludwig-Maximilians-Universität München Standort Innenstadt und Großhadern Direktor: Prof. Dr. med. Peter Bartenstein [123 I]-ADAM und [ 99m Tc]-TRODAT-1: Szintigraphische in vivo Darstellung der serotonergen und dopaminergen Transportersysteme anhand von Micro-SPECT im ZNS von Ratten Dissertation zum Erwerb des Doktorgrades der Medizin an der Medizinischen Fakultät der Ludwig-Maximilians-Universität München Vorgelegt von Sandro Valle aus München 2009 - ii - Mit Genehmigung der Medizinischen Fakultät der Ludwig-Maximilians-Universität München Berichterstatter: Prof. Dr. med. Peter Bartenstein Mitberichterstatter: Priv. Doz. Dr. Thomas Zetzsche Priv. Doz. Dr. Diethilde Theil Mitbetreuung durch den promovierten Mitarbeiter: Dr. med. Christian la Fougère Dekan: Prof. Dr. med. Dr. h.c. M. Reiser, FACR, FRCR Tag der mündlichen Prüfung: 10.12.2009 - iii - Ὁκόσα φάρµακα οὐκ ἰῆται, σίδηρος ἰῆται • ὁσσα σίδηρος οὐκ ἰῆται, πῦρ ἰῆται • ὁσσα δὲ πῦρ οὐκ ἰῆται ταῦτα χρὴ νοµίζειν ἀνίητα. Quae medicamenta non sanant, ferrum sanat; quae ferrum non sanat, ignis sanat; quae vero ignis non sanat, insanabilia reputari oportet. Hippokrates, Aphorismen 7,87 Inhaltsverzeichnis - iv - Inhaltsverzeichnis 1 EINLEITUNG ..................................................................1 2 DAS SEROTONERGE SYSTEM ..................................................4 2.1 Allgemeiner Überblick über prä- und postsynaptische Übertragung.............4 2.2 Serotonin ....................................................................................6 2.3 Anatomie des serotonergen Systems im ZNS........................................ 10 2.4 Serotoninrezeptoren .................................................................... 13 2.5 Erkrankungen des serotonergen Systems ........................................... 16 2.5.1 Depression.......................................................................... 17 2.5.1.1 Definition, Klinik und Epidemiologie .................................... 17 2.5.1.2 Ursachen - Serotonin und Depression ................................... 18 2.5.1.3 Liquor- und Blutuntersuchungen ......................................... 20 2.5.1.4 Postmortem-Untersuchungen............................................. 21 2.5.1.5 Therapie der Depression .................................................. 22 3 DAS DOPAMINERGE SYSTEM ................................................ 25 3.1 Allgemeine prä- und postsynaptische Übertragung................................ 25 3.2 Dopamin.................................................................................... 25 3.3 Anatomie des dopaminergen Systems im ZNS ...................................... 28 3.4 Dopaminerge Projektionen............................................................. 29 3.5 Dopaminrezeptoren ..................................................................... 30 3.6 Erkrankungen des dopaminergen Systems .......................................... 33 3.6.1 Morbus Parkinson .................................................................. 33 3.6.2 Depression.......................................................................... 34 3.6.2.1 Therapie der Depression .................................................. 35 3.6.3 Störungen aus dem schizophrenen Formenkreis .............................. 35 3.6.3.1 Postmortem-Untersuchungen............................................. 37 3.6.4 ADHS und Methylphenidat........................................................ 38 - v - Inhaltsverzeichnis 4 DARSTELLUNG DES MONOAMINERGEN SYSTEMS ............................. 40 4.1 Prinzipien der Bildgebung .............................................................. 40 4.1.1 Grundlagen szintigraphischer Darstellung ..................................... 40 4.1.2 Gammakamera..................................................................... 44 4.1.3 SPECT (Single-Photon-Emissionscomputertomographie) ..................... 45 4.1.4 Bildrekonstruktion................................................................. 46 4.1.5 Micro-SPECT am Kleintiermodell ................................................ 46 4.1.6 Anwendung von Micro-SPECT bei Kleintieren.................................. 47 4.2 Bildgebung des serotonergen Systems ............................................... 48 4.2.1 Radiopharmaka für die Darstellung des Serotonintransporters (SERT) .... 49 4.2.1.1 PET-Radiopharmaka........................................................ 49 4.2.1.2 SPECT-Radiopharmaka..................................................... 50 4.2.2 Darstellung des serotonergen Systems bei Depression ....................... 51 4.2.3 Darstellung des serotonergen Systems bei Schizophrenie ................... 53 4.2.4 [123 I]-ADAM.......................................................................... 54 4.3 Bildgebung des dopaminergen Systems .............................................. 56 4.3.1 Radiopharmaka für die Darstellung des Dopamintransporters (DAT) ...... 56 4.3.1.1 PET-Radiopharmaka........................................................ 56 4.3.1.2 SPECT-Radiopharmaka..................................................... 58 4.3.2 Darstellung des dopaminergen Systems bei Depression...................... 58 4.3.3 Darstellung des dopaminergen Systems bei Schizophrenie.................. 60 4.3.4 [99m Tc]-TRODAT-1.................................................................. 61 5 MATERIAL UND METHODIK ................................................. 64 5.1 Pharmazeutika und Radiomarkierung................................................ 64 5.1.1 [123 I]-ADAM.......................................................................... 64 5.1.2 [99m Tc]-TRODAT-1.................................................................. 65 5.1.3 Fluoxetin und Methylphenidat ................................................... 66 5.2 Bildakquisition und -verarbeitung .................................................... 66 5.2.1 Aufbau der Pinholekollimatoren................................................. 66 5.2.2 Bildakquisition und Auswertung ................................................. 68 5.2.3 Bildrekonstruktion und -nachbearbeitung ..................................... 70 5.2.4 Phantomexperimente ............................................................. 71 Inhaltsverzeichnis - vi - 5.2.5 Tierversuche ....................................................................... 72 5.2.5.1 Versuchsaufbau............................................................. 72 5.2.5.2 [123 I]-ADAM und Fluoxetin ................................................. 75 5.2.5.3 [99m Tc]-TRODAT-1 und Methylphenidat.................................. 77 5.2.6 Regions of Interest ................................................................ 78 5.3 Auswertung der spezifischen Bindung der Radioliganden........................ 79 5.4 Statistische Analyse...................................................................... 80 6 ERGEBNISSE ................................................................ 81 6.1 Tierversuche mit [ 123 I]-ADAM .......................................................... 81 6.1.1 Darstellung des SERT bei nicht prämedizierten Versuchstieren ............ 81 6.1.2 Darstellung des SERT nach Fluoxetin-Gabe .................................... 81 6.2 Tierversuche mit [ 99m Tc]-TRODAT-1.................................................. 86 6.2.1 Darstellung des DAT bei nicht prämedizierten Versuchstieren ............. 86 6.2.2 Darstellung des DAT nach Methylphenidat-Gabe.............................. 87 7 DISKUSSION ................................................................ 90 7.1 Darstellung des monoaminergen Systems mit Micro-SPECT...................... 90 7.2 Tierversuche mit [ 123 I]-ADAM .......................................................... 91 7.2.1 Darstellung des SERT bei nicht prämedizierten Versuchstieren ............ 91 7.2.2 Darstellung des SERT nach Fluoxetin-Gabe .................................... 95 7.3 Tierversuche mit [ 99m Tc]-TRODAT-1.................................................. 97 7.3.1 Darstellung des DAT bei nicht prämedizierten Versuchstieren ............. 98 7.3.2 Darstellung des DAT nach Methylphenidat-Gabe............................. 100 8 ZUSAMMENFASSUNG ......................................................103 - vii - Inhaltsverzeichnis LITERATURVERZEICHNIS ..........................................................106 ABBILDUNGSVERZEICHNIS ........................................................125 TABELLENVERZEICHNIS ...........................................................128 ABKÜRZUNGEN ...................................................................129 DANKSAGUNG ....................................................................131 LEBENSLAUF .....................................................................132 1. Einleitung 1 1 EINLEITUNG Die Entdeckung der radioaktiven Strahlung stellt für die Entwicklung der modernen Medizin einen wichtigen Schritt dar. Wilhelm Conrad Röntgen, Henri Becquerel, Marie und Pierre Curie, Max Planck, Albert Einstein, Nils Bohr, Ernest Rutherford und Ernest Lawrence bereiteten im 19. und 20. Jahrhundert den Weg von der Entdeckung der Röntgenstrahlen bis zur Protonentherapie. In den letzten Jahrzehnten des 20. Jahrhunderts erfuhren bildgebende Verfahren einen großen technischen Fortschritt und wurden immer weiter verbreitet. Der Arzt greift dabei auf ein reiches Repertoire an technischen Hilfsmitteln und Geräten zurück. Häufiger Bestandteil der Diagnostik sind hierbei
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