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Dissertation DISSERTATION Titel der Dissertation „Synthesis of Novel PET-Tracers for the Norepinephrine Transporter“ verfasst von Christina Rami-Mark, Bakk. MSc. angestrebter akademischer Grad Doktorin der Naturwissenschaften (Dr. rer. nat.) Wien, 2015 Studienkennzahl lt. Studienblatt: A 796 605 419 Dissertationsgebiet lt. Studienblatt: Chemie Betreut von: Assoc. Prof. Mag. Dr. Wolfgang Wadsak 2 “Discovery consists of looking at the same thing as everyone else and thinking something different.” ― Albert Szent-Györgyi 3 4 ACKNOWLEDGEMENTS "You don't write because you want to say something; you write because you've got something to say." -F. Scott Fitzgerald Most of all, I would like to thank my supervisor and mentor Prof. Dr. Wolfgang Wadsak for his endless support, understanding, guidance and discussions. He gave me the possibility to take my own path, to learn a lot and has placed his trust on me all the way. Danke Wolfgang, dass du mich immer unterstützt hast, danke für deinen Rat und Hilfe, wenn mal was nicht so funktioniert hat und für dein Vertrauen in mich. I would also like to express my gratitude to Prof. Dr. Markus Mitterhauser for his support and bracing discussions. Danke Markus, für all die inspirierenden Meetings und deine Unterstützung. Thanks to Dr. Johanna Obermair, she made me learning a lot. Danke Jo, für alles was du mir beigebracht hast. To all my teammates and friends at the Radiochemistry and Biomarker Development unit, helping me survive all this stress in the orange world of the AKH by always cheering me up. Thanks for your patience when knocking on your doors asking for help. You all have become good friends. Danke euch allen für all die unzähligen Stunden die wir gemeinsam verbracht haben, den Spaß und eure offenen Ohren. Danke an euch Chrysou, Cécile, Moni, Resi, Sarah, Neydher, Luki – für all den gemeinsamen Unsinn und die sinnvollen Experimente den wir in all den Jahren gemacht haben. Ich hab euch sehr liebgewonnen. Last but not least, I want to express my gratitude to my family, for their everlasting support to follow my ambitions. Thank you Michael for all your unceasing support, encouragement and understanding in the hard and easy times. Danke, von ganzem Herzen. 5 6 TABLE OF CONTENTS ABSTRACT (english) .............................................................................................................. 9 ABSTRACT (german) ............................................................................................................10 1. INTRODUCTION ......................................................................................................12 1.1. RADIOCHEMISTRY FOR MOLECULAR IMAGING ...................................................12 1.1.1. Positron emission tomography ............................................................................12 1.1.2. Radiochemistry and Radiopharmaceuticals for PET-imaging ..............................13 i. Fluorine-18 .........................................................................................................15 ii. Carbon-11 ...........................................................................................................19 iii. Automation of Radiosyntheses ...........................................................................21 iv. Quality control of PET-tracers .............................................................................22 1.2. NEUROTRANSMISSION ..........................................................................................24 1.3. THE (NOR-)ADRENERGIC SYSTEM ........................................................................25 1.2.1 Adrenoreceptors .................................................................................................26 1.2.2 Norepinephrine Transporter (NET)......................................................................27 i. Involvement in neurological disorders .................................................................28 ii. Involvement in cocaine addiction ........................................................................28 iii. NET in cardiovascular diseases ..........................................................................29 iv. NET in BAT .........................................................................................................29 1.4. NET INHIBITORS AND RADIOPHARMACEUTICALS ...................................................31 1.4.1 NET inhibitors ....................................................................................................31 i. Reboxetine and aryloxy morpholine derivatives ..................................................32 ii. Benzo[d]imidazolone and indolyl-phenyl propanamine based NET inhibitors ......32 iii. Aryloxytetralines and aryloxyindanes as NET inhibitors ......................................33 iv. Phenoxyisochromane and phenoxychromane derived NET inhibitors .................34 v. Phenylbenzothiadiazole based NET inhibitors ....................................................35 1.4.2 NET radiopharmaceuticals ..................................................................................36 i. [11C]MeNER ........................................................................................................36 ii. [18F]FMeNER-D2 ................................................................................................37 iii. [11C]Me@APPI and [11C]Me@HAPTHI ...............................................................37 1.5. PRECLINICAL EVALUATION OF PET-TRACERS .....................................................38 1.5.1 Affinity and Selectivity .........................................................................................40 1.5.2 Lipophilicity and Blood Brain Barrier Penetration ................................................41 1.5.3 Metabolic Stability Testing ..................................................................................42 1.5.4 Autoradiography .................................................................................................43 1.5.5 Biodistribution .....................................................................................................44 1.5.6 µPET – in vivo imaging .......................................................................................44 7 2. AIM OF THE THESIS ...................................................................................................46 3. SCIENTIFIC PART .....................................................................................................47 3.1 PUBLISHED DATA ......................................................................................................47 3.1.1 Authors contribution ............................................................................................47 3.1.2 Manuscript #1 .....................................................................................................49 3.1.3 Manuscript #2 .....................................................................................................68 3.1.4 Manuscript #3 .....................................................................................................82 3.1.5 Manuscript #4 ...................................................................................................102 3.1.6 Manuscript #5 ...................................................................................................121 3.1.7 Manuscript #6 ...................................................................................................137 3.2 UNPUBLISHED DATA ..........................................................................................160 3.2.1 NET-ligand Database........................................................................................160 3.2.2 [18F]FE@APPI ..................................................................................................163 3.2.3 [11C]FAPPI and [18F]FAPPI ...............................................................................165 3.2.4 [18F]FMeNER-D2 and its metabolic stability ......................................................167 4 SUMMARY AND DISCUSSION ................................................................................171 4.1. REBOXETINE DERIVED NET-PET-TRACER: [18F]FMENER-D2 ........................ 171 4.2. 11C AND 18F LABELED BENZOIMIDAZOLONE DERIVATIVES ................................. 172 4.3. 11C-LABELED BENZOTHIADIAZOLE DERIVATIVED PET TRACERS ................ 173 5 CONCLUSION AND OUTLOOK ............................................................................174 6 REFERENCES ..........................................................................................................176 7 APPENDIX ...............................................................................................................198 7.1 LIST OF ABBREVIATIONS .........................................................................................198 7.2 CURRICULUM VITAE ............................................................................................ 200 7.3 LIST OF SCIENTIFIC PUBLICATIONS ....................................................................202 8 ABSTRACT (english) A vast number of psychiatric, neurodegenerative and cardiac diseases are characterized by a perturbation of the norepinephrine transporter (NET) indicating its substantial relevance in medical research. Thus, non-invasive imaging techniques, as for instance positron emission tomography (PET), are the method of choice in order to gain thorough insight into the molecular changes of the NET involved in these pathologies.
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