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Phd Afhandling F A C U L T Y O F H E A L T H S C I E N C E S U N I V E R S I T Y O F C O P E N H A G E N t5 ! 9 Serotonin receptor studies in the pig brain: pharmacological intervention and positron emission tomography tracer development Academic advisor: Gitte Moos Knudsen Submitted: 01/07/10 Defended: 15/10/10 Preface The present PhD thesis is the result of a 3½-year integrated Master’s/PhD programme in Human Biology at The Faculty of Health Sciences, University of Copenhagen. The work was carried out from February 2007 to July 2010 primarily at the Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet. This thesis is based on the following manuscripts which in the text are referred to by their Roman numerals: I. Ettrup A, Kornum BR, Weikop P, Knudsen GM. An Approach for Serotonin Depletion in Pigs: Effects on Serotonin Receptor Binding. Synapse. 2010 Jun 16. (Epub ahead of print) II. Ettrup A, Palner M, Gillings N, Santini MA, Hansen M, Kornum BR, Rasmussen LK, Någren K, Madsen J, Begtrup M, Knudsen GM. Radiosynthesis and evaluation of 11C-CIMBI- 5 as a high affinity 5-HT2A receptor agonist radioligand for PET. Journal of Nuclear Medicine. 2010 Nov. (article proofs) III. Ettrup A, Hansen M, Santini MA, Paine J, Gillings N, Palner M, Lehel S, Madsen J, Begtrup 11 M, Knudsen GM. In vivo evaluation of a series of substituted C-phenethylamines as 5-HT2A agonist PET tracers. Manuscript The following publications are related to the work described in the thesis, and are referred to as regular references: 1. Holm P*, Ettrup A*, Klein AB, Santini MA, El-Sayed M, Elvang AB, Stensbøl TB, Mikkelsen JD. Knudsen GM, Aznar S. Plaque Deposition Dependent Decrease in 5-HT2A Serotonin Receptor in APPswe/PS1dE9 Amyloid Overexpressing Mice. Journal of Alzheimer’s Disease 2010;20(4):1201-13. 2. Kornum BR*, Stott SR*, Mattsson B, Wisman L, Ettrup A, Hermening S, Knudsen GM, Kirik D. Adeno-associated viral vector serotypes 1 and 5 targeted to the neonatal rat and pig striatum induce widespread transgene expression in the forebrain. Experimental Neurology 2010 Mar;222(1):70-85. *equal contributions by the two authors - 2 - Table of Contents Preface........................................................................................................................ 2 Acknowledgements.................................................................................................... 4 Summary in English................................................................................................... 5 Resumé på dansk........................................................................................................ 7 Abbreviations............................................................................................................. 9 Introduction..............................................................................................................10 The serotonin system............................................................................................10 5-HT receptors......................................................................................................11 Effects of 5-HT2A activation.................................................................................12 High- and low-affinity states of 5-HT2A receptors...............................................13 The serotonin system in human disease ...............................................................14 Serotonin depletion...............................................................................................15 PET measurements of the human 5-HT system...................................................18 PET tracer development .......................................................................................19 Measuring endogenous neurotransmitter release with PET.................................21 Aims .........................................................................................................................24 Methods....................................................................................................................25 The pig as an experimental animal.......................................................................25 In vitro quantification of 5-HT and metabolites...................................................26 In vitro receptor autoradiography.........................................................................27 Autoradiograms and image analysis.....................................................................29 Positron emission tomography (PET) ..................................................................30 PET image analysis ..............................................................................................31 Results and discussion .............................................................................................34 pCPA-treatment causes serotonin depletion in the pig brain ...............................34 5-HT4 receptor binding is increased in a porcine model of serotonin depletion..35 11 [ C]Cimbi-5 is a novel 5-HT2A receptor agonist PET tracer...............................36 [11C]Cimbi-36 displays improved PET tracer properties over [11C]Cimbi-5 ......39 Conclusions and perspectives ..................................................................................43 References................................................................................................................45 - 3 - Acknowledgements First of all, I would like to thank my supervisor Gitte Moos Knudsen for excellent advice and guidance through both successful times and the others times. Your broad scientific understanding, vision, and ability to focus on what is important are truly impressing and inspiring. Secondly and maybe most important, I am grateful to all my colleagues at Neurobiology Research Unit (NRU) for making it a great place to be and to work. Equal parts of intellect, professional diversity, sympathetic attitude, and fun make NRU special. Thanks to my predecessor and practical supervisor Birgitte R. Kornum for learning me practically all that is worth knowing about pig brains and to Hanne D. Hansen for continuing the line of pig research at NRU. Lab managers Susana Aznar and Jens D. Mikkelsen and technicians Hans-Jørgen Jensen and Christine Janssens should be acknowledged for running an efficient and smooth lab. Also, I thank Dorthe Givard, Pia Farup, and Dorte Frejwald for administrative support. Special thanks to office mate and friend Anders Bue Klein for your pleasant being. Big thanks to the end less list of present and former Master’s and PhD students at NRU, it has been a privilege to work with you all. Practical work with the pigs was conducted at the Department of Experimental Medicine, Faculty of Health Sciences, University of Copenhagen. Gratitude should be expressed to animal caretakers Pia Lander Sørensen and Anne-Mette Freising for excellent technical assistance in animal handling during noisy i.m. injections. Gratitude should also be expressed to veterinary nurses Letty Klarskov and Mette Værum Olesen for skilful assistance with the pig operations. HPLC analyses of pig brain tissue were done at NeuroSearch A/S, and here Pia Weikop is thankfully acknowledged for the collaboration, while the technical assistance by Britta Carlson is further appreciated. The PET scans were conducted at the PET- and Cyclotron Unit, Copenhagen University Hospital, Rigshospitalet. The pig scans in this thesis could not have been done without the assistance by numerous people in the unit. HRRT scanner operators Bente Dall, Kamilla Sloth Knudsen, and Anna Ljunggren are thanked for always helpful assistance. I would also like to thank radio chemists Jacob Madsen, Kjell Någren, Szabolcs Lehel, and Matthias Herth for producing the radioligands. Thanks also to Nic Gillings, Lasse Kofoed Bech, Jack Frausing Nielsen, and Blerta Shuka for doing radiometabolite analyses, to computer scientists Sune Keller and Mererence Sibomana for reconstructing images, and to Flemming Andersen for granting access to the pig brain atlas. Also thanks to James Paine, Martin Hansen, and Lars Kyhn Rasmussen who produced lots of labelling precursors and reference compounds. The project was funded by Faculty of Health Sciences, University of Copenhagen, Lundbeck Foundation Center for Integrated Molecular Brain Imaging (CIMBI), The Lundbeck Foundation, and the EU 6th Framework program Diagnostic Molecular Imaging (DiMI). Last but by no means least, huge thanks to Ditte and my family and friends for their encouragement and support. Anders Ettrup, Copenhagen, June 2010 - 4 - Summary in English Serotonin (5-HT) is an important neurotransmitter that modulates significant behavioural effects such as mood, anxiety, appetite, and sleep. Accordingly, dysfunction in the serotonergic system has been implicated in the pathophysiology of a wide range of neuropsychiatric disorders. The 5-HT2A receptor is the most abundant excitatory 5-HT receptor in the human brain, it mediates the hallucinogenic effects of several recreational drugs and is the target of atypical antipsychotics. Positron emission tomography (PET) is a powerful technique to map and quantify receptors in the living brain, and PET scanning is widely used to investigate 5-HT receptors in both human and animal studies. For 5-HT2A receptor imaging with PET, only antagonist PET tracers are currently in use, however, agonist PET tracers hold promise to image receptors in the high-affinity state selectively and thereby to serve as a more
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