Implications of serotonin transporter distribution in the healthy and diseased human brain, investigated by positron emission tomography Doctoral thesis at the Medical University of Vienna in the program Clinical Neurosciences for obtaining the academic degree Doctor of Medical Science submitted by Mag. rer. nat. Georg S. Kranz supervised by Assoc.-Prof. PD Dr. Rupert Lanzenberger Functional, Molecular and Translational Neuroimaging Lab – PET & MRI Department of Psychiatry and Psychotherapy Medical University of Vienna Waehringer Guertel 18-20, 1090 Vienna, Austria http://www.meduniwien.ac.at/neuroimaging/ Vienna, 05/2013 i Declaration This work was carried out at the Functional, Molecular & Translational Neuroimaging Lab (http://www.meduniwien.ac.at/neuroimaging/, head: Assoc.-Prof. PD Dr. med. Rupert Lanzenberger) at the Department of Psychiatry and Psychotherapy (head: O.Univ.-Prof. Dr. h.c.mult. Dr. med. Siegfried Kasper), Medical University of Vienna. PET measurements were performed at the Department of Nuclear Medicine, radiotracer synthesis was done at the Radiopharmaceutical Sciences (http://www.radiopharmaceutical- sciences.net/joomla/, heads: Assoc.-Prof. PD. Dr. Wolfgang Wadsak [Production Manager PET], PD. Dr. Markus Mitterhauser [Radiopharmacy]), Medical University of Vienna. ii Table of Contents Declaration ..................................................................................................................................................... ii Abstract .......................................................................................................................................................... v Kurzfassung ................................................................................................................................................... vi Publications arising from this thesis ............................................................................................................ viii Acknowledgments and project funding ........................................................................................................ ix I. BACKGROUND ............................................................................................................................. 1 1.1. General introduction ............................................................................................................................. 1 1.2. The serotonin transporter (SERT) and its role in psychiatry and psychopharmacological treatment .. 2 1.2.1. SERT structure and function .................................................................................................. 2 1.2.2. SERT regulation ...................................................................................................................... 5 1.2.3. SERT blockage in relation to antidepressant treatment ....................................................... 7 1.3. Quantification of the brain SERT with PET and [11C]DASB..................................................................... 9 1.3.1. PET and SPECT to study the SERT .......................................................................................... 9 1.3.2. PET and SPECT radiopharmaceuticals for the SERT............................................................. 11 1.3.3. Quantitative data analysis ................................................................................................... 12 1.4. Imaging the SERT in the healthy and diseased human brain .............................................................. 16 1.4.1. SERT distribution in the human brain.................................................................................. 16 1.4.2. Imaging the SERT in psychiatric disorders ........................................................................... 18 1.4.3. SERT occupancy measured with PET and its relation to treatment outcome..................... 20 1.5. Open questions .................................................................................................................................... 21 II. AIMS OF THE THESIS .................................................................................................................. 23 III. RESULTS .................................................................................................................................... 24 3.1. First publication: Cerebral Serotonin Transporter Asymmetry in Females, Males and Male-to-Female Transsexuals measured by PET in vivo ..................................................................... 24 3.1.1. Abstract ............................................................................................................................... 25 3.1.2. Introduction ......................................................................................................................... 26 3.1.3. Material and methods ......................................................................................................... 28 3.1.4. Results ................................................................................................................................. 30 3.1.5. Discussion ............................................................................................................................ 34 3.1.6. Conclusions .......................................................................................................................... 38 3.1.7. References ........................................................................................................................... 39 iii 3.2. Second publication: Regional differences in SERT occupancy after acute and prolonged SSRI intake investigated by brain PET......................................................................................................... 54 3.2.1. Abstract ............................................................................................................................... 55 3.2.2. Introduction ......................................................................................................................... 56 3.2.3. Methods .............................................................................................................................. 59 3.2.4. Results ................................................................................................................................. 62 3.2.5. Discussion ............................................................................................................................ 68 3.2.6. Conclusion ........................................................................................................................... 73 3.2.7. References ........................................................................................................................... 75 3.2.8. Appendices .......................................................................................................................... 89 3.3. Third publication: Prediction of SSRI treatment response in major depression based on serotonin transporter interplay between median raphe nucleus and projection areas ..................................... 92 3.3.1. Abstract ............................................................................................................................... 93 3.3.2. Introduction ......................................................................................................................... 94 3.3.3. Methods .............................................................................................................................. 96 3.3.4. Results ............................................................................................................................... 100 3.3.5. Discussion .......................................................................................................................... 106 3.3.6. Conclusions ........................................................................................................................ 110 3.3.7. References ......................................................................................................................... 112 3.3.8. Supplementary Information .............................................................................................. 119 IV. GENERAL DISCUSSION ............................................................................................................. 122 V. CONCLUSION AND FUTURE PROSPECTS ................................................................................... 125 VI. REFERENCES ............................................................................................................................ 126 APPENDIX – CV ............................................................................................................................... 138 iv Abstract The serotonin transporter (SERT), an integral part of the serotonergic system, has developed into a subject of great interest in the field of biological psychiatry. Sustained SERT blockage was shown to have strong antidepressant and anxiolytic effects, which led to the development of today’s most widely prescribed antidepressants, the selective serotonin reuptake inhibitors (SSRIs). The regional distribution of the SERT in the human brain and its blockage by SSRIs can be effectively studied with positron emission tomography (PET) and suitable radioligands in vivo. Although several imaging studies on the SERT have been performed in the last decades, basic knowledge