The Cyclotron Production and Cyclometalation Chemistry of 192-Ir by Graeme Langille B.Sc., Simon Fraser University, 2012 Thesis Submitted in Partial Fulfillment of the Requirements for the Degree of Master of Science in the Department of Chemistry Faculty of Science c Graeme Langille 2014 SIMON FRASER UNIVERSITY Fall 2014 All rights reserved. However, in accordance with the Copyright Act of Canada, this work may be reproduced without authorization under the conditions for "Fair Dealing". Therefore, limited reproduction of this work for the purposes of private study, research, criticism, review and news reporting is likely to be in accordance with the law, particularly if cited appropriately. APPROVAL Name: Graeme Langille Degree: Master of Science (Chemistry) Title: The Cyclotron Production and Cyclometalation Chemistry of 192-Ir Examining Committee: Chair: Dr. Hua-Zhong Yu Professor Dr. Corina Andreoiu Senior Supervisor Associate Professor Dr. Paul Schaffer Co-Supervisor Adjunct Professor Dr. Tim Storr Supervisor Associate Professor Dr. Krzysztof Starosta Supervisor Associate Professor Dr. Robert Young Internal Examiner Professor Date Defended/Approved: December 11, 2014 ii Partial Copyright Licence iii Abstract The goal of this thesis is to demonstrate the cyclotron production, radiochemical isola- tion, and cyclometalate chemistry of radio-iridium isotopes. In recent work, Luminescence Cell Imaging (LCI) has been combined with radioisotopes, leading to compounds that can be imaged with both optical microscopy and nuclear techniques. Radiometals excel in this multifunctional setting, providing ideal chemical and nuclear properties for luminescence, bi- ological targeting, nuclear diagnostics, and therapy. Iridium cyclometalate compounds have demonstrated potential in LCI with excellent photophysical properties. Independently, low specific activity 192Ir has been successfully applied in brachytherapy as a high-intensity β− emitter. Despite this, radio-iridium has not yet been applied to cyclometalate chemistry, nor a radiochemical isolation method developed for its cyclotron production. Herein is demon- strated the feasibility of the production and isolation of radio-iridium, and its application to cyclometalate chemistry as a potential tool for nuclear medicine research. Natural osmium was electroplated onto a silver disc from basic media, and the thin deposits obtained were weighed and characterized with scanning electron microscopy. These targets were irradi- ated using the TRIUMF TR13 cyclotron, delivering 12.7 MeV protons to the target disc to access the AOs(p; n)AIr reaction channels. Three irradiations were performed at 5 µA for 1 hour, and one at 20 µA for 2 hours. Gamma spectra of the targets were collected and a range of iridium isotopes (186-190, 192) identified and quantified. The irradiated material was then oxidized, dissolved from the target backing, and separated via anion exchange. Once isolated, the isotopes were applied to an adapted cyclometalation procedure, and the compounds were identified and quantified against non-radioactive standards using high performance liquid chromatography with coupled γ-ray and ultraviolet detectors. The pro- cedure developed here has enabled the study of radio-iridium cyclometalates, a potentially new class of theranostic compounds for nuclear medicine. Keywords: nuclear medicine; radiochemistry; radiopharmacy; radiometals; theranos- tics; radiochemical separations; isotope production; 192Ir; cyclometalate chemistry iv Acknowledgments The breadth of this project required the support and direction of a diverse group of people, without whom I would most certainly still be toiling away in the lab. It has been a privilege to work with Dr. Corina Andreoiu, whose enthusiasm for nuclear science inspired my own exploration. I am grateful to Dr. Paul Schaffer for sharing his broad knowledge of nuclear medicine, and constant positive attitude. My committee members, Dr. Tim Storr and Dr. Krzysztof Starosta, have my gratitude for not only their input in this project, but also their ongoing roles throughout my scientific education. There are many members of the Nuclear Medicine Division at TRIUMF to whom I am indebted: for his targetry prowess and laboratory conversations, Dr. Stefan Zeisler; for their inorganic expertise, Dr. Hua Yang and Dr. Qing Miao; and, for their expert handling of the cyclotron, Linda Graham and Dave Prevost. At SFU I had the fortune to work with many other skilled individuals: Dr. Jean-Claude Brodovitch, an excellent radiochemist and human being; Dr. Bob Young, for his review of my thesis and the occasional use of his lab; the members of the Storr group, for enduring my occupation of their fume hoods; and finally, the Starosta and Andreoiu groups, for their support and friendship. v Contents Approval ii Partial Copyright License iii Abstract iv Acknowledgmentsv Contents vi List of Tables viii List of Figures ix 1 Introduction1 1.1 Nuclear Medicine Basics.............................2 1.1.1 Radioactive Decay............................2 1.1.2 Nuclear Reactions............................4 1.1.3 Radiopharmacy: Imaging and Therapy.................8 1.2 Iridium cyclometalate Chemistry........................ 10 1.2.1 Luminescence Cell Imaging and Transition Metal Lumophores... 10 1.2.2 Iridium cyclometalates.......................... 12 1.2.3 Radio-Iridium............................... 14 1.3 Thesis Overview................................. 15 2 Targetry 16 2.1 Experimental................................... 16 2.1.1 Reagents and Instrumentation..................... 16 2.1.2 Distillation of OsO4 ........................... 17 2.1.3 Osmium Electroplating......................... 17 2.2 Discussion..................................... 18 vi 2.2.1 Proton Attenuation in Matter...................... 20 2.3 Conclusion.................................... 20 3 Isotope Production 21 3.1 Experimental................................... 22 3.1.1 Osmium Target Bombardment..................... 22 3.1.2 Gamma-Ray Spectroscopy........................ 23 3.1.3 Isolation of Radio-Iridium........................ 24 3.2 Discussion..................................... 25 3.2.1 Irradiation................................ 25 3.2.2 Isotope Identification and Quantification................ 26 3.2.3 Radiochemical Separation........................ 29 3.3 Summary..................................... 30 4 Cyclometalation 31 4.1 Experimental................................... 31 4.1.1 Reagents & Instrumentation...................... 31 4.1.2 Non-Radioactive Syntheses....................... 32 4.1.3 Carrier-Added Radio-Synthesis of Compound 2 ............ 33 4.2 Discussion..................................... 34 4.2.1 Radiosynthesis.............................. 36 4.3 Summary..................................... 37 5 Conclusion 38 Bibliography 40 Appendix A Derivations and Characterization Data 45 vii List of Tables 1.1 Types of radioactive decay............................2 3.1 Isotopic composition of naturally abundant osmium............. 21 3.2 Produced nuclides and characteristic γ-rays.................. 27 3.3 Calculated isotope yields............................. 28 4.1 HPLC conditions for reaction component separation............. 34 viii List of Figures 1.1 An excerpt from the chart of nuclides.....................3 1.2 192Ir decay product level schemes........................5 1.3 Cyclotron design schematic...........................6 1.4 192Os(p; n)192Ir reaction excitation function..................7 1.5 Radiation interactions with biological matter.................8 1.6 Operating principle of targeted radiopharmacy................9 1.7 Three generations of diagnostic radiopharmaceutical............. 10 1.8 Bimodal imaging agents............................. 11 1.9 Cyclometallate luminescence cell imaging example.............. 12 1.10 Two step cyclometalation reaction scheme................... 13 1.11 Representative iridium cyclometalate compounds............... 13 1.12 A schematic pathway of the cyclometalation reaction............. 14 1.13 The chart of nuclides focused on long lived iridium isotopes......... 15 2.1 Osmium target electroplating methodology.................. 18 2.2 Scanning electron micrographs of the osmium target material........ 19 3.1 Polymer structure of Dowex 1X8 anion exchange material.......... 22 3.2 The TRIUMF TR13 cyclotron......................... 23 3.3 Target holder employed in all irradiations................... 24 3.4 A sample spectrum collected from an irradiated target plate......... 25 3.5 Elution profile of radio-iridium from anion exchange column......... 26 3.6 The radiochemical separation procedure.................... 29 4.1 Reaction scheme for the synthesis of the dimer compound 1 ......... 32 4.2 Reaction scheme for the synthesis of 2 ..................... 33 4.4 UV absorption calibration curve........................ 35 4.5 UV-HPLC traces of reaction components................... 36 4.6 Overlaid radio- and UV-chromatograms of compounds 1 and 2 ....... 37 ix Chapter 1 Introduction Radioactivity has played a fundamental role in the development of modern medicine. The radiation produced by the different types of nuclear decay have applications unmatched by conventional diagnostic and therapeutic methods. Furthermore, the observational power afforded by the tracer principle has led to many discoveries fundamental to our current un- derstanding of human physiology and biochemistry. As these systems are better understood, however, new questions arise that