Arsenic-72, 77 as a Matched Pair Radiopharmaceutical for Imaging and Radiotherapy A Dissertation presented to the Faculty of the Graduate School at the University of Missouri-Columbia In partial fulfillment of the requirements for the degree Doctor of Philosophy By Yutian Feng Professor Silvia S. Jurisson, Dissertation Supervisor MAY 2018 © Copyright by Yutian Feng 2018 All Rights Reserved The undersigned, appointed by the dean of the Graduate School, have examined the dissertation entitled Arsenic-72, 77 as a Matched Pair Radiopharmaceutical for Imaging and Radiotherapy Presented by Yutian Feng, a candidate for the degree Doctor of Philosophy, and hereby certify that, in their opinion, it is worthy of acceptance. Professor Silvia S. Jurisson Professor Susan Z. Lever Professor Timothy J. Hoffman Professor Alan R. Ketring Professor Kent S. Gates Professor Cathy S. Cutler Acknowledgments First and foremost, I give my utmost thankfulness to my graduate advisor Professor Silvia S. Jurisson for her great kindness, encouragement, support, patience and caring for me. Thanks to her I couldn’t have enjoyed more my time as a graduate student. I’m fortunate and proud to have her as my mentor because of not only her expertise and wisdom, but also her hardworking attitude and persistence. Secondly I would like to thank my wife Jingjie Huang, without whom I couldn’t have been able to survive the inevitable frustration from research and get back on my feet time and time again. Apart from that, I couldn’t have done my work without the support from the University of Missouri Chemistry Department. I also want to thank Drs. Cathy Cutler and Alan Ketring for my work at the MU Research Reactor and Dr. Tim Hoffman for my work at the Truman VA Hospital. I’m grateful for all the support and guidance I received. Collaborating with different institutes taught me invaluable communication skills and prepared me for my career. I’m grateful for the instruction, inspiration and insight provided by my graduate committee, Dr. Susan Lever and Dr. Kent Gates. In addition, I would like to thank Dr. Anthony J. DeGraffenreid for all the help, advice and enlightenment when I first entered the field. I couldn’t have done my work without his fundamental research. I would like to thank Dr. Wei Wycoff for all her help with the NMR facility, Dr. Fabio Gallazzi for the LC-MS facility, Dr. Charles Barnes for X-ray facility and Professor Michael Harmata for help in organic synthesis. I want to thank undergraduate Michael Phipps and graduate student Firouzeh Najafi Khosroshahi. Working as their trainer taught me how to give advice and work collaboratively. ii Finally I want to thank my friends and family for all the support over the years. My parents always support me to pursue my dream emotionally and financially and they have taught me to become a better person. iii Table of Contents Acknowledgments ...........................................................................................................ii List of Illustrations..........................................................................................................vi List of Figures ............................................................................................................vi List of Tables .............................................................................................................xi List of Schemes ........................................................................................................ xiii List of Abbreviations .....................................................................................................xv Academic Abstract ....................................................................................................... xvi Chapter 1: Arsenic as a Matched Pair Radiopharmaceutical .................................................. 1 Introduction ............................................................................................................... 1 Nuclear Properties of Radionuclides and their Applications in Nuclear Medicine .................. 5 Imaging ................................................................................................................. 5 Therapy ................................................................................................................10 Specific Activity of Radionuclide..............................................................................15 Conclusion and Outline of Thesis .................................................................................16 Chapter 2: Production of Radioarsenic (72,77As) ..................................................................19 Introduction ..............................................................................................................19 Production of Arsenic-72 ............................................................................................22 Experimental .........................................................................................................22 Results and Discussion ............................................................................................27 Conclusion ............................................................................................................35 Production of Arsenic-77 ............................................................................................35 Experimental .........................................................................................................35 Results and Discussion ............................................................................................37 Conclusion ............................................................................................................39 Future Studies ...........................................................................................................39 Chapter 3: Dithiol Aryl Arsenic Compounds as Potential Diagnostic and Therapeutic Radiopharmaceuticals ....................................................................................................40 Introduction ..............................................................................................................40 Experimental .............................................................................................................42 Materials ...............................................................................................................42 Physical Measurements ...........................................................................................43 Synthesis...............................................................................................................43 iv Results and Discussion ...............................................................................................55 Conclusion................................................................................................................79 Chapter 4: Trithiol: a Potential Chelate for 72,77As Matched Pair Theranostic Complex with High in vivo Stability .............................................................................................................80 Introduction ..............................................................................................................80 Experimental .............................................................................................................81 Materials ...............................................................................................................81 Physical Measurement.............................................................................................82 Syntheses ..............................................................................................................83 Results and Discussion ...............................................................................................94 Conclusion.............................................................................................................. 111 Synthesis of a linkable trithiol analogue with improved hydrophilicity ............................. 112 Introduction ......................................................................................................... 112 Experimental ....................................................................................................... 114 Results and Discussion .......................................................................................... 122 Conclusion .......................................................................................................... 125 Structural and stability analysis of an arsenic trihydroxyl compound: 4-ethyl-2,6,7-trioxa-1- arsabicyclo[2.2.2]octane............................................................................................ 127 Introduction ......................................................................................................... 127 Experimental ....................................................................................................... 128 Results and Discussion .......................................................................................... 129 Conclusion .......................................................................................................... 144 Chapter 5: Conclusions................................................................................................. 145 Appendix A: Supplemental Data for Chapter 3................................................................. 147