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Development of Selective High-Affinity Fluorescent Sensors For DEVELOPMENT OF SELECTIVE HIGH-AFFINITY FLUORESCENT SENSORS FOR IMAGING NEUROTRANSMITTERS AND APPLICATION IN CELLS AND TISSUE _______________________________________________________ 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 LE ZHANG Dr. Timothy E. Glass, Dissertation Supervisor July, 2019 The undersigned, appointed by the dean of the Graduate School, have examined the dissertation entitled DEVELOPMENT OF SELECTIVE HIGH-AFFINITY FLUORESCENT SENSORS FOR IMAGING NEUROTRANSMITTERS AND APPLICATION IN CELLS AND TISSUE presented by Le Zhang, a candidate for the degree of doctor of philosophy, and hereby certify that, in their opinion, it is worthy of acceptance. _______________________________________________________ Professor Timothy E. Glass _______________________________________________________ Professor Michael Harmata _______________________________________________________ Professor Kent S. Gates _______________________________________________________ Professor Kevin D. Gillis ACKNOWLEDGEMENTS Foremost, I would especially like to acknowledge my PhD advisor, Professor Timothy Glass for his advice, support and encouragement throughout my career here. His guidance helps me all the time with brainstorming, trouble-shooting, setting my career goal and dissertation writing. I could not have a better advisor and mentor in my PhD career. I would like to thank the members of my graduate committee: Dr. Gates, Dr. Harmata and Dr. Gillis for their thoughtful and helpful guidance, advice and comments during the doctoral process. I want to thank all the collaborators Dr. Shinghua Ding, Dr. Wallace Thoreson and Dr. Xin Alice Liu for their imaging work with my sensors. My sincere thanks to Jerry Brightwell and Holly Oswald for their administrative help. I would like to thank the Glass group members, past and present, and to all the fellow chemists in the department. Thank you to all the advisors and mentors for their knowledge, guidance and encouragement during my career. Lastly, thank you to my friends and families for their huge support and encouragement. ii TABLE OF CONTENTS ACKNOWLEDGEMENTS ............................................................................................ II LIST OF FIGURES ...................................................................................................... VII LIST OF TABLES ........................................................................................................ XII LIST OF SCHEMES ................................................................................................... XIII ABSTRACT .................................................................................................................. XIV CHAPTER ONE ............................................................................................................... 1 INTRODUCTION............................................................................................................. 1 1.1 FLUORESCENT SENSING ...................................................................................................... 1 1.1.1 Molecular Recognition ............................................................................................................ 1 1.2. FLUORESCENT IMAGING MECHANISMS .............................................................................. 2 1.2.1 Internal Charge Transfer (ICT) ................................................................................................ 2 1.2.2 Fӧrster Resonance Energy Transfer (FRET) ........................................................................... 3 1.2.3 Photoinduced Electron Transfer (PET) ................................................................................... 6 1.3. IMAGING NEUROTRANSMITTERS ........................................................................................ 8 1.3.1. Electrochemistry .................................................................................................................... 10 1.3.2. Autofluorescence ................................................................................................................... 12 1.3.3. Biosensors ............................................................................................................................. 13 1.3.4. Supramolecular Chemistry Methods ..................................................................................... 15 1.3.5. Fluorescent False Neurotransmitters ..................................................................................... 17 1.3.6. FM Dyes ................................................................................................................................ 20 1.4. FLUORESCENT SENSORS FOR DIRECT DETECTION NEUROTRANSMITTERS ...................... 21 iii 1.4.1. Fluorescent Sensor for Dopamine ......................................................................................... 22 1.4.2. Fluorescent Sensor for Amino Acids ..................................................................................... 22 1.4.3. Fluorescent Sensor for Catecholamines ................................................................................. 23 1.4.4. NeuroSensor 521 ................................................................................................................... 25 1.4.5. ExoSensor 517 ....................................................................................................................... 26 1.4.6. NeuroSensor 715 ................................................................................................................... 28 1.4.7. Fluorescent Sensor for Zn2+ and Glutamate ........................................................................... 29 CHAPTER TWO ............................................................................................................ 32 SELECTIVE FLUORESCENT SENSOR FOR IMAGING NOREPINEPHRINE AND APPLICATION ..................................................................................................... 32 2.1 OVERVIEW ........................................................................................................................ 32 2.1.1. Introduction ........................................................................................................................... 32 2.1.2. Previous Work ....................................................................................................................... 33 2.2 NEUROSENSOR 16 ............................................................................................................. 34 2.2.1 Design and Synthesis ............................................................................................................. 34 2.2.2 Spectroscopic Data ................................................................................................................ 35 2.2.3 Cell Studies ............................................................................................................................ 38 2.3 NEUROSENSOR 510 ........................................................................................................... 40 2.3.1. Design and Synthesis ............................................................................................................. 40 2.3.2. Spectroscopic Data ................................................................................................................ 43 2.3.3. Cell Studies ............................................................................................................................ 46 2.3.4. Monitoring Exocytosis via Correlation of TIRF and Amperometry ...................................... 51 2.4. CONCLUSIONS ................................................................................................................... 56 CHAPTER THREE ........................................................................................................ 57 iv NEAR-IR HIGH AFFINITY FLUORESCENT SENSOR FOR IMAGING SEROTONIN................................................................................................................... 57 3.1 OVERVIEW ........................................................................................................................ 57 3.1.1. Introduction ........................................................................................................................... 57 3.1.2. Previous Work ....................................................................................................................... 60 3.2 NEUROSENSOR 659 ........................................................................................................... 63 3.2.1. Design and Synthesis ............................................................................................................. 63 3.2.2. Spectroscopic Data ................................................................................................................ 71 3.2.3. Cell Studies ............................................................................................................................ 76 3.3 CONCLUSIONS ................................................................................................................... 76 CHAPTER FOUR ..........................................................................................................
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