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Synthesis and Radiolabeling of Potassium Trifluoroborate Benzylidene Anabaseine Derivatives

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Synthesis and Radiolabeling of Potassium Trifluoroborate Benzylidene Anabaseine Derivatives University of Tennessee, Knoxville TRACE: Tennessee Research and Creative Exchange Doctoral Dissertations Graduate School 12-2006 Synthesis and Radiolabeling of Potassium Trifluoroborate Benzylidene Anabaseine Derivatives Aaron Landon Smith University of Tennessee - Knoxville Follow this and additional works at: https://trace.tennessee.edu/utk_graddiss Part of the Chemistry Commons Recommended Citation Smith, Aaron Landon, "Synthesis and Radiolabeling of Potassium Trifluoroborate Benzylidene Anabaseine Derivatives. " PhD diss., University of Tennessee, 2006. https://trace.tennessee.edu/utk_graddiss/2039 This Dissertation is brought to you for free and open access by the Graduate School at TRACE: Tennessee Research and Creative Exchange. It has been accepted for inclusion in Doctoral Dissertations by an authorized administrator of TRACE: Tennessee Research and Creative Exchange. For more information, please contact [email protected]. To the Graduate Council: I am submitting herewith a dissertation written by Aaron Landon Smith entitled "Synthesis and Radiolabeling of Potassium Trifluoroborate Benzylidene Anabaseine Derivatives." I have examined the final electronic copy of this dissertation for form and content and recommend that it be accepted in partial fulfillment of the equirr ements for the degree of Doctor of Philosophy, with a major in Chemistry. George W. Kabalka, Major Professor We have read this dissertation and recommend its acceptance: Ziling Xue, Richard Pagni, Daniel Roberts Accepted for the Council: Carolyn R. Hodges Vice Provost and Dean of the Graduate School (Original signatures are on file with official studentecor r ds.) To the Graduate Council: I am submitting herewith a dissertation written by Aaron Landon Smith entitled “Synthesis and Radiolabeling of Potassium Trifluoroborate Benzylidene Anabaseine Derivatives.” I have examined the final electronic copy of this dissertation for form and content and recommend that it be accepted in partial fulfillment of the requirements for the degree of Doctor of Philosophy, with a major in Chemistry. George W. Kabalka Major Professor We have read this dissertation and recommend its acceptance: Ziling Xue___________________ Richard Pagni_________________ Daniel Roberts________________ Accepted for the Council: Linda Painter________________ Interim Dean of Graduate Studies (Original signatures are on file with official student records.) SYNTHESIS AND RADIOLABELING OF POTASSIUM TRIFLUOROBORATE BENZILIDENE ANABASEINE DERIVATIVES A Dissertation Presented for the Doctor of Philosophy Degree The University of Tennessee, Knoxville Aaron L. Smith December, 2006 DEDICATION To: Ruby K. Smith Marion K. Robinette David and Vivian Morrow Terry and Judy Smith Derrick A. Smith and Elizabeth S. Jallo I can not thank you enough. ii ACKNOWLEDGEMENTS I thank Dr. George W. Kabalka for his guidance, patience, tolerance, and financial support throughout the progress of this research. I thank Dr. Peter Zhang for my initial training in the beginning of my graduate career which helped my success in the lab and kept me ambitious. I thank Dr. David Baker for time spent in his lab during my undergraduate studies which spurred my interest in the field of organic synthesis. I also thank the remaining members of my doctoral defense committee not yet mentioned, Dr. Richard Pagni, and Dr. Daniel Roberts. I thank the chemistry department for providing me with the opportunity to teach chemistry in return for the financial support throughout my graduate studies. I thank Dr. Alan Hazari for helping me become a better speaker in front of very large audiences. I thank all of the professors for whom I taught, Dr. Adcock, Dr. Turner, Dr. Zhang, Dr. Pagni, and Dr. Green, for their influence in helping me become a better teacher. I thank all of the professors from which I’ve taken classes, Dr. Ron Magid, Dr. Lee Magid, Dr. Pagni, Dr. Zhang, Dr. Baker, Dr. Xue, Dr. Kabalka, Dr. Bartmess, and Dr. Cook, for increasing my knowledge in the field of chemistry. I thank Art Pratt for being an excellent glassblower and helping me create some necessary tools for the completion of my research. I thank Pat McDaniel Kershieter for being a good friend as well as a diligent worker during my time spent in Dr. Kabalka’s lab. I thank Dr. Hongjun Pan for helping me understand the NMR instruments better than I could have on my own. I thank the members of the electronics shop, Bill Gurly, Johnny Jones, Gary Wynn, and Gene French, iii for helping me with computer related problems and elecronic repairs. I thank the members of the machine shop, Eddie Wilson, Tim Free, and John Nelson, for their assistance. I thank the members of the stockroom, Traymon Allen and Darrel Lay, for helping get the supplies I needed. I thank Dr. Murthy, Dr. Yao, Dr. Wu, Dr. Bollu, and Dr. Mereddy for their hands-on help and advice with my research. I thank all of my former and present labmates including Andy, Yin, Abhijit, Dong, Travis, Scott, Kristy, Brandy, Eric, Juhong, Lana, Nisha, Li Li, and Sankar for their contribution to a more pleasurable working environment. I also thank Dr. Nicie Conley Murphy for always being a great friend when I needed one most. Finally, I thank my family for standing by me, encouraging me, and supporting me during the past five and a half years as well as my entire life. iv ABSTRACT Anabaseine has demonstrated a high, non-selective, affinity for the α7- bungarotoxin sensitive neuronal nicotinic acetylcholine receptor binding site found in small cell lung carcinoma. The benzylidene anabaseine derivatives of anabaseine have shown a selective affinity for these binding sites. These studies suggest that radiolabeled benzylidene anabaseine derivatives could act as potential imaging agents to aid in the early detection of lung cancer. This dissertation outlines the strategy and methods employed in the synthesis of a family of potassium trifluoroborate derivatives of benzylidene anabaseine and their subsequent halogenation. Two of the trifluoroborate salts were converted to their radiolabeled analogues for potential use as single photon emission tomography (SPECT) agents through incorporation of iodine-123, or positron emission tomography (PET) agents, using bromine-76, for the early detection of lung cancer. One derivative, 5-[123I]-iodo-2,4-dimethoxybenzyidene anabaseine was employed in an investigation using a new hamster lung tumor model. En route to the synthesis of the radiolabeled benzylidene analogues, an investigation into a convenient synthesis of anabaseine was conducted. The synthesis was achieved in four steps and in high overall yields. v TABLE OF CONTENTS CHAPTER 1 INTRODUCTION..........................................................................1 1.1 EMISSION TOMOGRAPHY ...........................................................................1 1.1.1 Single Photon Emission Computed Tomography ...............................1 1.1.2 Positron Emission Tomography..........................................................2 1.2 SMALL CELL LUNG CARCINOMA .............................................................3 1.2.1 α7-Nicotinic Acetylcholine Receptor...................................................4 1.3 α7-NICOTINIC ACETYLCHOLINE RECEPTOR BINDING LIGANDS ......5 1.3.1 NNK [4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone] ..................5 CHAPTER 2 LITERATURE REVIEW..............................................................6 2.1 SINGLE PHOTON EMISSION COMPUTED TOMOGRAPHY....................6 2.1.1 Historical perspective of SPECT ........................................................6 2.1.2 Principle of SPECT.............................................................................9 2.2 POSITRON EMISSION TOMOGRAPHY.....................................................11 2.2.1 Historical perspective of PET ..........................................................11 2.2.2 Principle of PET ...............................................................................16 2.2.3 A Comparison of PET and SPECT ...................................................22 2.3 RADIOPHARMACEUTICALS......................................................................25 2.3.1 Historical Perspective of Radiopharmaceuticals .............................25 2.3.2 Receptor Binding Radiotracers.........................................................28 2.4 SCLC AND NICOTINIC ACETYLCHOLINE RECEPTORS ......................29 2.4.1 Lung Cancer......................................................................................29 vi 2.4.2 α7-Nicotinic Acetylcholine Receptor (nAChR)..................................30 2.4.3 Lung Cancer and α7-nAChR’s ..........................................................33 2.5 BINDING LIGANDS AND RADIOTRACERS FOR α7-nAChR’s ...............34 2.5.1 NNK [4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone] ................34 2.5.2 α-Bungarotoxin (α-BTX)...................................................................34 2.5.3 Oxystilbene Derivatives ....................................................................36 2.5.4 Nicotine Derivatives..........................................................................36 2.5.5 Epibatadine Derivatives....................................................................39 2.5.6 Pyridyl Ether Derivatives .................................................................39 2.5.7 Quinuclidine Derivatives ..................................................................39 2.5.8 Anabaseine Derivatives ....................................................................43
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