Synthesis of Novel 6-Nitroquipazine Analogs for Imaging the Serotonin Transporter by Positron Emission Tomography
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University of Montana ScholarWorks at University of Montana Graduate Student Theses, Dissertations, & Professional Papers Graduate School 2006 Synthesis of novel 6-nitroquipazine analogs for imaging the serotonin transporter by positron emission tomography David B. Bolstad The University of Montana Follow this and additional works at: https://scholarworks.umt.edu/etd Let us know how access to this document benefits ou.y Recommended Citation Bolstad, David B., "Synthesis of novel 6-nitroquipazine analogs for imaging the serotonin transporter by positron emission tomography" (2006). Graduate Student Theses, Dissertations, & Professional Papers. 9590. https://scholarworks.umt.edu/etd/9590 This Dissertation is brought to you for free and open access by the Graduate School at ScholarWorks at University of Montana. It has been accepted for inclusion in Graduate Student Theses, Dissertations, & Professional Papers by an authorized administrator of ScholarWorks at University of Montana. For more information, please contact [email protected]. Maureen and Mike MANSFIELD LIBRARY The University of Montana Permission is granted by the author to reproduce this material in its entirety, provided that this material is used for scholarly purposes and is properly cited in published works and reports. **Please check "Yes" or "No" and provide signature** Yes, I grant permission No, I do not grant permission Author's Signature: Date: C n { ( j o j 0 ^ Any copying for commercial purposes or financial gain may be undertaken only with the author's explicit consent. 8/98 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. SYNTHESIS OF NOVEL 6-NITROQUIPAZINE ANALOGS FOR IMAGING THE SEROTONIN TRANSPORTER BY POSITRON EMISSION TOMOGRAPHY by David B. Bolstad B.S. Chemistry, Central Washington University, 2001 B.A. Biology, Central Washington University, 2001 Presented in partial fulfillment of the requirements for the degree of Doctor of Philosophy The University of Montana July 2006 Approved by: (fU rson Dean, Graduate School - g, - o c , Date Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. UMI Number: 3228603 Copyright 2006 by Bolstad, David B. All rights reserved. INFORMATION TO USERS The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleed-through, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. ® UMI UMI Microform 3228603 Copyright 2006 by ProQuest Information and Learning Company. All rights reserved. This microform edition is protected against unauthorized copying under Title 17, United States Code. ProQuest Information and Learning Company 300 North Zeeb Road P.O. Box 1346 Ann Arbor, Ml 48106-1346 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Bolstad, David B. Ph.D., July 2006 Chemistry Synthesis of Novel 6-Nitroquipazine Analogs for Imaging the Serotonin Transporter by Positron Emission Tomography Chairperson: John M. Gerdes A positron emission tomography (PET) imaging agent that can effectively quantify the serotonin transporter (SERT) in brain regions with moderate to low densities of SERT has yet to be identified. The recent literature has suggested that the need for such an agent may be filled by a selective, high affinity SERT ligand that displays extended in vivo kinetic profiles, concurrent with a reduction of in vivo nonspecific binding. Recently, our group has identified 2’-alkyl-6- nitroquipazine analogs as novel SERT ligands displaying very high affinity for SERT (picomolar concentration range). We have utilized the 6-nitroquipazine molecular construct for the development of new SERT PET imaging agents, by generating a series of racemic 2’-alkyl-6-nitroquipazine analogs that can incorporate the carbon-11 or the longer-lived fluorine-18 radionuclides. We expect that the increased SERT affinity of our new ligands will afford more efficacious SERT PET agents that can effectively quantify low density SERT regions in living brain. A large focus of the present study was to expand our initial racemic lead agents by synthesizing each of them in enantiomerically pure form. Our synthetic strategy utilized an efficient asymmetric synthesis of the piperazine head-group from amino acid starting materials. The syntheses afforded non-radiolabelled target ligands and the appropriate radioligand precursors in good yields. Preliminary pharmacological data suggests a marked difference in binding affinity between the enantiomers of our agents. Furthermore, using racemic amino acids and the same asymmetric synthetic strategy, we were also able to generate novel 2’-aryl-6-nitroquipazine analogs that were not synthetically accessible using our derived methods for the 2’-alkyl agents. The racemic radiotracer [18F]2’-(3-fluoropropoxymethyl)-6-nitroquipazine agent was synthesized and evaluated in rat for initial radiotracer distribution. The studies in rat have demonstrated favorable accumulation of the tracer in the brain indicating efficient passage through the blood brain barrier. Furthermore, these studies indicate the greatest concentration of radiotracer in regions of the brain with known SERT density. The studies of the initial, racemic tracer have shown that [18F]2’-(3-fluoropropoxymethyl)-6-nitroquipazine demonstrates potential as a new SERT PET imaging agent. ii Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. ACKNOWLEDGEMENTS I am eternally grateful to Dr. John Gerdes for the enlightening introduction to organic synthesis he provided me as an undergraduate researcher. This experience was the seminal influence that led me to pursue organic chemistry and profoundly altered my current life’s direction. My abilities as a scientist and researcher have developed as a result of his expert guidance and attention to detail. For the many years you’ve served as a mentor and a friend, I give my most gracious thanks. To all of the current and former members of the Gerdes research group I give thanks for all of their support and friendship over the years. Of course, Brian Kusche probably deserves his name on this work too and the last six years have shown just what a fantastic lab partner and tremendous friend he has been. I couldn’t have completed this journey without him. The fantastic scientists of the Lawrence Berkeley National Lab also deserve praise for their contributions toward the completion of this work. Without the radiochemical abilities of Dr. Jim O’Neil, my dissertation would only tell a partial story. We are indebted to Dr. O’Neil for the current and future successes of this project. To Dr. Andy Gibbs I say thanks for the assistance with certain experiments, but mostly for being a great friend. I must also recognize the members of my committee who have provided advice and support over the past few years. Dr’s Ed Waali, Don Kiely, Sean Esslinger and Michael Kavanaugh have my gratitude for their participation in my iii Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. graduate education and their continued kindness throughout my time at the University of Montana. I must also thank my family who has provided constant encouragement throughout my seemingly endless years of education. My accomplishments are a result of their continuous support and I am forever grateful for their love and motivation. To all of my friends in Montana and Washington, I thank you for the countless hours of fun a excitement that have helped me to maintain my sanity and made the last few years of my life the most rewarding yet. It has been an exciting ride and one that I hope continues. Most importantly, I must give thanks to my wife, Erin S. Davis Bolstad, whose unwavering love, support and encouragement has maintained my inspiration and allowed me to succeed in life and in my education. Without her love, I would not have accomplished all that I have and I would not be the person that I have become. Thank you for being my best friend. iv Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. TABLE OF CONTENTS LIST OF FIGURES.................................................................................................... VI LIST OF TABLES...........................................................................................................X LIST OF SCHEMES..................................................................................................... XI LIST OF ABBREVIATIONS....................................................................................... XIII 1. INTRODUCTION, BACKGROUND AND PURPOSE........................................ 1 1.1 Serotonin Biology ............................................................................................1 1.2 The Serotonin Transporter ............................................................................. 4 1.3 The Serotonin Transporter and Disease ........................................................6 1.4 Positron