Pdf4 Complex I and the Aryl Palladium Precursor II Underwent Sequential Single Electron Abstraction from Aryl Pd(II) Complex

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Pdf4 Complex I and the Aryl Palladium Precursor II Underwent Sequential Single Electron Abstraction from Aryl Pd(II) Complex Design, synthesis, methodology development, and evaluation of PET imaging agents targeting cancer and CNS disorders By Gengyang Yuan B.S. in Chemical Engineering and Technology, Zhejiang University of Technology M.S. in Pharmaceutical Engineering, Zhejiang University A dissertation submitted to The Faculty of the College of Science of Northeastern University in partial fulfillment of the requirements for the degree of Doctor of Philosophy April 21, 2017 Dissertation directed by Michael P. Pollastri Associate Professor and Chair of Chemistry and Chemical Biology Co-directed by Neil Vasdev Adjunct Associate Professor of Chemsitry and Chemical Biology Associate Professor of Radiology, Massachusetts General Hospital and Harvard Medical School Dedication To my parents Zhijun and Yongmian and my wife Ran and daughter Isabella ii Acknowledgements This dissertation would not have been possible without the support, guidance and encouragement of numerous people who have helped me along the way. First and foremost, I would like to thank Northeastern University and the Department of Chemistry and Chemical Biology for supporting me to pursue my doctoral study. I would like to especially thank my current advisor Professor Michael Pollastri for helping me out when I needed it the most. I appreciate you for taking me into your group and giving me full support to finish my thesis projects. I also especially thank my co-advisor Professor Neil Vasdev for taking me into his group at Mass. General Hospital & Harvard Medical School and teaching me the PET radiochemistry and PET imaging. I could not image how I could accomplish this work without your help. I also got a lot of help from Dr. Lori Ferrins and enjoyed the stay with other group members in Pollastri’s laboratory. I want to further extend my gratitude to my thesis committee: Professor Mary Jo Ondrechen and Professor Ke Zhang. I appreciate your time commitment and value your expertise. I would also like to thank my former advisor Professor Graham Jones for initially taking me to his group and providing me the opportunity to collaborate with Professor Neil Vasdev’s group. Thank you for encouraging me to grow as an independent researcher. I recognize the help I got from Dr. Sara Sadler, Dr. Nadeesha Ranasinghe and Dr. Chiara Chapman at the beginning of my research as well as Dr. Enrico M. Mongeau, Dr. Meaghan Fallano, Katie Hargrove, Tanner Jankins, Chris Patrick and Nick Gedeon for their support along my work at Jones’ laboratory. I am also indebted to Professor Michail Sitkovsky and his students Dr. Stephen Hatfield and Phaethon Philbrook for performing the immunoassays for me. iii I would like to especially thank Professor Mary Jo Ondrechen for allowing me to explore the field of molecular modeling and encouraging me to achieve my goals. I also want to thank Jenifer Winters and Timothy Coulther for teaching me how to use YASARA and Glide to carry out my research. I would like to acknowledge other people who also gave me tremendous help during my research at MGH, besides Professor Neil Vasdev. I would like to thank Professor Steven H. Liang for guiding me through in this process. I also want to give special thanks to Dr. Benjamin Rotstein for his encouragement and support as well as Dr. Lu Wang, Dr. Lee Collier and Ran Cheng for their support. Last, but certainly not least, I would like to thank my family and friends for their support during this long journey. I could not have done it without their help and encouragement. I especially want to thank my parents, wife and daughter for their endless love and support. iv Abstract of Dissertation As a non-invasive imaging technique, positron emission tomography (PET) is capable of in vivo quantification of biochemical and pharmacological progress via radiolabeled molecular probes. This dissertation highlights the development of a novel PET radiotracer for imaging α-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, 18F labeling methodology for 18 [ F]arylCF2H functionality, and design and synthesis of PET tracers targeting the endocanabinoid system in the brain (i.e. fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL)) and the adenosine A2A receptor (A2AR) in the immune system. Chapter 2 describes the radiosynthesis of 2-(1-(3-[18F]fluorophenyl)-2-oxo-5-(pyrimidin-2-yl)- 1,2-dihydropyridin-3yl)benzonitrile ([18F]2-11), which shows similar biodistribution results in mice as that of its [11C]2-11 isotopologue. In combination with the longer half-life of fluorine-18, [18F]2-11 is beneficial to the PET imaging studies when translated to higher species. Chapter 3 introduces a metal-free benzylic C-H bond activation enabled 18F labeling of 18 [ F]arylCF2H functionality. This methodology features a superior specific activity compared with those reported in literature as well as a diverse substrate scope. Chapter 4 highlights the molecular modeling-assisted elucidation of the severe adverse event brought by the FAAH inhibitor BIA 10-2474 in phase 1 clinical trial and the development of series of novel covalent and non-covalent MGL inhibitors as potential PET radiotracers. Chapter 5 describes the design and synthesis of series of compounds targeting A2AR as potential cancer immunotheraputics, following the hypothesized hypoxia-adenosinergic pathway. This project results in one promising compound 5-34 with satisfactory results in cAMP and IFN- gamma immunoassays. v Table of Contents Dedication .................................................................................................................................. ii Acknowledgements ................................................................................................................... iii Abstract of Dissertation ...............................................................................................................v Table of Contents ...................................................................................................................... vi List of Figures .............................................................................................................................x List of Schemes ........................................................................................................................xiv List of Abbreviations................................................................................................................xxi Chapter 1: PET imaging and synthesis of PET radiotracers ..................................................1 1.1 Background ...........................................................................................................................1 1.2 Application of fluorine in medicinal chemistry ......................................................................9 1.3 Fluorine-18 labeling chemistry ............................................................................................ 12 1.3.1 [18F]-fluorine production .................................................................................................. 12 1.3.2 Nucleophilic 18F-fluorination of alky groups ..................................................................... 14 1.3.3 Aromatic 18F-fluorination via [18F]F- fluoride ................................................................... 16 1.3.4 Aromatic electrophilic 18F-Fluorination ............................................................................ 30 1.3.5 18F-trifluorination and difluorination of (hetero)arenes...................................................... 33 18 18 1.3.6 F-labeling of aryl-SCF3, OCF3 and OCHF2 with [ F]fluoride ........................................ 37 1.4 Carbon-11 labeling chemistry .............................................................................................. 38 1.5 Summary ............................................................................................................................. 44 vi References ................................................................................................................................ 46 Chapter 2: Radiosynthesis and preliminary PET evaluation of [18F]2-11 as AMPA radiotracer ............................................................................................................................... 53 2.1 Background ......................................................................................................................... 53 2.2 AMPA receptor as a drug discovery target........................................................................... 58 2.3 AMPA PET radiotracers ...................................................................................................... 63 2.4 Radiosynthesis of [18F]2-11 as AMPA radiotracer ............................................................... 70 2.5 Preliminary PET imaging evaluation of [18F]2-11 ................................................................ 83 2.6 Radiosynthesis of the para-analogue [18F]2-36 as potential AMPA PET tracer .................... 88 2.7 Summary ............................................................................................................................. 90 Experimental Section ................................................................................................................ 91 References .............................................................................................................................. 102 18 Chapter 3: Metal-free F labeling of aryl-CF2H via nucleophilic radiofluorination and oxidative
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