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Development of Radiotracers for Neuroimaging

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Development of Radiotracers for Neuroimaging Development of Radiotracers for Neuroimaging Niral Patel Submitted for the degree of Doctor of Philosophy Department of Medical Physics and Biomedical Engineering University College London Declaration I, Niral Patel, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been referenced accordingly. This thesis is based on research conducted between September 2011 to May 2014 at the Chemistry Department and Centre for Advanced Biomedical Imaging (CABI), University College London, U.K. Niral Patel 2 Abstract Nuclear imaging enables quantitative measurements of biological processes in vivo and has revolutionised biomedical research, drug development and clinical practice. Despite the advances made in this field, the ability to image fundamental aspects of neurological diseases remains a challenge. This is partly due to the limited availability of radiotracers for imaging excitatory neurotransmission and detection of inflammation as well as an array of other biochemical processes central to the operational function of the brain. The aim of this research was to expand the arsenal of radiotracers available for neuroimaging in order to study key pathological processes involved in neurological diseases. With the aim to target neuronal Voltage Gated Sodium Channels (VGSCs), Vascular Cell Adhesion Molecule – 1 (VCAM-1) and N-methyl-D-Aspartate Receptors (NMDARs), radiotracers have been synthesised and evaluated. Abnormal expression of these receptors has been implicated in a number of pathological conditions including epilepsy, multiple sclerosis and neurodegeneration. The radiotracers were characterised and evaluated via in vivo imaging (MRI and SPECT/CT) and ex-vivo studies (phosphorimaging, biodistribution and metabolite analysis) in order to determine if they hold significant potential as tools to study neuronal pathways as well as for diagnostic imaging and treatment monitoring. Iodinated analogues of the iminodihydroquinoline WIN17317-3, and the 1- benzazepin-2-one BNZA have been evaluated as neuronal VGSC tracer candidates in healthy mice. Whilst the WIN17317-3 analogue suffered from poor brain uptake and was rapidly metabolised in vivo, the BNZA analogue exhibited excellent in vivo stability and its promising uptake in the brain warrants further investigations. Even though N-(1-Napthyl)-N’-(3-[123I]-iodophenyl)-N’-methylguanidine ([123I]CNS-1261) has demonstrated favourable pharmacokinetics for brain imaging in clinical studies, [125I]CNS-1261 was not successful in discriminating NMDAR expression between naïve rats and those induced with status epilepticus using lithium and pilocarpine. 3 Promisingly, a multi modal contrast agent comprising micron sized particles of iron oxide conjugated to I-125 radiolabelled antibodies, highlighted the up-regulation of VCAM-1 in rat models of cerebral inflammation and in the lithium pilocarpine model of status epilepticus. This versatile imaging agent presents an exciting opportunity to identify an early biomarker for epileptogenesis. 4 Acknowledgements I would like to begin by acknowledging the invaluable support of my supervisors: Erik Årstad has been an inspiration due to his breadth of knowledge and my accomplishments over the last 4 years would not have been possible without his guidance; I am indebted to Adam Badar for teaching me about biological evaluations and for ongoing support both academically and personally; and Mark Lythgoe whose passion fostered an incredible environment for learning and for wonderful insight that has driven my research. Many people have also actively contributed to the work contained within this thesis and therefore their help is greatly appreciated: Carlos Perèz-Medina for help with radiolabelling, Eva Galante for assistance with HPLC and LC-MS, Ben Duffy for teaching me the animal models and collaborating on a VCAM-1 project, Mathew Robson, Valerie Taylor and Asif Machhada for help with animal models and radiotracer administrations, Abil Aliev for help with NMR acquisition and Vineeth Rajkumar for help with phosphorimaging. I am also thankful to Kerstin Sander, Ran Yan, Thibault Gendron and Tammy Kalber for their in depth discussions and advice. I wish to thank the people who have surrounded me during my years at UCL: Vincent Gray and Rachel Lannigan from the Chemistry department: Vessela Vassileva from the Cancer Institute and the past and current members of CABI: Adrienne Campbell, Angela D’Esposito, Ben Duffy, Bernard Siow, Daniel Stuckey, Holly Holmes, Isabel Christie, Jack Wells, James O’Callaghan, Johannes Riegler, Katherine Ordidge, Laurence Jackson, Louise Kiru, Miguel Goncalves, Morium Ali, Ozama Ismail, Peter Johnson, Ruth Oliver, Rupinder Ghatrora, Simon Walker- Samuel, Thomas Roberts and Yanan Zhu. My close friends have been a great support system and I wish to thank them dearly: Rajiv Ramasawmy for introducing me to your uniqueness and creative outlook on life, Carlos Perèz-Medina for always inspiring me, Elena Yiannaki for sharing this PhD journey with me through tears and laughter and Anthony Price for encouraging me throughout. Also, Ahmed Akhbar, Atif Elahi and Bhavesh Premdjee have been the best friends whose love and support I will always cherish. 5 Finally, my deepest gratitude goes to my family who have been my backbone and whose unconditional love and support have allowed me to achieve this. 6 Table of Contents Abstract ................................................................................................................................... 3 Acknowledgements ................................................................................................................ 5 List of Figures ....................................................................................................................... 11 List of Tables ........................................................................................................................ 12 List of Schemes ..................................................................................................................... 12 List of Equations .................................................................................................................. 13 Abbreviations ....................................................................................................................... 14 Publications arising from this thesis................................................................................... 17 Conference Poster ................................................................................................................ 17 Conference Presentation ..................................................................................................... 17 Thesis Outline ....................................................................................................................... 18 Chapter 1 Introduction ........................................................................................................ 19 1.1 Nuclear Imaging ..................................................................................................... 19 1.1.1 SPECT ................................................................................................................... 20 1.1.2 PET ....................................................................................................................... 22 1.1.3 PET vs. SPECT, Clinical vs. Pre-Clinical............................................................. 24 1.1.4 Autoradiography and Phosphorimaging ............................................................... 26 1.2 Radiotracers ........................................................................................................... 27 1.2.1 Radionuclides ........................................................................................................ 27 1.2.2 Isotopes and Radioisotopes of Iodine ................................................................... 28 1.2.3 Pharmacokinetics .................................................................................................. 29 1.3 Radiotracer Development ...................................................................................... 36 1.4 Radiotracers for Neuroimaging .............................................................................. 38 1.5 Summary ................................................................................................................ 39 Chapter 2 Experimental Methods for Radiolabelling and Quantitative Analysis ......... 40 2.1 Radiolabelling with Iodine ........................................................................................... 40 2.1.1 Radioiodination of Small Organic Molecules ....................................................... 43 2.2 Radio - High Performance Liquid Chromatography .................................................... 44 2.3 Specific Activity .......................................................................................................... 46 2.4 Quantitative Accuracy for Imaging .............................................................................. 47 2.4.1 In Vivo SPECT ...................................................................................................... 47 7 2.4.2 Phosphorimaging .................................................................................................. 50 2.4.3 Biodistribution .....................................................................................................
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