PET radiochemistry for the investigation of the biology of pain and inflammation

• Main Author: Fairclough, Michael Edward
• Format: Dissertation
• Language: English
• Published: University of Manchester 2015
• Subjects: Carbon-11; Fluorine-18; Inflammation Imaging; Opioids; PET; Radiochemistry; Zirconium-89

Positron emission tomography (PET) is an important and powerful nuclear imaging modality and is essential in a range of medical fields. A suitable radiotracer must be identified in order for PET imaging to provide high quality and quantifiable data about the pathology. This includes the design and implementation of optimal radiochemistry that will reliably deliver the radiotracer that can answer the pertinent biological questions being asked. PET can be used to study the biological processes which are involved in pain perception and inflammatory responses that can occur in a number of chronic and acute conditions. This thesis aims to demonstrate how PET radiochemistry can enhance our knowledge of these biological processes and permits access to the underlying molecular mechanisms behind pain and inflammation. This thesis has been written in an alternative format, comprising the different areas which have been investigated. The work encompasses the study of the endogenous opioid system using the opioid receptor antagonist [11C]diprenorphine. This includes the design and automation of [11C]diprenorphine radiochemistry followed by the development of a method to reliably analyse its metabolism. Finally the application of [11C]diprenorphine in a clinical PET study, investigating opioid receptor occupancy by endogenous opioids as well as up-regulation of opioid receptors in the brain, is described. In the study of inflammation a pro-inflammatory cytokine, recombinant human interleukin-1 receptor antagonist (rhIL-1RA), was radiolabelled with novel 18F radiochemistry permitting pharmacokinetic study in pre-clinical models. This is followed by the design of a new technique to radiolabel white blood cells with 89Zr for quantifiable cell trafficking with PET. For this technique, chitosan nanoparticles are used to deliver the radio-metal cargo into white blood cells with a proposed application in inflammatory models. The process of chitosan nanoparticle construction is described alongside development of a procedure that is optimised for use in the proposed application. This thesis covers a variety of topics illustrating the contribution of PET radiochemistry in the area of pain and inflammation. The synergy between identification of new biological targets and development of radiotracers and radiolabelling strategies ensure PET radiochemistry will continue to contribute to our knowledge of pain and inflammation and aid understanding of its role in countless medical conditions.