Imaging probes for brain inflammation and blood-brain-barrier penetration
File(s)
Author(s)
Woolley, Benjamin
Type
Thesis
Abstract
This thesis describes the synthesis of imaging probes for brain inflammation and blood-brain-barrier (BBB) penetration. The imaging and therapy of many central nervous system disorders such as Alzheimer's disease is often inhibited by a compound’s inability to be able to cross the BBB. The importance of neuroinflammation, particularly involving activated microglia, is also thought to be an important biomarker of disorders such as Alzheimer's disease, and could lead to earlier diagnoses and more effective therapies.
Chapter 2 describes the synthesis of a range of lanthanide complexes containing macrocyclic ligands appended with a tetrazine unit for bio-orthogonal click chemistry. The resulting lanthanide-tetrazine complexes are evaluated by luminescence spectroscopy and relaxivity measurements.
Chapter 3 details the subsequent bio-orthogonal click chemistry reactions using the lanthanide-tetrazine complexes synthesised in Chapter 2. These complexes are clicked to BBB penetration vectors such as cyclic peptides and their relaxivity is evaluated.
Chapter 4 describes the synthesis of the formyl peptide receptor 2 agonist Quin C1 for designing optical and MR imaging probes for targeting activated microglia under neuroinflammatory conditions. A rhodamine-Quin C1 optical probe is evaluated for its BBB penetration with focused ultrasound and microbubbles, as well as its colocalisation with microglia via immunohistochemistry staining.
Chapter 5 details the radiochemical synthesis of the first Quin C1-based PET probe, along with in vitro and in vivo biological evaluation of the 18F-based probe in a model of neuroinflammation. The radiochemical synthesis of an 11C-labelled version of the Quin C1 structure is also described.
Chapter 6 summarises the conclusions in this thesis and ideas for future work of this research.
Chapter 7 includes the experimental procedures for the synthetic chemistry and radiochemistry, along with biological procedures for any in vitro and in vivo work conducted. Chapter 8 contains an appendix for additional data not directly included within the preceding chapters.
Chapter 2 describes the synthesis of a range of lanthanide complexes containing macrocyclic ligands appended with a tetrazine unit for bio-orthogonal click chemistry. The resulting lanthanide-tetrazine complexes are evaluated by luminescence spectroscopy and relaxivity measurements.
Chapter 3 details the subsequent bio-orthogonal click chemistry reactions using the lanthanide-tetrazine complexes synthesised in Chapter 2. These complexes are clicked to BBB penetration vectors such as cyclic peptides and their relaxivity is evaluated.
Chapter 4 describes the synthesis of the formyl peptide receptor 2 agonist Quin C1 for designing optical and MR imaging probes for targeting activated microglia under neuroinflammatory conditions. A rhodamine-Quin C1 optical probe is evaluated for its BBB penetration with focused ultrasound and microbubbles, as well as its colocalisation with microglia via immunohistochemistry staining.
Chapter 5 details the radiochemical synthesis of the first Quin C1-based PET probe, along with in vitro and in vivo biological evaluation of the 18F-based probe in a model of neuroinflammation. The radiochemical synthesis of an 11C-labelled version of the Quin C1 structure is also described.
Chapter 6 summarises the conclusions in this thesis and ideas for future work of this research.
Chapter 7 includes the experimental procedures for the synthetic chemistry and radiochemistry, along with biological procedures for any in vitro and in vivo work conducted. Chapter 8 contains an appendix for additional data not directly included within the preceding chapters.
Version
Open Access
Date Issued
2024-10-02
Date Awarded
2025-04-01
Copyright Statement
Attribution-NonCommercial 4.0 International Licence (CC BY-NC)
License URL
Advisor
Long, Nicholas
Publisher Department
Department of Chemistry
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)