Lipophilic and cationic gallium-68 complexes for the detection of mitochondrial dysfunction
File(s)
Author(s)
Osborne, Bradley Edward
Type
Thesis
Abstract
This thesis gives an account of the synthesis of macrocyclic and acyclic ligands for radiolabelling with gallium-68 to afford lipophilic and cationic radiotracers to report on mitochondrial dysfunction. These radiotracers are designed to be lipophilic enough to ensure the successful permeation of lipid bilayer membranes, and to also possess a cationic charge in order to be attracted into the mitochondria in a manner dependent on the mitochondrial membrane potential.
The synthesis of novel macrocyclic chelators for gallium-68 labelling is described in chapter 2. The synthesis of three sets of macrocyclic compounds are discussed, beginning with a focus on triarylphosphonium functionalisation to afford lipophilic and cationic compounds.
All three sets of compounds described in chapter 2 were successfully radiolabelled with generator-produced gallium-68. Chapter 3 describes this radiolabelling, starting with the optimisation of radiochemical yields through a series of altering reaction condition experiments. Initial screening of these radiolabelled compounds was performed through the measurement of their log D values. RadioHPLC analysis was used to investigate the purity of the reaction mixture and assess the presence of speciation.
Chapter 4 described the candidate radiotracer’s behaviour in a preclinical model. The cardiac uptake and retention of the candidate radiotracer was determined using the ex vivo Langendorff isolated perfused heart model in both healthy and depolarised mitochondria, with MIBI used as a baseline for this model. This work provides the foundation for additional, more thorough, biological evaluation of such radiotracers, as well as informing on the design and development of future lipophilic and cationic gallium-68 radiotracers.
As well as macrocyclic ligands discussed in chapter 2, several acyclic ligand families were also synthesised. These series of acyclic ligands are described in chapter 5, including a focus on bis(salicylaldimine) compounds and some phosphinic acid functionalised analogues, two series of tridentate ligands which have been shown to selectively form 2:1 complexes with metals in the oxidation state of +3, and a final series of bis(semicarbazone) chelates with a focus on triarylphosphonium functionalisation to yield lipophilic and cationic compounds.
Chapter 6 summarises the conclusions of this thesis and ideas for future work of this research. Chapter 7 summarises the experimental procedures for the synthetic chemistry and radiochemistry. Chapter 8 contains an Appendix for NMR, MS and DFT data.
The synthesis of novel macrocyclic chelators for gallium-68 labelling is described in chapter 2. The synthesis of three sets of macrocyclic compounds are discussed, beginning with a focus on triarylphosphonium functionalisation to afford lipophilic and cationic compounds.
All three sets of compounds described in chapter 2 were successfully radiolabelled with generator-produced gallium-68. Chapter 3 describes this radiolabelling, starting with the optimisation of radiochemical yields through a series of altering reaction condition experiments. Initial screening of these radiolabelled compounds was performed through the measurement of their log D values. RadioHPLC analysis was used to investigate the purity of the reaction mixture and assess the presence of speciation.
Chapter 4 described the candidate radiotracer’s behaviour in a preclinical model. The cardiac uptake and retention of the candidate radiotracer was determined using the ex vivo Langendorff isolated perfused heart model in both healthy and depolarised mitochondria, with MIBI used as a baseline for this model. This work provides the foundation for additional, more thorough, biological evaluation of such radiotracers, as well as informing on the design and development of future lipophilic and cationic gallium-68 radiotracers.
As well as macrocyclic ligands discussed in chapter 2, several acyclic ligand families were also synthesised. These series of acyclic ligands are described in chapter 5, including a focus on bis(salicylaldimine) compounds and some phosphinic acid functionalised analogues, two series of tridentate ligands which have been shown to selectively form 2:1 complexes with metals in the oxidation state of +3, and a final series of bis(semicarbazone) chelates with a focus on triarylphosphonium functionalisation to yield lipophilic and cationic compounds.
Chapter 6 summarises the conclusions of this thesis and ideas for future work of this research. Chapter 7 summarises the experimental procedures for the synthetic chemistry and radiochemistry. Chapter 8 contains an Appendix for NMR, MS and DFT data.
Version
Open Access
Date Issued
2022-11
Date Awarded
2023-05
Copyright Statement
Creative Commons Attribution NonCommercial NoDerivatives Licence
Advisor
Long, Nicholas
Publisher Department
Chemistry
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)