Exploiting the Gallium-Fluoride Bond in the Design of New Radiopharmaceuticals

© 2020 Hui Jing KoayPositron emission tomography (PET) is a molecular imaging technique that produces three-dimensional images in high resolution and is used to assist in the diagnosis and monitoring of disease. The technique relies on molecules radiolabelled with a positron-emitting radionuclide called ‘tracers’ injected into patient at ‘trace’ concentrations. The most used radionuclide for PET is fluorine-18. Conventional approaches to fluorine-18 radiolabelling rely on the formation of a covalent C-18F bond and such synthetic chemistry can be challenging. It has been suggested that coordinate bond formation between Al3+/Ga3+ and F- may lead to complexes of sufficient stability due to the high metal fluoride bond energy. The work presented in this thesis investigates the potential of the formation of Ga3+-F- complexes as alternative method for rapid incorporation of fluorine-18 into molecules. A series of pentadentate acyclic ligands based on the dipicolinic acid scaffold (H2L3-5) that coordinate to Ga3+ were prepared. Characterisation of [GaL3(OH)], [GaL3Cl] and [GaL3F] by X-ray crystallography revealed that in each case the ligand acted as tetradentate donor with a weak interaction with a sixth nitrogen donor. Treatment of [GaL3(OH)] / [GaL3Cl] with [18F]/H2O at room temperature readily formed [GaL3F]. Although the synthesis of [GaL3F] was straightforward, it was only possible to form [18F][GaL3F] in very low radiochemical yields. In a second approach a family of macrocyclic ligands was adopted to develop a single chelate system that has the potential to be radiolabelled with three radionuclides; fluorine-18, copper-64 and gallium-68. A stilbene derivative attached to the NODA chelator, H2L12 was designed to bind to amyloid b (Ab) plaques associated with Alzheimer’s disease (AD). The ability to identify the burden of insoluble aggregates in the brain in a non-invasive manner may assist our understanding of AD. The new ligand, H2L12 binds to extracellular Ab plaques present in human brain tissue, but there was no evidence that [GaL12F] and [CuL12] bound to Ab plaques. The radiolabelled [18F][GaL12F], [68Ga][GaL12F] and [64Cu][CuL12] formed in high radiochemical purity at pH 4-5.5. The biodistribution and PET imaging potential of [18F][GaL12F] and [64Cu][CuL12] was evaluated in mice and this revealed the initial uptake in brain of [18F][GaL12F] and [64Cu][CuL12] were 0.85 +- 0.13% IA/g and 0.71 +- 0.03% IA/g respectively. An increase in uptake in bone suggested that the [18F]Ga3+-F- system is unstable in vivo. A tetradentate azamacrocyclic ligand with N4 donor set, tetramethyltetraaza[14]annulene (tmtaa) was investigated to replace the carboxylate donor groups in [GaL3F] and [GaL12F]. A five coordinate Ga3+-F- complex of tmtaa was prepared. [Ga(tmtaa)F] was characterised by X-ray crystallography revealing the complex has a saddle-shaped geometry. The radioactive complex, [18F][Ga(tmtaa)F] can be prepared by a halogen exchange reaction starting with [Ga(tmtaa)Cl]. Functionalisation at the methine carbon atoms of H2tmtaa could see future development to include biomolecules. Translation of the non-radioactive Ga3+-F- chemistry to systems containing fluorine-18 remains challenging. The work presented here demonstrated that the [18F]Ga3+-F- complexes are less stable than the Al3+ analogues. It would be of great interest to investigate the potential of the [18F]Al3+-F- complexes of these families of ligands as PET imaging agents