Cobalt complexes as responsive MRI contrast agents

Abstract

Responsive magnetic resonance imaging (MRI) contrast agents are capable of responding to the chemical environment by altering the paramagnetism of the metal centre. The most common metal centre used is gadolinium, which has toxicity concerns and exerts residual paramagnetism in its off state. Since accumulation of gadolinium complexes in their off state can provide a false positive in the observed relaxation rate of water molecules, fully diamagnetic cobalt(III) and the reductive switch to cobalt(II) is presented in this thesis as a potential solution. A number of cobalt ligand scaffolds were investigated for their ability to act as off-to-on MRI probes in response to a reducing chemical environment that would be present in tissue hypoxia. A series of TPA derivatives with varying charge was synthesised, and accumulation and activation of complexes within tumour spheroids were investigated using a combination of inductively coupled plasma mass spectrometry (ICP-MS), MRI and nuclear magnetic resonance (NMR) spectroscopy techniques. One complex, Co-TPA3, showed selective uptake in the quiescent non-proliferating hypoxic regions of the tumour spheroid and activation to Co(II)TPA3 could be detected by MRI. Speciation and stability could also be determined by paramagnetic 1H NMR, and Co-TPA3 could be a suitable candidate for future MRI hypoxia imaging, as well as a scaffold for theranostic applications. The paramagnetic 1H NMR signals of another cobalt complex, CoMe6TrenCl were investigated in the presence of various anions in solution. Unique 1H NMR signals were observed for each anion tested even in complex solutions and the binding affinities of anions and relaxation parameters of the paramagnetic signals were characterised by a variety of NMR spectroscopic techniques.