This thesis details the design and synthesis of a small library of 19F MRI MMP probes containing an MMP substrate bound to a paramagnetic agent (gadolinium contrast agent) with a fluorine containing group at the opposite terminus. The largest obstacle in the synthesis of the probe was the conjugation of the paramagnetic agent. Multiple different modifications to the GdIII chelators AAZTA (6-amino-6-methylperhydro-1,4-diazepinetetraacetic acid) and DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) are detailed, as well as methods for the conjugation. Once a successful method was achieved the probes were carried forward for in vitro testing. Whilst the agent was whole or non-cleaved the paramagnetic relaxation effect (a distance dependent effect) of the GdIII eliminated the 19F NMR/MRI signal. The introduction of an MMP to the probe caused the probe to be cleaved. This cleavage then resulted in the increased distance between the GdIII complex and the 19F containing group, which in turn reduced the PRE, resulting in the emergence of a 19F NMR/MRI signal. This enzymatic activity was visualised using high field NMR (600 MHz AV(III)400) by the increase in signal peak height with 19F NMR, as well as the changes in the T1 and T2* (observed as a change in linewidth) values observed before and after cleavage of the probe showed a diagnostic change in the magnetic properties of the probe. Reaction rates were ascertained whilst altering the solvent (H2O vs D2O), and the temperature of the reaction. A reduction in the rate of cleavage was noticed as the D2O concentration was increased as expected, however, the change in temperature did not always follow an expected reaction profile change.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:689833 |
| Date | January 2016 |
| Creators | Krupa, James L. |
| Publisher | University of Nottingham |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://eprints.nottingham.ac.uk/32777/ |
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