High-intensity contrast agents in medical imaging

Smith, David Peter Thomas (2009). High-intensity contrast agents in medical imaging. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.00010055

Abstract

This research project focused on the formation of novel, high-contrast MRI agents based on cyclen (1,4,7,10-tetraazacyclododecane) for the complexation of Gd³⁺. The aim of the project was to attach a number of these gadolinium contrast agents to a silicon-based central scaffold. This would allow several cyclen units to be attached to the scaffold, producing a contrast agent in which the number of bound gadoliniums was limited only by the number of binding sites on the scaffold.

The Gd³⁺ was complexed in a ligand based on a tetrasubstituted cyclen (1,4,7,10-tetraazacyclododecane) in which three of the four amines were used for attachment of carboxylic acids for complexation to the gadolinium, while the fourth amine was used for the attachment of the linking arm used to bind to the silicon-based scaffold. Two types of cyclen ligand were investigated. Firstly, an eight-coordinate cyclen ligand based on acetic acid arms with but-3-enal for the binding arm, where the carbonyl on the but-3-enal was bound to the gadolinium to improve complex stability; and secondly, a seven-coordinate cyclen system consisting of succinic acid arms and a straight-chain alkene for the hydrosilylation reaction.

While the acetic acid based complexes failed due to stability issues, with the but-3-enal linking arm being hydrolysed during the deprotection of the acetic acid groups. As a result of this the research concentrated on the seven-coordinate ligand system. The advantage of the seven-coordinated system was that the extra non-coordinating three acid groups from the succinic acid on the cyclen would increase the solubility of the target molecules, and would also repel any anions in solution when used in biological systems.

The first scaffolds investigated were based on silsesquioxane cages. The experiments showed that this approach was problematic due to the decomposition of the cyclen system and the silsesquioxane cage to form an insoluble gel like product. This decomposition was found to be due to several unforeseen factors, which included the trapping of water with in the cyclen molecule, the decomposition of the cyclen ligand by the platinum catalyst producing a secondary amine. The decomposition of the silsesquioxane cage was inpart due to this secondary amine. Because of these problems an alternative scaffold was used. The new scaffold was based on silanes attached to a benzene ring, rather than to the siloxanes of the cages.

The MRI T2 relaxation rates showed that the complexes that contained one or two gadoliniums had a relaxivity in relation to molar concentration of complex of 4.8 r_1p/mM^-1s^-1and 4.5 r_1p/mM^-1s^-1 (or 2.25 r_1p/mM^-1s^-1 per gadolinium) respectively, and so were similar to the commercial MRI contrast agent DOTA-Gd (4.3 r_1p/mM^-1s^-1 The trisubstituted scaffold compound 1,3,5-tris((pentane- sD03A)dimethylsilyl)benzene-Gd3 (247) showed a marked increase in the relaxivity (13.1 r_1p/mM^-1s^-1 in relation to molar concentration, and 4.3 r_1p/mM^-1s^-1 in relation to the gadolinium concentration.

The thesis is split into six chapters, with the first one covering the background of the MRI technique and current research into MRI contrast agents. The second chapter deals with the formation of the cyclen ligands. The third chapter is about the attachment of the cyclen ligands to the silicon scaffold. The fourth chapter concerns the formation of the lanthanide complexes and the measurements undertaken. The final two chapters involve the conclusion and the experimental section.