Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Chemistry

Supervisor

Dr. Robert H. E. Hudson

Abstract

Magnetic resonance (MR) has outstanding potential as a noninvasive imaging modality. Possessing spatial resolution at the millimeter scale, MR imaging of anatomical features is unrivalled by other imaging techniques. Although MR imaging has outstanding spatial resolution it suffers from inherently low signal intensity. With a low sensitivity, the signal to noise ratio is low; thus MRI scans may take upwards of an hour to generate an acceptable image without a contrast agent. This drawback clearly justifies the need for contrast agents and the long held interest in their development.

Our development of novel MRI contrast agents focuses on the synthesis and evaluation of cyclen based agents for magnetic resonance spectroscopy (MRS), spin-lattice relaxation (T1), spin-spin relaxation (T2) and paramagnetic chemical exchange saturation transfer (ParaCEST).

Chapters 2 and 3 discuss contrast agents based on tetra(propargyl) DOTAM lanthanide complexes for magnetic resonance spectroscopy (MRS), relaxation and ParaCEST. With respect to MRS, temperature sensitivity values from 1.05 ppm/°C to 1.76 ppm/°C were determined, which represents a 2–3 fold improvement over currently available lanthanide temperature-responsive contrast agents. Tetra(propargyl) DOTAM was further functionalized through Huisgen “click” chemistry reactions with a glucosyl azide. These complexes were characterized by a combination of 1HNMR, single-crystal X-ray crystallography, relaxation and CEST experiments.

Chapter 4 focuses on the evaluation of a highly shifted amide suitable for ParaCEST imaging. The Tm3+ chelate of DOTAM [1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane] possessing sterically demanding t-butyl amide substitution favors TSAP geometry. This geometry shifts the amide signal to -100 ppm, which is beyond the frequency of macromolecule magnetization transfer and thus represents a prototype contrast agent for potential in vivo use.

Chapter 5 discusses a series of Dy3+ and Tm3+ tetra(substituted) DOTAM paraCEST agents incorporating para-substituted anilines. The aniline and p-methoxyaniline agents response to changes in pH near the physiologic range have been evaluated. Two distinct amide signals are observed in the CEST spectrum for Tm3+-p-methoxyaniline complex, corresponding to SAP and TSAP isomers. A crystal structure of this agent indicates TSAP geometry with the absence of an inner sphere water molecule. Due to the lack of coordinated water, this agent produces minimal shortening of T2 relaxation time constants. The benefit of a long T2 relaxation is demonstrated in the higher signal to noise ratio for the agent that does not contain an inner sphere water compared to agents that have bound water.

Chapter 6 discusses a water soluble gold nanoparticle (AuNP) conjugated to over 50 Gd3+ chelators which has been prepared using an interfacial Michael addition. The agent was determined to be non-acutely toxic to mice and T1-weighted in vivo images of mouse kidneys were obtained.

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