Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Chemistry

Supervisor

Robert H. E. Hudson

Abstract

MRI is a non-invasive technique used in medical imaging. Although contrast agents have been used to enhance the image generated by MRI, it still suffers the major shortcoming of low sensitivity. This has led to a thrust to develop contrast agents that improve sensitivity by relaxivity and CEST. This thesis describes attempts made to aid in the development of sensitive MRI contrast agents.

Chapter 2 investigated pH dependent reversible binding on CEST effect and relaxivity in DO3AM complexes possessing a lone p-nitrophenol arm. Unfortunately, only the Tb3+complex had a small CEST signal. T1 relaxivity of the Gd3+ complex showed high relaxivity at acidic pH and low relaxivity at basic pH.

Chapter 3 discussed rigidification of the DOTAM structure to promote formation of the SAP isomer for CEST signal generation. These ligands were rigidified by at least one cyclohexyl group and were found to be very selective toward transition metals. Regrettably, none of the complexes produced a CEST signal.

Chapter 4 examined electronic effects on the amide CEST signal of DOTAM-tetraanilides containing various para-substituents on the aniline ring. Due to the insolubility of the other complexes, only the p-H and p-OMe complexes were evaluated. The X-ray crystal structure of Tm3+-p-OMe showed no metal bound water. The CEST spectrum of this complex also revealed two amide signals. Absence of water exchange allowed these agents to have higher signal to noise ratios because of reduced relaxation.

Chapter 5 involved a study that assessed electronic effects of para-substituents on the amide CEST signal and relaxivity of DO3A-monoanilide complexes. CEST spectra of only the Tm3+complexes could be acquired, with CEST effects observed at different pH values. T1 relaxivities of all complexes were low but the Dy3+ complexes had much higher T2 relaxivities as compared to the Tm3+-based ones.

Finally, Chapter 6 highlighted the attempt to synthesize analogues of the DOTAM-tetraanilides of the p-H and p-OMe complexes mentioned previously, which would be suitable for in vivo studies. These complexes were to possess a monophosphate group in the para position of one aniline ring. Due to synthetic challenges, the synthesis of these modified complexes is still ongoing.


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