Transition metal ion paraCEST contrast agents for MRI
Dorazio, Sarina J.
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The design of contrast agents to enhance magnetic resonance images for early detection, diagnosis, and prognosis of disease is an important area of research. The field of paramagnetic chemical exchange saturation transfer (paraCEST) is an emerging area which exploits the differences in chemical exchange which occur when the local environment is altered due to changes in pH or temperature when disease is present. The goal of this research is to design transition metal ion azamacrocycle complexes to be used as paraCEST contrast agents for magnetic resonance imaging (MRI). In this thesis, the reader is first introduced to concepts and considerations involved in paraCEST and the use of transition metal ions as the paramagnetic species for this purpose in Chapter One. Chapter Two provides data addressing initial concerns of utilizing FeII as a paramagnetic metal ion for paraCEST MRI contrast agents. The ligands and resulting complexes [Fe(TCMT)] 2+[Fe(TCMC)] 2+and [Fe(STHP)] 2+ were synthesized for this project. Characterization of the Fe II complexes through magnetic moment, cyclic voltammetry, thermodynamic stability constants, kinetic inertness, and ascorbate consumption were determined. The pH-dependence of the CEST effect and exchange properties were explored for the Fe II complexes of amide- and alcohol- appended azamacrocycles. Fe II complexes from Chapter Two were further studied in relation to temperature-dependence of NMR properties with both paraCEST spectroscopy and paramagnetic chemical shift spectroscopy (paraCSS) as the application focus of Chapter Three. Narrow 1 H NMR signals of paramagnetically shifted exchangeable amide protons make [Fe(TCMT)] 2+ and [Fe(TCMC)] 2+ amenable to paraCEST thermometry, while the narrow methylene resonances of [Fe(STHP)] 2+ were monitored via paraCSS thermometry. Chapter Four provides examples of some Co II azamacrocycle complexes containing amide pendent groups for paraCEST. [Co(TCMT)] 2+[Co(TCMC)] 2+and [Co(CCRM)] 2+were studied under similar experimental conditions to those of the first Fe II and Ni II complexes for paraCEST. Additionally, ratiometric pH-dependent behavior is observed for [Co(CCRM)] 2+providing a concentration-independent method to analyze the contrast obtained. This thesis provides an overview of some of the first examples of transition metal ion-based paraCEST contrast agents, namely Fe II and Co II azamacrocyclic complexes. I hope these initial studies will help future researchers and provide a foundation to build upon toward the development of contrast agents which are more sensitive and safe for early detection of diseases such as cancer. Improving detection of disease so that the appropriate treatment begins at an early stage is one of the most important strategies in successful return of health.