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Access Type

WSU Access

Date of Award

January 2023

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Chemistry

First Advisor

Matthew J. Allen

Abstract

The research projects described in this dissertation are focused on fluorous interactions with divalent and trivalent lanthanides. These interactions lay the foundation to overcome concentration dependence of contrast agents for MRI and strategies to synthesize small-molecule thermometers that enable mapping temperatures over a biologically relevant range. Furthermore, dual-mode tumor imaging using probes that are responsive to hypoxia and hypoxia-induced pathological conditions have been described to contextualize the new research described in this dissertation with respect to reported examples. A brief overview of responsive contrast agents for MRI in chapter 1 is followed by chapter 2 that described dual-mode imaging of hypoxia and related pathophysiological conditions using dual-mode imaging modalities. Compared to single-mode imaging techniques, dual-modal imaging enables accurate diagnosis of diseases while overcoming the limitations of single imaging modalities. Chapter 2 also provides detailed descriptions of pre-clinical and clinical examples of different imaging techniques to image hypoxia. These two chapters offer context for the remaining chapters. EuII- and EuIII-containing complexes having 4, 12, and 24 fluorine atoms are described in chapter 3. These complexes were used to quantify hypoxia using a ratiometric method. The ratio between T1 relaxation due to the presence of EuII-containing complex and 19F signal due to the presence of EuIII-containing complex were correlated with the amount of oxygen present in the environment. Out of all three complexes, the complex with 4 fluorine atoms was found to possess the steepest slope of the hypoxia index curve, therefore, it enables more sensitive differentiation between regions with different concentrations of oxygen. However, the complex with 12 fluorine atoms displayed the best combination of signal and solubility of the three complexes. Prior to the research presented in chapter 4, lanthanide-containing contrast agents for MRI have been used to report temperature but there was a lack of small-molecule MRI thermometers that can use without encapsulating in macromolecular hydrogel systems or liposomes to increase contrast enhancement with increasing temperature. A fluorinated GdIII-containing complex is reported in chapter 4 of this dissertation that increases its inner-sphere relaxivity with increasing temperature over a biologically relevant range. The basis of the temperature-dependent relaxivity response of the fluorinated contrast agent is the modulation of water exchange caused by trifluoromethyl groups that forms a cage-like structure around the inner-sphere water molecule. The ability to use fluorinated contrast agents for MRI is important to enhance the sensitivity of the experiment. Furthermore, weak fluorous interactions between fluorine atoms involve in chemical control of parameters relevant to MRI. Therefore, fluorinated lanthanide-based contrast agents not only enhance the quality of MRI experiments but also, they are useful in innovative future biomedical applications. Chapter 5 summarizes the future outlook of the applications of dual-mode hypoxia imaging with responsive probes, potential in vivo applications of fluorinated Eu-based concentration independent probes, and potential modifications to the metal complexes to use fluorinated lanthanide-based contrast agents for MRI thermometry.

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