NOVEL SYNTHETIC AND EXPERIMENTAL APPROACHES FOR CREATING 13C- AND 15N- HYPERPOLARIZED MOLECULES VIA SABRE-SHEATH

Author

Thomas Robert Gebhardt, Southern Illinois University CarbondaleFollow

Date of Award

8-1-2024

Degree Name

Master of Science

Department

Chemistry

First Advisor

Goodson, Boyd

Abstract

Nuclear magnetic resonance (NMR) is a powerful tool for collecting information on molecules that cannot be easily observed using other technologies. Although extremely powerful, NMR is not without flaws. First, because NMR relies on magnetism and other quantum properties such as nuclear spin, NMR is only compatible with particular nuclear isotopes—many of which that do not have large natural abundances, contributing to low sensitivity for both NMR and magnetic resonance imaging (MRI). Second, the low sensitivity problem is greatly exacerbated by the ordinarily small differences in the populations of the nuclear spin states—i.e., low nuclear spin polarization (and hence, detectable nuclear magnetization). To help remedy the low sensitivity of NMR and MRI, many methods of exploiting “tricks” from physics have been developed. Dynamic nuclear polarization (DNP), spin exchange optical pumping (SEOP), parahydrogen induced polarization (PHIP), and signal amplification by reversable exchange (SABRE) are all “hyperpolarization” methods that exploit such tricks of physics to reach signal levels in NMR and MRI that would otherwise be impossible for the involved substances and isotopes. This thesis is organized into 3 chapters. The first chapter offers insight into the background concepts of NMR and MRI technology, covering topics such as: spin, chemical shifts, and J-coupling. This chapter also touches more on the low sensitivity of NMR and why it is problematic, as well as introducing the idea of signal enhancement methods like hyperpolarization, including its limitations. Chapter 2 discusses each of the hyperpolarization techniques in detail. This chapter also serves as a brief history of hyperpolarization techniques, as each section is organized roughly in a chronological order, taking the reader through the limitations and breakthroughs of each technology. SABRE and SABRE-SHEATH are some of the last sections of this chapter and most relevant to the works in this thesis, thus serving as a segue into chapter 3. Chapter 3 (the final chapter) comprises a summary of findings within this thesis, with a heavy emphasis on synthetic methods and procedures developed and used to produce selected agents required for the involved SABRE experiments to work. Chapter 3 is a culmination of many years of research, and is organized into 3 subsections each summarizing work with the sub-branches of SABRE agents studied here: so-called cleavable substrates; long-chain hyperpolarization agents; and symmetric di-imidazole substrates. Except where stated otherwise, the agents detailed within were devised with the goal of one day being used within a pre-clinical or clinical MRI setting. As such, the agents selected have biologically relevant counterparts; the underlying physiological reasoning behind their designs are provided in the cleavable substrates section. This final chapter concludes with additional thoughts and suggestions for future researchers looking to continue this work, also including some findings while compiling this discussion that do not fit elsewhere.