CHEMICAL SYNTHESIS AND CHARACTERIZATION OF NOVEL HYPERPOLARIZED MRI CONTRAST AGENTS FOR THE EARLY DETECTION OF CANCER AND OTHER DISEASES

Author

• Ishani Maheshika Senanayake, Southern Illinois University CarbondaleFollow

Date of Award

5-1-2026

Degree Name

Doctor of Philosophy

Department

Chemistry

First Advisor

Goodson, Boyd

Abstract

Nuclear Magnetic Resonance (NMR) spectroscopy is a potent analytical method that uses the magnetic characteristics of certain atomic nuclei to ascertain the surroundings, dynamics, and structure of molecules. It is particularly useful for clarifying the structures of organic compounds and biomolecules in the fields of chemistry and biochemistry. However, as compared to other analytical techniques like mass spectrometry, NMR's low detection sensitivity is one of its main drawbacks. NMR depends on the tiny energy difference between nuclear spin states in a magnetic field; hence it produces a faint signal that necessitates high sample concentrations and lengthy acquisition times, which contributes to its limited sensitivity. Increased magnetic field strengths, cryoprobes, and hyperpolarization methods have all been developed to improve the sensitivity of NMR-based methods and make it possible to identify low-abundance species and use small sample volumes. NMR spectroscopy can be made much more sensitive by using hyperpolarization techniques such as Signal Amplification By Reversible Exchange (SABRE) and Parahydrogen-Induced Polarization (PHIP). The special characteristics of parahydrogen, a spin isomer of molecular hydrogen with paired nuclear spins, are the basis for both techniques. In PHIP, a hydrogenation procedure employing parahydrogen transfers the high polarization straight to a substrate, increasing the intensity of the hydrogenated product's NMR signal. SABRE, on the other hand, uses a metal complex catalyst to temporarily link the parahydrogen and the target molecule, enabling spin polarization to be transferred by reversible exchange, achieving hyperpolarization without requiring chemical modification of the substrate. These methods provide quick and affordable solutions to increase the sensitivity of NMR detection by several orders of magnitude, creating new opportunities in low-concentration metabolite analysis, reaction monitoring, and molecular imaging—to name just a few key applications. Several molecules that can potentially be used as imaging agents for cancer and other diseases are discussed throughout the text. Among them is the 15N labeled variant of metronidazole (MNZ), a potential hypoxia-sensing agent that is structurally similar 18F-FMISO (a PET imaging agent). We were able to successfully map the 15N chemical shift differences of its anticipated downstream metabolic products. We also carried out several in vitro enzymatic assays with the nitro-reductases CYP1A1 and CYP1A2 but with no positive results. Then we switched to cell based (HeLa and HEK239) assays where we found indications of successful conversion of MNZ to its downstream metabolic products. Also discussed is an agent that could potentially be used as a so-called “dual-reporter” agent—one that could potentially provide spectral information about the local environment in both fluorescence imaging and magnetic resonance. This molecule. named (E)-4-(4-(1H-Imidazol-1-yl)styryl)-N,N-diphenylaniline, has already been demonstrated as a fluorescence imaging agent and we were also able to show that the molecule successfully binds to the SABRE catalyst and that it can be hyperpolarized. The next chapter discusses a hyperpolarization setup that is used to prepare hyperpolarized propane gas; the goal of this work is to use HP propane gas as a lung imaging agent in the future. A final topic discussed concerns the synthesis of F3O4@SiO2@α-Fe2O3/TiO2-rGO nanohybrids, which can be used for the photocatalytic transformation of lignocellulose biomass; this work was performed in collaboration with the lab of Prof. Jia Liu. Although this effort does not directly concern the creation of MRI contrast agents, it did serve to expand my repertoire of synthetic methods and analytical/characterization techniques; moreover, related superparamagnetic iron-oxide nanoparticles (SPIONs) are indeed under study as MRI contrast agents—including for combined use with hyperpolarized agents.