The Design, Synthesis and Application of Redox-Responsive MRI Contrast Agents

Abstract

Reactive oxygen species (ROSs), such as hydroxyl radicals, superoxide anions and hydrogen peroxide, are side products of aerobic respiration. Although ROSs regulate several physiological processes, they have been implicated in the pathology of many health conditions. The need to elucidate the specific roles that ROSs play in these disorders has spurred the development of various techniques to detect oxidative stress. Such techniques have the promise to better understand the pathologies and allow the early diagnosis of several diseases. Magnetic resonance imaging (MRI) is particularly attractive due to its good visalization depth which allows it to be used in non-invasive whole body imaging. MRI contrast agents are commonly utilized to shorten the relaxation time of protons and enhance the contrast. In this dissertation, three different categories of manganese-based MRI contrast agents were syntheszied and characterized. Each has a redox-active ligand that can react with hydrogen peroxide. Upon activation, the contrast agents undergo structural changes that can alter either the overall paramagnetism or the hydration number of the manganese ions with concomitant changes to the longtitudinal relaxation time (T1). The ability of [Mn(H4qtp2)Br2] to identify doxorubicin-induced oxidative stress in the ex vivo imaging of rat hearts demonstrates the viability of this strategy as a means to detect the over-production of ROSs before they can damage tissues.