Development of Mn(III) Porphyrins as High Relaxivity MRI Contrast Agents for Blood Pool and Targeted Imaging

Magnetic Resonance Imaging (MRI) provides detailed anatomical information and has become indispensable for a wide range of medical applications. To further broaden our diagnostic capabilities, about 40% of clinical MRI scans are performed with the administration of MRI contrast agents (CAs). There are, however, two major limitations to the current clinical CAs which are mainly small Gd-based chelates. 1) They exhibit low relaxivities at high magnetic fields, requiring high dose in modern clinical MRI scanners and 2) the release and accumulation of Gd ions in vivo is correlated with Nephrogenic Systemic Fibrosis (NSF) in some patients with renal dysfunction. These challenges motivate us to develop a new class of CAs using more biocompatible metal species. Paramagnetic Mn-porphyrin (MnP) was the building block of choice as it is stable and exhibits high relaxivities at high fields. This thesis focuses on the development of MnP MRI CAs for blood pool and targeted imaging purposes. In Chapter 2, a water-soluble MnP dimer, MnP2 was designed as a high-relaxivity T1 agent. Preliminary in vivo study of MnP2 showed prolonged blood circulation, desirable for MR angiography (MRA). In Chapter 3, MnP2 was systematically evaluated as a BPA in vitro and in vivo. Using different spectroscopic methods, MnP2 was found to form a tight and non-covalent interaction with HSA. Via a competitive binding study using ligands with known HSA binding site, results suggest MnP2 to be bound in subdomain IB. In Chapter 4, a second generation dimer, m-MnP2 was developed. m-MnP2 exhibited slightly lower relaxivity than MnP2, likely due to its smaller size. The relaxivity of m-MnP2 did not increase upon binding to HSA and is similar to that of the MnP2â HSA complex. This suggests that both CAs are potential BPAs and that the tumbling rate may be excessively slow. (Chapter 5) Towards the goal of active targeted imaging, a versatile covalent protein tagging MnPNCS was synthesized. Successful tagging of multiple MnPs onto HSA was demonstrated and the resulting MnPâ HSA exhibited excellent blood pool properties. Overall, through rational design, the highly sensitive MnPs have shown promise as the next generation Gd-free MRI CAs.Ph.D.2017-12-30 00:00:0