Synthesis And Relaxivity Of Multi-Nuclear Gadolinium Complexes As New MRI Contrast Agents

Nuclear Magnetic Resonance Imaging (MRI) has become a powerful tool in modern medical diagnostics due to continuing improvements both in the relevant technology and in the development of a new class of pharmaceuticals able to enhance, after administration, the image contrast between normal and diseased tissues. These pharmaceuticals, commonly referred to as contrast agents, are based on metal complexes of paramagnetic ions, which enhance the nuclear magnetic relaxation rates of the bulk water protons in the tissues where they are distributed. Due to the high magnetic moment and the relatively long electronic relaxation time of the metal ion, Gd (III) ion complexes are currently the most used contrast agents in clinical MRI diagnostics. Nowadays, several Gd (III) complexes are available in the market and many others are undergoing clinical trials. In this thesis, a series of MRI contrast agents were designed and synthesized.These contrast agents were characterized by 1H NMR, IR. Their relaxivities, in vitro properties were also evaluated. The main results and conclusions are summarized as fellows:1. The research progress of Bio-responsive MRI contrast agent was reviewed, one of the most exciting areas of MRI contrast agent research at present is the development of responsive or'smart'contrast agents. The relaxivity and the corresponding signal intensity of these agents respond to changes in physiological environment such as pH, metal ion concentration, partial pressure of oxygen, enzyme activity or temperature were discussed.2. A series of multimeric gadolinium(â…¢) contrast agents: di-EDTA, di-DTPA, tri-EDTA, tri-DTPA, tetra-EDTA, and tetra-DTPA, have been synthesized by using terephthalic acid, trimesic acid, pyromellitic dianhydride, ethanolamine, DTPAMA, EDTAMA as starting material. These kinds of contrast agents increase the number of Gd per molecule and introduce more globular structure, slowing rotation and increasing relaxivity. Relaxivity studies showed that these gadolinium complexes possess higher relaxation efectiveness than that of the clinically used Gd-DTPA,and low dosage. 3.Nicotinic acid appended-DTPA/EDTA have been synthesized in order to attain higher relaxivity and to reduce the vivo toxicity. Methyl nicotinate was covalently appended to EDTAA, DTPAA with a ethanolamine linker. Relaxivity studies showed that these gadolinium complexes possess higher relaxation efectiveness than that of the clinically used Gd-DTPA.4.A series of bisamide amino acid EDTA have been synthesized in order to attain higher relaxivity, to reduce the vivo toxicity and to enhance solubility. The thermodynamic stability of hexadentate ligand EDTA Gadolinium (â…¢) is not fit for clinical use. Amino acid has introduced to give more haptos in order to raise its thermodynamic stability.