Synthesis And Properties Of Dimeric Gadolinium(â…¢) Complexes As Liver Targeting MRI Contrast Agents

Magnetic resonance imaging (MRI) is a new and rapid developing clinical diagnostic modality that relies on the detection of NMR signals of water protons in human body. MRI contrast agents are paramagnetic materials that can increase the proton relaxation rates of water, thus enhance the contrast between the normal and abnormal tissue pathologically. The most challenging aspects in the development of MRI contrast agent are high relaxivity, low toxicity as well as tissue selectivity (or targeting). In order to meet the raising demands of accurate and sensitive diagnosis in the liver diseases threatening the health of mankind widely and seriously, the research of hepatocyte-specific (targeting) contrast agents for MRI is of great significance and very urgency. In this thesis, the progress of water-soluble MRI contrast agents was reviewed, and the emphasis was focused on the design and synthesis of novel paramagnetic complexes with liver selectivity and molecular recognition function. The research results so far indicated that presence of hydrophobic on metal chelates leading to hepato-cellular uptake and excretion into the bile ducts. As a new kind of MRI contrast agent, multimeric paramagnetic metal complexes may have the advantages of both mono-structure and higher relaxivity belong to small and macromlecular agents, respectively. Based on this idea, our focus is on the design and synthesis of dimeric-Gd(â…¢) complexes containing hydrophobic groups, which will be used as model molecules of liver-targeting MRI contrast agents in our future work In this thesis, three new series of potential dimeric ligands were synthesized: (1) Nine amphiphilic dimeric ligands were prepared by the reaction of DTPA(EDTA) monoanhydride with L-lysine long chain alkyl esters and benzyl esters, respectively, their gadolinium(â…¢) complexes were also prepared; (2) Likewise, nine amphiphilic dimeric ligands were obtained by the reaction of DTPA / EDTA monoanhydride with N-substituted butyl, phenyl, benzyl, p-toluenesukfonyl, p-bromophenyl and toluenyl diethanolamine, respectively; (3) Similarly, four amphiphilic dimeric ligands derived from amino acids were prepared by the reaction of DTPA/EDTA monoanhydride with L-N,N-bis- (2-hydroxyethyl) alanine and L-N,N-bis(2-hydroxyethyl) isoleucine. All corresponding gadolinium(â…¢) complexes were also prepared. The chemical structures of these dimeric ligands and gadolinium(â…¢) complexes were characterized by 1H NMR and IR. The longitudinal relaxivity of these complexes were measured. Two of complexes which have higher relaxivities in each series were chosen for the acute toxicity measurement, and one of them(Gd-4b) was chosen for the T1-weighted imaging test. The results indicate that all complexes have higher R1 relativities than Gd-DTPA. The acute toxicity test showed no obvious toxicity. In MRI experiments, this dimeric Gdâ…¢complex exhibits highly enhanced signal intensity (the average intensity up to 24%, 25~40min post injection) and the increasing duration in rat liver tissue compared to Gd-DTPA. This exhibits a good bright/potential foreground for this kind of new contrast agents.