The overall goal of this proposal is to develop paramagnetic hepatobiliary contrast agents for magnetic resonance (MR) imaging. These agents will be selectively extracted by normal liver parenchyma leading to decreases in the proton relaxation times T1 and T2 and enhanced MR image contrast. This strategy will improve the ability of MR imaging to detect focal liver cancer and assess hepatocellular funtion.
The specific aims i nclude: synthesis and chemical characterization of novel hepatobiliary agents, and assessment of biodistribution, tissue relaxivity, image inhancement, and toxicity of these agents. The agents will be comprised of paramagnetic iron (III) or gadolinium (III) complexes with multidentate ligands that possess high formation constants for the metal ions as well as appropriate structural features (e.g., phenyl rings and other lipophilic groups) for the selective uptake and biliary excretion by functioning hepatocytes. Chemical properties of the metal chelates related to their use as hepatobiliary agents, such as relaxivity, lipophilicity, protein-binding affinity, and stability, will be assessed. The agents will be evaluated for liver specificity by biodistribution screening studies in both rats and rabbits using radiotracers. In addition, selected agents will be evaluated for dose-dependent liver uptake and their effect on the proton relaxation times, T1 and T2, of tissue. Imaging studies using optimized pulse sequences will be used to assess liver enhancement kinetics and correlated with biodistribution studies. Our work will result in improvements in the design of paramagnetic agents for greater specificity, stability, and tissue relaxation ability. These or other agents resulting from this work will ultimately be used clinically to obtain """"""""functional"""""""" tomograms of diagnostic utility.
