Hepatobiliary MRI Contrast Media

Metasyn, Inc. is developing targeted relaxation agents for magnetic resonance imaging (MRI) ofthe liver. These agents will be used to enhance the detection of cancer which has spread to the liverfrom distant sites. The agents are in the form of gadolinium(III)-containing complexes that are taken upby hepatocytes and bind to cytosolic proteins. The binding to proteins increases the relaxation abilityof the agents, yielding high MRI enhancement at low doses. The overall goals of the project are todemonstrate the feasibility of certain gadolinium(III) diethylenetriaminepentaacetate [Gc(DTPA)2-]derivatives with one or more aryl ring substituents and determine structure-activity relationships (SAR)to aid in compound selection. There are several specific aims of this research: 1. to determine theimportance of overall lipophilicity and the number and orientation of aryl groups attached to the chelatesin governing hepatocellular uptake (in isolated rat hepatocytes) and relativity; 2. to analyze the SAR forepatocellular uptake and relativity and select a basic framework for the agent; 3. to confirm theperformance of selected agents in in vivo biodistribution and MRI studies in rats; 4. to synthesize andtest additional derivatives of the selected framework; 5. to select two to four optimal prototypecompounds for further development. In Phase II, we will evaluate the compounds in dose dependence,uptake inhibition, and formal pharmacology/toxicology studies as well as Phase I clinical trials.