Metasyn, Inc. is developing a high-efficiency contrast agent for magnetic resonance imaging (MRI) to improve the detection of brain and spine tumors. Current MRI agents are small molecular weight gadolinium(III) chelates which have limited water proton relaxation ability (relaxivity) and thus, in certain circumstances, limited MRI enhancement capability. Multiple doses are often used, at high cost (app. $250), to insure detection of small lesions. Metasyn is planning to compete with these products with an agent with much higher relaxivity and the same cost as a single dose of the conventional agents (app. $85). In addition, it is anticipated that a high-efficiency agent would lead to a longer window of enhancement which is in demand for use in lengthy MRI exams. The overall goal of this proposal is to test the feasibility of certain gadolinium(III) chelates which bind reversibly to human serum albumin (HSA) in blood and tissues. The increase in the rotational tumbling time of the chelate leads to increased relaxivity. A series of chelates will be synthesized and tested for relaxivity, HSA binding ability, and biodistribution in rats (including blood clearance rates). Structure- activity relationships will be determined as a function of the lipophilicity of the chelates. The tumor MRI enhancement capability for the agents with the highest relaxivity and blood concentration will be evaluated in a rat tumor model (mammary adenocarcinoma R3230AC) and compared to conventional agents. Selected agents will undergo further testing in Phase II of this SBIR project, which will include formal pharmacokinetic and toxicological studies, investigational new drug (IND) application submission, and Phase I clinical trials.
