NOVEL CONTRAST AGENTS FOR MAGNETIC RESONANCE IMAGING

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A series of Zyn-Linker molecules bearing chelated gadolinium will be synthesized and tested as novel contrast agents for magnetic resonance imaging (MRI). Structural variations include number and length of alkyl chains Characteristic of Zyn-Linkers. Binding of magnetically active small molecules to human serum albumin (HSA) through interaction of alkyl "tails" with binding sites on HSA should allow tailoring of blood pool half-lives. HSA binding will be measured and molar relaxivity constants determined by MRI. HSA binding should increase molar relaxivity constants compared to chelated gadolinium alone. A higher constant should reduce the amount of material required for diagnostic imaging. Different rates of release of Zyn-Linked Gadolinium chelates from HSA should produce a family of MRI contrast agents with widely varying blood pool half-lives. Current agents are rapidly cleared from the blood pool and require repeat administration and higher doses for prolonged clinical evaluation. Feasibility will be demonstrated if at least one compound can be identified which exhibits >5x increase in relaxivity compared with Gd-DTPA. Phase Il will explore the uses of these compounds for blood pool imaging studies including short term assessment of vascular perfusion and longer term assessment of vascular permeability. PROPOSED COMMERCIAL APPLICATION: The market for MRI studies was $420 million in 1995 and is projected to be $700 million in 1999 (Medical & Healthcare Market-place Guide). Studies on essential hypertensIon, angina pectorIs and other forms of Ischemic heart disease accounted for 60% of the approximately 10 million MRI studies performed In 1995, with conditions Involving altered vascular perfusion and/or vascular permeability (e.g. inflammation, tumor growth, occult bleeding) accounting for the remainder . Approximately 30% of all MRI studies were enhanced with contrast agents. These figures suggest that at least 3 million procedures used MRI contrast agents in 1995. that the numbers are growing.