Coronary heart disease is the number one cause of death in western societies. A rapid and noninvasive method of early detection would be important for the timely institution of therapy. Several noninvasive methods have been applied. NMR imaging is a promising, new noninvasive technique that has several possible advantages over other existing methods, i.e. electrocardiographic and radionuclide. Combined with functionally specific contrast agents, NMR imaging has the potential to enable the early detection of abnormalities in myocardial perfusion and of damaged myocardium. These agents affect the contrast of water proton T1, or T2, differently in different tissues, between normal and diseased states, and between intracellular, interstitial and vascular compartments thus effecting functional enhancement of contrast in images obtained by NMR. The central aim of this proposal is to develop clinically applicable paramagnetic contrast agents for NMR imaging of damaged myocardium and of regional myocardial perfusion. The research will be focused around the development of two agents, one that would be preferentially retained in the myocardium in proportion to perfusion, and another that would highlight infarcted heart tissue. In our search for these two agents a systematic approach will be followed based on the anticipated chemical, transport and magnetic properties of certain complexes of paramagnetic metals, in particular of gadolinium. Guided by the optimization of these properties, synthesis of new ligands for gadolinium will be carried out within several, carefully selected families of organic compounds. These will include nonhydrolyzable derivatives of polyphosphates and lipophilic fatty acid and phospholipid derivatives. The magnetic and transport properties of the most promising agents will be tested in vitro and in animal heart tissue. To ensure lack of clinical hazard, detailed toxicology studies will also be performed. Ultimately, the most promising agents will be evaluated using NMR imaging in dog models.
