Research Project
6791664
DESCRIPTION (provided by applicant): There remains a clinical need for myocardial perfusion tracers that more accurately reflect cardiac blood flow over a wide range of flow rates while simultaneously demonstrating a reduced accumulation and/or rapid clearance from the tissues adjacent to the heart. Despite the excellent myocardial extraction and flow kinetics of thallium-201 for evaluating myocardial perfusion and ischemia, the energy spectrum of thallium- 201 makes it particularly prone to soft tissue attenuation artifacts. While there are two FDA-approved Tc-99m perfusion tracers, having more favorable energy spectra for imaging, Myoview(TM) (tetrofosmin) and Cardiolite(TM)(sestamibi), the first pass extraction fraction for both of these tracers is approximately 50% of TI-201, and they exhibit unfavorable abdominal artifacts. At very low flow rates sestamibi and tetrofosmin overestimate flow and at high flow rates (above 2 ml/min/g) underestimate myocardial blood flow. Because extraction of these Tc-99m tracers reaches a plateau at high flow rates, there is a concern that these tracers may not have adequate sensitivity to detect intermediate coronary artery disease during pharmacological stress, when blood flow is increased several times over baseline. Our plan is to exploit our versatile tridentate chelates by synthesizing a series of novel tridentate etherfunctionalized chelates (TECs) and synthesize the corresponding rhenium-TEC complexes, [Re(CO)3(L)3]+, for structural identification. The carrier-free Tc-99m TEC complexes will be prepared using [99mTc(CO)3(H2O)3]+ followed by determination of the in vivo distribution and pharmacokinetic properties of the 99mTc-TECs in rats. Comparisons with TI-201, 99mTc-sestamibi and 99mTc-Tetrofosmin will be performed as a benchmark for initial heart accumulation. Finally, in vitro partition studies of lead compounds with human blood components will be analyzed. This evaluation in normal resting animals will allow for the evaluation of the Tc-99m complexes as potential myocardial perfusion tracers. Successful completion of this project will enable a more rapid and accurate assessment of myocardial perfusion. Since heart disease is the major cause of death in the United States, accounting for nearly 40% of all deaths, as estimated by the American Heart Association, a more accurate agent to assess myocardial perfusion would warrant further development. The current market utilization is approximately 6 million procedures annually in the USA alone.
