The objective of this application is to develop a superior Tc-99m renal tubular transport imaging agent that would provide an accurate, reproducible, cost-effective, and rapid measurement of effective renal plasma flow (ERPF). Measurement of ERPF will aid in the diagnosis and management of patients with prerenal azotemia which occurs in 3-5% of hospitalized patients and, when sustained, is the most common cause of ischemic tubular necrosis. Such an agent will also improve the management of patients with renal disease, particularly those whose renal function may be unstable (i.e., renal transplantation, diabetes, nephrotoxic drugs). The first Tc-99m tubular transport imaging agent, [Tc-99] mercaptoacetyltriglycine (MAG3), introduced by our NIH-sponsored research, has serious limitations. Its clearance does not measure a standard renal functional parameter, is less than half that of PAH, and, based on recent data, cannot reliably detect changes in renal function as great as 35%. Our research has elucidated structural properties of the best existing Tc-99m agents, especially in solution, and led to hypotheses characteristics associated with efficient tubular transport and low protein binding needed to design a superior agent. To test hypotheses, the clearance and biodistribution of Tc-99m complexes of new ligands will be determined in rats; glomerular filtration and the effects of protein binding on tubular extraction will be evaluated using micropuncture studies and the isolated perfused rat kidney. Promising complexes will be tested in normal volunteers. The structures of the best Tc-99m complexes will be assessed through non-radioactive rhenium (Re) complexes which have comparable structures. The structures will be graphically superimposed, the points of overlap identified, and new agents designed. Our iterative approach has already led to a novel class of Tc-99m ligands as well as 3 new tubular agents promising in preliminary rat biodistribution studies. In addition to the clinical advantages an ERPF agent should result in competitive pricing and reduced costs for tubular tracers. MAG3 is under-utilized because it is 14 times as expensive as the diagnostically inferior agent, DTPA. At current levels of MAG3 use, a 30% reduction in cost of tubular agents would save 9 million dollars annually. Lower costs should also increase accessibility; a 10% increase in use would provide superior diagnostic studies to an additional 25 million Americans. Finally, our introduction of efficient building-block routes to versatile novel chelates and continued contributions to the understanding of Tc and Re chemistry will facilitate the development of new diagnostic (Tc-99m) and therapeutic (Re-186 and Re-188) radiopharmaceuticals.
Showing the most recent 10 out of 24 publications
