We seek support to develop a new non-invasive, cost effective, accurate, and reproducible measure of effective renal plasma flow (ERPF) to enhance the care of patients with impaired renal function and to facilitate research into the mechanisms and treatment of renal diseases. Our objective is to develop new anionic and cationic Tc-99m renal agents with a clearance higher than that of the discontinued tracer, I-131 ortho-iodohippuran (OIH) and equivalent to the gold standard of ERPF, para-aminohippurate (PAH). The feasibility of our approach is demonstrated by the fact that our NIH-funded program has already led to the identification of two of the best first-generation tubular imaging tracers in humans, one patent, and the development of five promising new agents comparable in rats to Tc99m mercaptoacetyltriglycine (MAG3), the best agent commercially available in the U.S. MAG3 has serious limitations. Its clearance does not measure a standard renal functional parameter and is less than half that of PAH; moreover, MAG3 cannot reliably detect changes in renal function as great as 35 percent. We hypothesize that an optimal tracer will be minimally bound to red cells and plasma proteins and will have key chemical features shown by experience to give a high renal clearance. To test these hypotheses, we will utilize a multifaceted approach. We propose (Aim 1) three classes of agents, including the largely unexplored cationic renal tracers, which offer the potential for breakthrough research and enhanced diagnostic accuracy. Most Tc-99m agents in the three classes will utilize novel ligands, each designed by an innovative approach to yield (via kit preparation) only one robust solution species at physiological pH. For all agents we will determine the biodistribution, rate and specificity of renal excretion in streamlined animal models (Aim 2); the best tracers will be assessed in human studies (Aim 3). Results from Aims 2 and 3 will iteratively direct modifications of agent design in Aim 1. The dosimetry of the best tracers at least equivalent to OIH in humans will be determined (Aim 4). An accurate measure of ERPF will have a significant impact on the diagnosis and management of patients with prerenal azotemia. This condition occurs in 3-5 percent of hospitalized patients and, when sustained, is the most common cause of ischemic tubular necrosis. A superior ERPF tracer will also improve the management of patients with renal insufficiency, especially those with unstable renal function, including conditions such as renal transplantation, diabetes, and drug nephrotoxicity. Finally, our recent success identifying tracers with high clearance has depended on our advances in technetium and rhenium chemistry and in ligand design and synthesis. These advances and additional advances expected from the proposed work are significant because they will also aid others in the development of non-renal Tc-99m diagnostic agents and of p-emitting Re-186 and Re-188 therapeutic agents.
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