Development of Tc-99m Renal Tubular Agents

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DESCRIPTION (provided by applicant): Eight million U.S. adults have kidney disease. We seek to enhance the care of patients with kidney disease and to facilitate research into the mechanisms and treatment of both kidney and related diseases by designing novel anionic and cationic 99m/Tc tracers to develop a new probe for the non-invasive, cost effective, accurate, and reproducible measure of effective renal plasma flow (ERPF). Specifically, our goal is to develop a 99m/Tc tracer with a higher renal clearance than the discontinued 131/I-ortho-iodohippuran (OIH) and equivalent to the ERPF gold standard, paraaminohippurate (PAH). The feasibility of our approach is demonstrated by the fact that our NIH program has already led to the identification of three of the best first-generation tubular imaging tracers in humans (MAG3, DD-EC, syn-DMAEC), one patent, and recently two promising new agents based on animal studies. 99m/Tc-mercaptoacetyltriglycine (MAG3), the best commercial agent, has serious limitations. The MAG3 clearance is less than half that of PAH, does Lotmeasure a standard renal functional parameter and cannot reliably reveal changes in renal function as great as 35%. We hypothesize that an optimal tracer will have minimal red cell and plasma protein binding and will have key chemical features shown by experience to give high renal clearances. We will utilize a multifaceted approach to test these hypotheses. We propose to (Aim 1) prepare novel tracers amenable to kit formulation by exploiting our extensive background in ligand design [These tracers will contain the traditional {Tc(V)O} 3+ core as well as the {Tc(CO)3} + and {Tc(V)N} 2+cores, not yet widely explored in renal agents, and some novel ligands incorporating, among other features, :he lanthionine backbone and serine.]; (Aim 2) determine each agent's biodistribution and rate and specificity of renal _xcretion in streamlined animal models; (Aim 3) assess the best tracers in humans [Results from Aims 2 and 3 will iteratively direct modifications of agent design in Aim 1.]; and (Aim 4) prepare the best agent for clinical trials. A superior ERPF tracer will (1) aid the evaluation of azotemic patients, especially those with suspected obstruction, (2) Provide a simple, accurate test to monitor changes in renal function, (3) impact the diagnosis and management ot patients with prerenal azotemia, (4) facilitate research in the pathophysiology of major diseases such as hypertension md diabetes, and finally (5) our recent success in identifying tracers with high clearance has drawn on our advances in Fc and Re chemistry and in ligand design and synthesis; these and additional advances expected from the proposed work will aid others in developing non-renal 99m/Tc diagnostic agents and beta-emitting l86Re and 188Re therapeutic agents, especially since the latter are often plagued by the high kidney retention our agents are specifically designed to avoid.