A first generation renal tubular agent, Tc-99m mercaptoacetyltriglycine (MAG3), developed during the first 3 years of this NIH-sponsored research is in Phase III clinical testing. An excellent kit formulation developed by Mallinckrodt yields 97% MAG3. The improved imaging characteristics of MAG3 make it a viable imaging agent for replacing I-131 hippurate (OIH) but the plasma clearance of the kit formulation is still only 49% that of OIH. To obtain an optimal agent with a clearance equal to effective renal plasma flow (ERPF), i.e. almost twice that of the essentially pure MAG3, new ligands have been designed based on the successful MAG3 core structure. Ligand design will be enhanced by molecular graphics modeling of selected agents to determine the structural components responsible for both optimal and suboptimal tubular transport. New ligands will be complexed with Tc- 99m and compared to OIH in mice and rats. Toxicity testing of highly promising agents will be performed and the pharmacokinetics and radiation dosimetry determined in human subjects. The higher clearance of second generation Tc-99m tubular agents will further improve image quality, target to background ratio, greatly increase the accuracy and reliability of quantitative measurements, and may provide a direct measurement of renal plasma flow. Furthermore, improved complexes will facilitate development of a new test to evaluate ureteral function. The radiation dose to patients with impaired renal function will be further reduced an dan improved agent will minimize the need for dual isotope (OIH and DTPA or OIH and MAG3) renal studies thereby reducing medical costs. The diagnostic potential of MAG3 will be compared with OIH and iothalamate in clinically relevant rodent models of renal injury. A major focus of the rodent research will be the sensitivity, specificity, and limitations of captopril challenge renography including coadministration of captopril with other medications known to affect GFR and renal blood flow such as aspirin, calcium channel blockers, beta blockers and atrial naturetic factor. The animal studies will help direct the clinical applications of Tc-99m MAG3 when it becomes commercially available and clarify the role of MAG3, OIH and GFR renography in screening for renovascular hypertension.