Renal Uptake of 99mTc-Dimercaptosuccinic Acid Is Dependent

99mTc-labeled dimercaptosuccinic acid (99mTc-DMSA) accumu-lates in the kidney cortex and is widely used for imaging of the renal parenchyma. Despite its extensive clinical use, the mech-anism for renal targeting of the tracer is unresolved. Megalin and cubilin are cooperating receptors essential to the proximal tubule endocytic uptake of proteins from the glomerular ultra-filtrate. We have used megalin/cubilin-deficient mice produced by gene knockout to determine whether receptor-mediated en-docytosis is responsible for the renal uptake of 99mTc-DMSA. Methods: Control or megalin/cubilin-deficient mice were injected intravenously with 0.5 MBq of 99mTc-DMSA or 99mTc-mercaptoacetyltriglycine (MAG3). Whole-body scintigrams and the activity in plasma, urine, and the kidneys were examined 6 h after injection. The size and identity of 99mTc-DMSA–bound pro-teins in urine were analyzed by fractionation by centrifugatio