In most types of peptide receptor radionuclide therapy, the maximum activity dose that can be administered is limited by high and persistent renal retention of the radiolabeled peptides, which is, at least partly, mediated by the megalin receptor. Several agents that interfere with renal reabsorption of radiolabeled peptides have been identified (e.g., lysine, arginine, succinylated gelatin solution), but none of these inhibit renal reabsorption completely. Albumin, a naturally abundant megalin ligand, might be a safe and potent alternative. In this study, we analyzed the effects of albumin and fragments of albumin (FRALB) on the renal reabsorption of 111In- diethylenetriaminepentaacetic acid (DTPA)-D-Phe1-octreotide ( 111In-octreotide), [Lys40(aminohexoic acid-DTPA- 111In)NH2]-exendin-4 (111In-exendin), and 111In-1,4,7,10-tetraazacyclododecane-N,N′,N″, N‴-tetraacetic acid (DOTA)-Glu1-minigastrin ( 111In-minigastrin). Methods: The effects of albumin and FRALB on megalin-associated binding of 111In-octreotide, 111In- exendin, and 111In-minigastrin were assessed in vitro using rat yolk sac epithelial (BN16) cells. In vivo, uptake and localization of 111In-albumin and 111In-FRALB in the kidneys of Wistar rats were determined, as well as the effect of lysine, succinylated gelatin solution, albumin, and FRALB on the kidney uptake of 111In- octreotide, 111In-exendin, and 111In-minigastrin. Results: FRALB significantly reduced binding and uptake of 111In-octreotide, 111In-exendin, and 111In-minigastrin by BN16 cells. In rats, renal uptake of 111In-labeled FRALB was significantly higher than that of 111In-labeled intact albumin (P < 0.001). FRALB administration effectively reduced renal uptake of 111In-octreotide, 111In-exendin, and 111In-minigastrin. Administration of 1-2 mg of FRALB reduced renal uptake of 111In-octreotide as efficiently as 80 mg of lysine. Conclusion: Renal uptake of 111In- octreotide and other radiolabeled peptides in rats can be effectively reduced by administration of albumin fragments. Additional studies to identify the albumin fragments responsible for inhibition of renal peptide uptake are warranted.

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Keywords 1,4,7,10 tetraazacyclododecane 1,4,7,10 tetraacetic acid, Albumin, Animals, Exendin, Isotope Labeling, Kidney, LDL-Receptor Related Protein 2, Male, Metabolic Clearance Rate, Minigastrin, Octreotide, Peptide Fragments, Peptides, Radiopharmaceuticals, Rats, Renal reabsorption, Serum Albumin, Tissue Distribution, Wistar, albumin, animal cell, animal experiment, animal tissue, article, controlled study, dose response, drug absorption, drug binding, drug distribution, drug uptake, exendin 4, gelatin, gelatin succinate, indium 111, isotope labeling, kidney, kidney tubule absorption, lysine, male, megalin, nonhuman, octreotide, pentetic acid, priority journal, rat, yolk sac
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Vegt, E., van Eerd, J.E.M., Eek, A., Oyen, W.J., Wetzels, J.F.M., de Jong, M., … Boerman, O.C.. (2008). Reducing renal uptake of radiolabeled peptides using albumin fragments. The Journal of Nuclear Medicine, 49(9), 1506–1511. doi:10.2967/jnumed.108.053249