The role of megalin in the renal uptake of radiolabeled peptides

Objectives Radiolabeled peptides used for peptide-receptor radionuclide therapy are excreted mainly via the kidneys and are partly reabsorbed and retained in the proximal tubular cells, limiting the maximum activity dose that can be administered. The mechanism of reabsorption and retention is not completely understood, but the scavenger receptor megalin has been shown to play a role in the reabsorption of In-111-octreotide. In this study we aimed to define the role of megalin in the reabsorption of various radiolabeled peptides in vivo, using small animal SPECT and autoradiography of kidney-specific megalin-deficient mice.

Methods Five megalin-deficient mice (A) and 5 wild-type mice (B) were injected with In-111-labeled DTPA-chelated octreotide, octreotate, exendin, neurotensin or minigastrin analogs. SPECT scans of the kidneys were acquired 3 h post injection. Renal radioactivity was quantified and expressed as percentage of the injected dose. After dissection kidney activity was determined quantitatively and visualized with autoradiography.

Results Renal retention of all studied peptides was 40-75% lower in the megalin-deficient mice than in wild-type mice. Autoradiography and SPECT data showed reduced uptake in the renal cortex of the megalin-deficient mice.

Conclusions Renal accumulation of these radiopeptides was significantly lower in the kidney-specific megalin-deficient mice, indicating that megalin plays an important role in the renal reabsorption and retention of these peptides, but to variable extents. Small animal SPECT is a useful tool to study renal uptake in vivo.