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Eur J Nucl Med Mol Imaging (2011) 38:623632 DOI 10.1007/s00259-010-1685-9
ORIGINAL ARTICLE
Renal uptake of different radiolabelled peptides is mediated by megalin: SPECT and biodistribution studiesin megalin-deficient mice
Erik Vegt & Marleen Melis & Annemarie Eek &
Monique de Visser & Maarten Brom & Wim J. G. Oyen &
Martin Gotthardt & Marion de Jong & Otto C. Boerman
Received: 5 August 2010 /Accepted: 15 November 2010 /Published online: 18 December 2010 # The Author(s) 2010. This article is published with open access at Springerlink.com
AbstractPurpose Radiolabelled peptides used for peptide receptor radionuclide therapy are excreted mainly via the kidneys and are partly reabsorbed and retained in the proximal tubular cells. The resulting high renal radiation dose can cause nephrotoxicity, limiting the maximum activity dose and the effectiveness of peptide receptor radionuclide therapy. The mechanisms of kidney reabsorption of these peptides are incompletely understood, but the scavenger receptor megalin has been shown to play a role in the reabsorption of 111In-octreotide. In this study, the role of megalin in the renal reabsorption of various relevant radiolabelled peptides was investigated.
Methods Groups of kidney-specific megalin-deficient mice and wild-type mice were injected with 111In-labelled somatostatin, exendin, neurotensin or minigastrin analogues. Single photon emission computed tomographic (SPECT) images of the kidneys were acquired and analysed
quantitatively, or the animals were killed 3 h after injection and the activity concentration in the kidneys was measured. Results Megalin-deficient mice showed significantly lower uptake of all studied radiolabelled peptides in the kidneys, ranging from 22% (111In-octreotide) to 65% (111In-exendin) of uptake in wild-type kidneys. Quantitative analysis of renal uptake by SPECT and ex vivo measurements showed a very good correlation.
Conclusion Megalin is involved in the renal reabsorption of radiolabelled octreotide, octreotate, exendin, neurotensin and minigastrin. This knowledge may help in the design of strategies to reduce this reabsorption and the resulting nephrotoxicity in peptide receptor radionuclide therapy, enabling more effective therapy. Small-animal SPECT is an accurate tool, allowing in vivo quantification of renal uptake and serial measurements in individual mice.
Keywords Kidney. Megalin . Peptide receptor radionuclide therapy. Octreotide . Octreotate . Exendin . Neurotensin . Minigastrin
Introduction
In peptide receptor radionuclide therapy (PRRT), radio-labelled peptide analogues are used to target tumours expressing particular receptors, such as the somatostatin receptor....