title: Renal uptake of different radiolabelled peptides is mediated by megalin: SPECT and biodistribution studies in megalin-deficient mice.
abstract: OBJECTIVE
  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 (111)In-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 (111)In-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% ((111)In-octreotide) to 65% ((111)In-exendin) of uptake in wild-type kidneys. Quantitative analysis of renal uptake by SPECT and ex vivo measurements showed a very good correlation.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Nuclear Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. ErikVegt@gmail.com
authors.forename: Erik
authors.initials: E
authors.lastname: Vegt
authors.forename: Marleen
authors.initials: M
authors.lastname: Melis
authors.forename: Annemarie
authors.initials: A
authors.lastname: Eek
authors.forename: Monique
authors.initials: M
authors.lastname: de Visser
authors.forename: Maarten
authors.initials: M
authors.lastname: Brom
authors.forename: Wim J G
authors.initials: WJ
authors.lastname: Oyen
authors.forename: Martin
authors.initials: M
authors.lastname: Gotthardt
authors.forename: Marion
authors.initials: M
authors.lastname: de Jong
authors.forename: Otto C
authors.initials: OC
authors.lastname: Boerman
mesh_terms: D000818:Animals; D005260:Female; D007150:Immunohistochemistry; D007553:Isotope Labeling; D007668:Kidney / Q000000981:diagnostic imaging* / Q000378:metabolism*; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000172:deficiency* / Q000378:metabolism*; D008297:Male; D051379:Mice; D009928:Organ Specificity; D010455:Peptides / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D021381:Protein Transport; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D026561:Low Density Lipoprotein Receptor-Related Protein-2; D010455:Peptides