Pharmacology (animal models/imaging)

Reduction of kidney uptake of radiolabeled peptides This project aims to elucidate the mechanisms responsible for retention of radiolabeled peptides in the kidney and to develop and optimize new strategies to reduce uptake of radiolabeled peptides in the kidneys. Name and affiliation of the collaborators - Prof.dr. M. de Jong, Erasmus Medical Centre, Rotterdam, The Netherlands - Prof.dr. O.C. Boerman, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands - Dr. Alice Laznickova, Charles University, Heyrovskeho, Hradec Kralove, Czech Republic - Dr. M. Behe, University of Freiburg, Freiburg, Germany Publications: Kidney protection during peptide receptor radionuclide therapy with somatostatin analogues. Rolleman EJ, Melis M, Valkema R, Boerman OC, Krenning EP, de Jong M. Eur J Nucl Med Mol Imaging. 2009 Nov 14. [Epub ahead of print] Albumin-derived peptides efficiently reduce renal uptake of radiolabelled peptides. Vegt E, Eek A, Oyen WJ, de Jong M, Gotthardt M, Boerman OC. Eur J Nucl Med Mol Imaging. 2009 Sep 1. [Epub ahead of print] Dose-response effect of Gelofusine on renal uptake and retention of radiolabelled octreotate in rats with CA20948 tumours. Melis M, Bijster M, de Visser M, Konijnenberg MW, de Swart J, Rolleman EJ, Boerman OC, Krenning EP, de Jong M. Eur J Nucl Med Mol Imaging. 2009 Jul 8. [Epub ahead of print] Radionuclide targeting of CCK2R expressing tumors with gastrin/CCK analogues This project aims to select the optimal gastrin/CCK analogues for targeting MTC and SCLC expressing the CCK2R. Twelve DOTA conjugated analogues have been synthesized at six different laboratories (Basel, Athens, Nijmegen, Naples, London, Innsbruck). Protocols have been designed for labeling, in vitro stability, affinity, internalization, biodistribution and microSPECT imaging studies. In vitro and in vivo studies are carried out in using A431 cells transfected with/without the CCK2 receptor. The IC50 of the 12 peptides has been determined in Berne. The stability of the 12 In-111-labeled peptides was determined in Innsbruck. The in vitro internalisation kinetics were determined in Rotterdam and in Naples. The biodistribution of the 12 In-111-labeled peptides 1 and 4 h p.i. in nude mice with CCK2R-expressing tumors was determined in Nijmegen and microSPECT imaging was carried out in London. Name and affiliation of the collaborators - Prof.dr. M. de Jong, Erasmus Medical Centre, Rotterdam, The Netherlands - Prof.dr. C. Decristoforo. UniversitatsKlinikum Innsbruck, Innsbruck, Austria - Prof.dr. H. Maecke, University Hospital Basel, Switzerland - Prof.dr. S. Mather. Queen Mary, University of London, UK - Dr. Petra Peitl. University Medical Centre Ljubljana, Slovenia - Dr. L. Aloj. Instituto Nazionale Tumori, Naples, Italy - Dr. M. Behe. University Freiburg, Freiburg, Germany - Prof.dr. O.C. Boerman. Radboud University Nijmegen, Nijmegen, The Netherlands - Prof. Jean Claude Reubi, University Berne, Institute of Pathology, Switzerland Publications: Cyclic minigastrin analogues for gastrin receptor scintigraphy with technetium-99m: preclinical evaluation. von Guggenberg E, Sallegger W, Helbok A, Ocak M, King R, Mather SJ, Decristoforo C. J Med Chem. 2009 Aug 13;52(15):4786-93. Targeting of CCK-2 receptor-expressing tumors using a radiolabeled divalent gastrin peptide. Sosabowski JK, Matzow T, Foster JM, Finucane C, Ellison D, Watson SA, Mather SJ. J Nucl Med. 2009 Dec;50(12):2082-9. Cyclic minigastrin analogues for gastrin receptor scintigraphy with technetium-99m: preclinical evaluation. von Guggenberg E, Sallegger W, Helbok A, Ocak M, King R, Mather SJ, Decristoforo C. J Med Chem. 2009 Aug 13;52(15):4786-93. 99mTc-HYNIC-Gastrin Peptides: Assisted Coordination of 99mTc by Amino Acid Side Chains Results in Improved Performance Both In Vitro and In Vivo. King R, Surfraz MB, Finucane C, Biagini SC, Blower PJ, Mather SJ. J Nucl Med. 2009 Apr;50(4):591-8. Molecular imaging with bioconjugates in mouse models of cancer. Mather S. Bioconjug Chem. 2009 Apr;20(4):631-43. Review. Highly efficient in vivo agonist-induced internalization of sst2 receptors in somatostatin target tissues. Waser B, Tamma ML, Cescato R, Maecke HR, Reubi JC. J Nucl Med. 2009 Jun;50(6):936-41. Peptide-based probes for cancer imaging. Reubi JC, Maecke HR. J Nucl Med. 2008 Nov;49(11):1735-8. Epub 2008 Oct 16. Review. Peptide radionuclide targeting of neuroendocrine tumors with somatostatin analogues. This project aims to optimize somatostatin analogues for peptide receptor radionuclide therapy of somatostatin receptor expressing tumors. Name and affiliation of the collaborators: - Prof.dr. M. de Jong, Erasmus Medical Centre, Rotterdam, The Netherlands - Prof.dr. H. Maecke, University Hospital Basel, Switzerland - Dr. Petra Peitl. University Medical Centre Ljubljana, Slovenia Publications: Highly efficient in vivo agonist-induced internalization of sst2 receptors in somatostatin target tissues. Waser B, Tamma ML, Cescato R, Maecke HR, Reubi JC. J Nucl Med. 2009 Jun;50(6):936-41. [(90)Yttrium-DOTA]-TOC response is associated with survival benefit in iodine-refractory thyroid cancer: long-term results of a phase 2 clinical trial. Iten F, Muller B, Schindler C, Rasch H, Rochlitz C, Oertli D, Maecke HR, Muller-Brand J, Walter MA. Cancer. 2009 May 15;115(10):2052-62. Initial direct comparison of 99mTc-TOC and 99mTc-TATE in identifying sites of disease in patients with proven GEP NETs. Cwikla JB, Mikolajczak R, Pawlak D, Buscombe JR, Nasierowska-Guttmejer A, Bator A, Maecke HR, Walecki J. J Nucl Med. 2008 Jul;49(7):1060-5. 1. STST Applicant: Maarten Brom, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands Host: Prof Stephen Mather / Jane Sosabowksi, Cancer Research UK, London, United Kingdom In this STSM the technology of small animal SPECT scanning was transfered. The group in Nijmegen recently has installed their small animal SPECT scanner (USPECT II/CT, Milabs). This scanner will be used to study the in vivo behavior of radiolabeled peptides for functional imaging and peptide radionuclide therapy in mice and rats with tumors. The group in London has ample experience in small animal imaging. Knowledge regarding SPECT/CT imaging, dynamic imaging, gated imaging and kinetic modelling was transferred. In addition, animal preparation and handling was discussed. Finally, SPECT scans were acquired of SCID mice with subcutaneous A431 tumours on the shoulder after injection of 111In-labelled DOTA-conjugated CCK2R binding ligands. This experiment is part of COST BM0607 action on ‘Targeted Radionuclide Therapy’ where eight European laboratories have agreed to screen a series of 10 DOTA-conjugated CCK2R binding ligands for their potential for radionuclide therapy of CCK2R expressing tumors (MTC, SCLC, a.o.). For this screening we performed biodistribution studies of these 10 ligands and the results of these biodistribution studies were discussed and compared with the preliminary SPECT data. The experience with SPECT/CT imaging of peptides learned during these experiments will be used for the implementation of small animal SPECT/CT imaging at the Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.