PURPOSE: Different attempts have been made to develop a suitable radioligand for targeting CCK-2 receptors in vivo, for staging of medullary thyroid carcinoma (MTC) and other receptor-expressing tumours. After initial successful clinical studies with [DTPA(0),D: Glu(1)]minigastrin (DTPA-MG0) radiolabelled with (111)In and (90)Y, our group developed a (99m)Tc-labelled radioligand, based on HYNIC-MG0. A major drawback observed with these derivatives is their high uptake by the kidneys. In this study we describe the preclinical evaluation of the optimised shortened peptide analogue, [HYNIC(0),D: Glu(1),desGlu(2-6)]minigastrin (HYNIC-MG11). METHODS: (99m)Tc labelling of HYNIC-MG11 was performed using tricine and EDDA as coligands. Stability experiments were carried out by reversed phase HPLC analysis in PBS, PBS/cysteine and plasma as well as rat liver and kidney homogenates. Receptor binding and cell uptake experiments were performed using AR4-2J rat pancreatic tumour cells. Animal biodistribution was studied in AR4-2J tumour-bearing nude mice. RESULTS: Radiolabelling was performed at high specific activities and radiochemical purity was >90%. (99m)Tc-EDDA-HYNIC-MG11 showed high affinity for the CCK-2 receptor and cell internalisation comparable to that of (99m)Tc-EDDA-HYNIC-MG0. Despite high stability in solution, a low metabolic stability in rat tissue homogenates was found. In a nude mouse tumour model, very low unspecific retention in most organs, rapid renal excretion with reduced renal retention and high tumour uptake were observed. CONCLUSION: (99m)Tc-EDDA-HYNIC-MG11 shows advantages over (99m)Tc-EDDA-HYNIC-MG0 in terms of lower kidney retention with unchanged uptake in tumours and CCK-2 receptor-positive tissue. However, the lower metabolic stability and impurities formed in the labelling process still leave room for further improvement.
PURPOSE: Different attempts have been made to develop a suitable radioligand for targeting CCK-2 receptors in vivo, for staging of medullary thyroid carcinoma (MTC) and other receptor-expressing tumours. After initial successful clinical studies with [DTPA(0),D: Glu(1)]minigastrin (DTPA-MG0) radiolabelled with (111)In and (90)Y, our group developed a (99m)Tc-labelled radioligand, based on HYNIC-MG0. A major drawback observed with these derivatives is their high uptake by the kidneys. In this study we describe the preclinical evaluation of the optimised shortened peptide analogue, [HYNIC(0),D: Glu(1),desGlu(2-6)]minigastrin (HYNIC-MG11). METHODS: (99m)Tc labelling of HYNIC-MG11 was performed using tricine and EDDA as coligands. Stability experiments were carried out by reversed phase HPLC analysis in PBS, PBS/cysteine and plasma as well as rat liver and kidney homogenates. Receptor binding and cell uptake experiments were performed using AR4-2J rat pancreatic tumour cells. Animal biodistribution was studied in AR4-2J tumour-bearing nude mice. RESULTS: Radiolabelling was performed at high specific activities and radiochemical purity was >90%. (99m)Tc-EDDA-HYNIC-MG11 showed high affinity for the CCK-2 receptor and cell internalisation comparable to that of (99m)Tc-EDDA-HYNIC-MG0. Despite high stability in solution, a low metabolic stability in rat tissue homogenates was found. In a nude mouse tumour model, very low unspecific retention in most organs, rapid renal excretion with reduced renal retention and high tumour uptake were observed. CONCLUSION: (99m)Tc-EDDA-HYNIC-MG11 shows advantages over (99m)Tc-EDDA-HYNIC-MG0 in terms of lower kidney retention with unchanged uptake in tumours and CCK-2 receptor-positive tissue. However, the lower metabolic stability and impurities formed in the labelling process still leave room for further improvement.
Authors: M de Jong; W H Bakker; B F Bernard; R Valkema; D J Kwekkeboom; J C Reubi; A Srinivasan; M Schmidt; E P Krenning Journal: J Nucl Med Date: 1999-12 Impact factor: 10.057
Authors: Peter Laverman; Martin Béhé; Wim J G Oyen; Peter H G M Willems; Frans H M Corstens; Thomas M Behr; Otto C Boerman Journal: Bioconjug Chem Date: 2004 May-Jun Impact factor: 4.774
Authors: Martin Béhé; Wolfgang Becker; Martin Gotthardt; Christa Angerstein; Thomas M Behr Journal: Eur J Nucl Med Mol Imaging Date: 2003-05-24 Impact factor: 9.236
Authors: L Aloj; M R Panico; C Caracó; A Zannetti; S Del Vecchio; C Di Nuzzo; C Arra; G Morelli; D Tesauro; S De Luca; C Pedone; M Salvatore Journal: Biopolymers Date: 2002 Impact factor: 2.505
Authors: Elisabeth von Guggenberg; Christine Rangger; Jane Sosabowski; Peter Laverman; Jean-Claude Reubi; Irene Johanna Virgolini; Clemens Decristoforo Journal: Mol Imaging Biol Date: 2012-06 Impact factor: 3.488
Authors: Luigi Aloj; Michela Aurilio; Valentina Rinaldi; Laura D'ambrosio; Diego Tesauro; Petra Kolenc Peitl; Theodosia Maina; Rosalba Mansi; Elisabeth von Guggenberg; Lieke Joosten; Jane K Sosabowski; Wouter A P Breeman; Erik De Blois; Stuart Koelewijn; Marleen Melis; Beatrice Waser; Karin Beetschen; Jean Claude Reubi; Marion de Jong Journal: Eur J Nucl Med Mol Imaging Date: 2011-04-20 Impact factor: 9.236
Authors: Maximilian Klingler; Christine Rangger; Dominik Summer; Piriya Kaeopookum; Clemens Decristoforo; Elisabeth von Guggenberg Journal: Pharmaceuticals (Basel) Date: 2019-01-15
Authors: Joachim Pfister; Dominik Summer; Christine Rangger; Milos Petrik; Elisabeth von Guggenberg; Paolo Minazzi; Giovanni B Giovenzana; Luigi Aloj; Clemens Decristoforo Journal: EJNMMI Res Date: 2015-12-15 Impact factor: 3.138
Authors: Theodosia Maina; Mark W Konijnenberg; Petra KolencPeitl; Piotr Garnuszek; Berthold A Nock; Aikaterini Kaloudi; Marko Kroselj; Katja Zaletel; Helmut Maecke; Rosalba Mansi; Paola Erba; Elisabeth von Guggenberg; Alicja Hubalewska-Dydejczyk; Renata Mikolajczak; Clemens Decristoforo Journal: Eur J Pharm Sci Date: 2016-05-14 Impact factor: 4.384
Authors: Maximilian Klingler; Clemens Decristoforo; Christine Rangger; Dominik Summer; Julie Foster; Jane K Sosabowski; Elisabeth von Guggenberg Journal: Theranostics Date: 2018-04-16 Impact factor: 11.556