UNLABELLED: Gastrin/cholecystokinin subtype 2 receptors (CCK-2Rs) are overexpressed in several tumor types and are, thus, a potential target for peptide receptor radionuclide therapy (PRRT) of cancer. To improve the in vivo performance of CCK-2R binding peptides, we have previously synthesized and screened a series of divalent gastrin peptides for improved biochemical and biologic characteristics. In this study, we explore in more detail the most promising of these compounds and compare its performance with a previously described monomeric peptide. METHODS: From six (111)In-labeled 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-conjugated divalent gastrin peptides based on the C-terminal sequence of minigastrin, the maleimide-linked compound DOTA-GSC(succinimidopropionyl-EAYGWNleDF-NH(2))-EAYGWNleDF-NH(2) (MGD5) was selected. The in vitro stability, receptor binding, and internalization of (111)In-MGD5 were studied and compared with those of monomer compound (111)In-APH070. In vivo biodistribution and imaging using a SPECT/CT camera were also performed. RESULTS: More than 90% of the labeled divalent peptide remained intact after 20 h of incubation in plasma. The inhibitory concentration of 50% of the divalent peptide was 1.0 versus 5.6 nM for the monomer, and the dissociation constant was 0.7 versus 2.9 nM. The rate of internalization of the divalent peptide was twice that of the monomer. Tumor uptake of the divalent peptide in vivo was about 6 times that of the monomer. The rate of washout of the divalent peptide from the tumor was lower than that of the monomer. CONCLUSION: Dimerization of the CCK-2R binding site results in an increase in binding affinity and an increase in tumor uptake both in vitro and in vivo. It is likely that these increases would result in improved tumor-targeting efficiency in patients with CCK-2R-positive tumors.
UNLABELLED: Gastrin/cholecystokinin subtype 2 receptors (CCK-2Rs) are overexpressed in several tumor types and are, thus, a potential target for peptide receptor radionuclide therapy (PRRT) of cancer. To improve the in vivo performance of CCK-2R binding peptides, we have previously synthesized and screened a series of divalent gastrin peptides for improved biochemical and biologic characteristics. In this study, we explore in more detail the most promising of these compounds and compare its performance with a previously described monomeric peptide. METHODS: From six (111)In-labeled 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-conjugated divalent gastrin peptides based on the C-terminal sequence of minigastrin, the maleimide-linked compound DOTA-GSC(succinimidopropionyl-EAYGWNleDF-NH(2))-EAYGWNleDF-NH(2) (MGD5) was selected. The in vitro stability, receptor binding, and internalization of (111)In-MGD5 were studied and compared with those of monomer compound (111)In-APH070. In vivo biodistribution and imaging using a SPECT/CT camera were also performed. RESULTS: More than 90% of the labeled divalent peptide remained intact after 20 h of incubation in plasma. The inhibitory concentration of 50% of the divalent peptide was 1.0 versus 5.6 nM for the monomer, and the dissociation constant was 0.7 versus 2.9 nM. The rate of internalization of the divalent peptide was twice that of the monomer. Tumor uptake of the divalent peptide in vivo was about 6 times that of the monomer. The rate of washout of the divalent peptide from the tumor was lower than that of the monomer. CONCLUSION: Dimerization of the CCK-2R binding site results in an increase in binding affinity and an increase in tumor uptake both in vitro and in vivo. It is likely that these increases would result in improved tumor-targeting efficiency in patients with CCK-2R-positive tumors.
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: N G R Dayan Elshan; Thanuja Jayasundera; Craig S Weber; Ronald M Lynch; Eugene A Mash Journal: Bioorg Med Chem Date: 2015-02-26 Impact factor: 3.641
Authors: Peter Laverman; Lieke Joosten; Annemarie Eek; Susan Roosenburg; Petra Kolenc Peitl; Theodosia Maina; Helmut Mäcke; Luigi Aloj; Elisabeth von Guggenberg; Jane K Sosabowski; Marion de Jong; Jean-Claude Reubi; Wim J G Oyen; Otto C Boerman Journal: Eur J Nucl Med Mol Imaging Date: 2011-04-02 Impact factor: 9.236
Authors: Peter A Knetsch; Chuangyan Zhai; Christine Rangger; Michael Blatzer; Hubertus Haas; Piriya Kaeopookum; Roland Haubner; Clemens Decristoforo Journal: Nucl Med Biol Date: 2014-10-13 Impact factor: 2.408