Species differences of bombesin analog interactions with GRP-R define the choice of animal models in the development of GRP-R-targeting drugs

Abstract

The biologic profiles of [(99m)Tc]Demobesin 1 ([(99m)Tc-N(4)(0-1),bzlg(0),d-Phe(6),Leu-NHEt(13),des-Met(14)]BB(6-14)) and [(111)In]Z-070 were compared using various gastrin-releasing peptide receptor GRP-R)-expressing tissues of human and animal origin.

Methods: The binding affinities of Demobesin 1, Z-070, and its metallated analogs were determined by receptor autoradiography on human cancer biopsy and mouse pancreas samples and by binding assays in rat AR4-2J and human PC-3 cell membranes. Biodistribution of [(99m)Tc]Demobesin 1 and [(111)In]Z-070 was compared in nude mice bearing AR4-2J and PC-3 xenografts.

Results: Demobesin 1, Z-070, and metallated Z-070 showed high affinity for the rat GRP-R in AR4-2J cell membranes (50% inhibitory concentration values = 0.17-0.45 nmol/L). In human PC-3 cell membranes, Demobesin 1 showed 11- to 15-fold higher affinity than the Z-070 peptides. These data were corroborated by results from human cancers and mouse pancreas. In AR4-2J and PC-3 tumor-bearing mice, [(99m)Tc]Demobesin 1 and [(111)In]Z-070 displayed similar uptake in the rat tumor. However, in the human PC-3 xenografts, [(99m)Tc]Demobesin 1 showed a 2- to 3-fold higher uptake than [(111)In]Z-070.

Conclusion: Considerable differences between rat or mouse and human GRP-R-expressing tissues were found for the in vitro and in vivo characteristics of 2 radiolabeled bombesin analogs. This finding may have a significant impact in the selection of experimental tools in the development of bombesin analogs for GRP-R-targeting applications in humans.