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Species Differences of Bombesin Analog Interactions with GRP-R Define the Choice of Animal Models in the Development of GRP-R–Targeting Drugs

¹ Institute of Radioisotopes–Radiodiagnostic Products, National Center for Scientific Research Demokritos, Athens, Greece
² Department of Radiology, University Hospital Basel, Basel, Switzerland
³ Department of Biomedica Life Sciences, S.A., Athens, Greece
⁴ Institute of Pathology, University of Bern, Bern, Switzerland

The biologic profiles of [^99mTc]Demobesin 1 ([^99mTc-N₄^0–1,bzlg⁰,D-Phe⁶,Leu-NHEt¹³,des-Met¹⁴]BB(6–14)) and [¹¹¹In]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 [^99mTc]Demobesin 1 and [¹¹¹In]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, [^99mTc]Demobesin 1 and [¹¹¹In]Z-070 displayed similar uptake in the rat tumor. However, in the human PC-3 xenografts, [^99mTc]Demobesin 1 showed a 2- to 3-fold higher uptake than [¹¹¹In]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.

Key Words: human gastrin-releasing peptide receptor • rodent gastrin-releasing peptide receptor • receptor targeting • radiolabeled bombesins

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