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

Journal of Nuclear Medicine

Jean-Claude Reubi¹  Theodosia Maina¹  Beatrice Waser¹  Hanwen Zhang¹  Helmut R. Maecke¹  Berthold A. Nock¹  Anastasia Nikolopoulou¹ 

关键词: human gastrin-releasing peptide receptor;    rodent gastrin-releasing peptide receptor;    receptor targeting;    radiolabeled bombesins;   

DOI  :  

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

The biologic profiles of [99mTc]Demobesin 1 ([99mTc-N40–1,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.

【 授权许可】

Unknown