A 99mTc(I)-postlabeled high affinity bombesin analogue as a potential tumor imaging agent.

Abstract

The overexpression of neuropeptide receptors observed in many cancers provides an attractive target for tumor imaging and therapy. Bombesin is a peptide exhibiting a high affinity for the gastrin releasing peptide (GRP) receptor, which is overexpressed by a variety of tumors such as breast or prostate cancer. In the present study, we have evaluated if the bombesin analogue [N(alpha)-histidinyl acetate]bombesin(7-14), radiolabeled with the novel [99mTc(OH(2))(3)(CO)(3)]+, has the potential to be used as a diagnostic radiopharmaceutical. Receptor saturation studies, carried out on the GRP receptor-expressing PC-3 human prostate cancer cell line, revealed for [99mTc(CO)(3)-N(alpha)-histidinyl acetate]bombesin(7-14) K(d) values in the subnanomolar range. Competitive binding assays, using the cold rhenium(I)-labeled analogue as a surrogate for the 99mTc-conjugate, also showed high affinity binding. Incubation of the radioconjugate with PC-3 cells resulted in a rapid temperature- and time-dependent specific internalization. At 37 degrees C more than 70% was internalized within the first 15 min and remained constant up to 2 h. Despite the weak proteolytic stability of [99mTc(CO)(3)-N(alpha)-histidinyl acetate]bombesin(7-14) in vitro, biodistribution studies, performed in PC-3 tumor-bearing mice, showed low uptake in the tumor (0.89 +/- 0.27% ID/g 30 min pi) but high uptake into the pancreas (7.11 +/- 3.93% ID/g 30 min pi), a GRP receptor-positive organ. Blockade experiment (coinjection of 300 microg bombesin/mouse with the radioligand) showed specificity of the uptake. Despite the low tumor uptake, tumor-to-blood ratios of 2.0 and 2.7 and tumor-to-muscle ratios of 8.9 and 8.0 were obtained at 30 min and 1.5 h postinjection, respectively. The promising results merit the future in vivo investigation of 99mTc/188Re-tricarbonyl-labeled bombesin analogues.

• Authors: R La Bella, E Garcia-Garayoa, M Bahler, P Bläuenstein, R Schibli, P Conrath, D Tourwé, P A Schubiger
• Journal: Bioconjugate chemistry (Bioconjug Chem) 2002 May-Jun Vol. 13 Issue 3 Pg. 599-604 ISSN: 1043-1802 [Print] United States
• PMID: 12009951 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chelating Agents
• Contrast Media
• Organotechnetium Compounds
• Radiopharmaceuticals
• Receptors, Bombesin
• Bombesin

Topics

• Animals
• Binding, Competitive
• Bombesin (analogs & derivatives, pharmacokinetics)
• Chelating Agents
• Contrast Media
• Female
• Humans
• Male
• Mice
• Mice, Nude
• Neoplasms, Experimental (diagnostic imaging, metabolism)
• Organotechnetium Compounds
• Radioligand Assay (methods)
• Radionuclide Imaging
• Radiopharmaceuticals
• Receptors, Bombesin (antagonists & inhibitors, metabolism)
• Tissue Distribution