title: 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: Center for Radiopharmaceutical Science, Paul Scherrer Institute, CH-5232 Villigen, Switzerland.
authors: R
authors: R
authors: La Bella
authors: E
authors: E
authors: Garcia-Garayoa
authors: M
authors: M
authors: Bahler
authors: P
authors: P
authors: Bläuenstein
authors: R
authors: R
authors: Schibli
authors: P
authors: P
authors: Conrath
authors: D
authors: D
authors: Tourwé
authors: P A
authors: PA
authors: Schubiger
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001839:Bombesin / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D002614:Chelating Agents; D003287:Contrast Media; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging* / Q000378:metabolism; D015609:Organotechnetium Compounds; D011869:Radioligand Assay / Q000379:methods; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals; D018004:Receptors, Bombesin / Q000037:antagonists & inhibitors / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D002614:Chelating Agents; D003287:Contrast Media; D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; D018004:Receptors, Bombesin; D001839:Bombesin