title: [99mTc]Demobesin 1, a novel potent bombesin analogue for GRP receptor-targeted tumour imaging.
abstract: Demobesin 1 is a potent new GRP-R-selective bombesin (BN) analogue containing an open chain tetraamine chelator for stable technetium-99m binding. Following a convenient labelling protocol, the radiopeptide, [(99m)Tc]Demobesin 1, formed in nearly quantitative yields and with high specific activities. Both unlabelled and labelled peptide demonstrated high-affinity binding in membrane preparations of the human androgen-independent prostate adenocarcinoma PC-3 cell line. The IC(50) values determined for Demobesin 1 and [Tyr(4)]BN were 0.70+/-0.08 n M and 1.5+/-0.20 n M, respectively, while the K(d) defined for [(99m)Tc/(99g)Tc]Demobesin 1 was 0.67+/-0.10 n M. [(99m)Tc]Demobesin 1 was rather stable in murine plasma, whereas it degraded rapidly in kidney and liver homogenates. After injection in healthy Swiss albino mice, [(99m)Tc]Demobesin 1 accumulated very efficiently in the target organs (pancreas, intestinal tract) via a GRP-R-mediated process, as shown by in vivo receptor blocking experiments. An equally high and GRP-R-mediated uptake was exhibited by [(99m)Tc]Demobesin 1 after injection in PC-3 tumour-bearing athymic mice. The initial high radioligand uptake of 16.2+/-3.1%ID/g in the PC-3 xenografts at 1 h p.i. remained at a similar level (15.61+/-1.19%ID/g) at 4 h p.i. Even after 24 h p.i., when the radioactivity had cleared from all other tissues, a value of 5.24+/-0.67%ID/g was still observed in the tumour. The high and prolonged localization of [(99m)Tc]Demobesin 1 at the tumour site and its rapid background clearance are very promising qualities for GRP-R-targeted tumour imaging in man.
authors.affiliation: Institute of Radioisotopes--Radiodiagnostic Products, National Center for Scientific Research Demokritos, 15310 Ag. Paraskevi, Attikis, Athens, Greece.
authors.forename: Berthold
authors.initials: B
authors.lastname: Nock
authors.forename: Anastasia
authors.initials: A
authors.lastname: Nikolopoulou
authors.forename: Efstratios
authors.initials: E
authors.lastname: Chiotellis
authors.forename: George
authors.initials: G
authors.lastname: Loudos
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Maintas
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Reubi
authors.forename: Theodosia
authors.initials: T
authors.lastname: Maina
mesh_terms: D000818:Animals; D001839:Bombesin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D002462:Cell Membrane / Q000000981:diagnostic imaging / Q000378:metabolism; D005260:Female; D019886:Gastrin-Releasing Peptide / Q000378:metabolism*; D006801:Humans; D007553:Isotope Labeling / Q000379:methods; D007668:Kidney / Q000000981:diagnostic imaging / Q000378:metabolism; D008099:Liver / Q000000981:diagnostic imaging / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D018482:Muscle, Skeletal / Q000000981:diagnostic imaging / Q000378:metabolism; D009368:Neoplasm Transplantation; D009928:Organ Specificity; D015609:Organotechnetium Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D011471:Prostatic Neoplasms / Q000097:blood / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured / Q000000981:diagnostic imaging / Q000378:metabolism
chemical_list: D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; C477441:technetium 99m demobesin 1; D019886:Gastrin-Releasing Peptide; D001839:Bombesin