[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.

68Ga/177Lu-NeoBOMB1, a Novel Radiolabeled GRPR Antagonist for Theranostic Use in Oncology

“…After the successful use of radiolabeled somatostatin peptide analogs in neuroendocrine tumors for nuclear imaging and therapy (5,6), multiple radiolabeled GRPR radioligands have been synthesized and studied in preclinical as well as in clinical studies, mostly in prostate cancer patients. Examples of such peptide analogs include AMBA, the Demobesin series, and MP2653 (7)(8)(9)(10)(11). Recent studies have shown a preference for GRPR antagonists compared with GRPR agonists (12,13).…”

“…The peptidic part of NeoBOMB1, however, is based on a different GRPR antagonist first described by Heimbrook et al (17) and generated by modification of the C-terminal Leu 13 -Met 14 -NH 2 and the replacement of Asn 6 by DPhe 6 of native bombesin (6)(7)(8)(9)(10)(11)(12)(13)(14). NeoBOMB1 was chosen for further studies because of its improved affinity for the GRPR (18,19).…”

18F-Labeled Bombesin Analog for Specific and Effective Targeting of Prostate Tumors Expressing Gastrin-Releasing Peptide Receptors

“…Several analogs of the natural GRPr ligand bombesin, a 14-amino-acid neuropeptide, have been labeled with various radionuclides for the diagnosis and treatment of GPRrpositive tumors in recent years (8)(9)(10)(11)(12). Potent 99m Tc-based (demobesin-1) and 111 In-based (RM-1) bombesin analogs that were designed for GRPr-based targeting and tested in the PC-3 xenograft model showed high absolute tumor uptake in animals (13,14). Few publications have reported on 18 F labeling of bombesin peptides (15)(16)(17)(18)(19).…”

Molecular Imaging of Breast Cancer Tissue via Site-Directed Radiopharmaceuticals

“…However, recent reports b y N o c k e t a l ., show compelling evidence that radiopharmaceutical design and development based upon antagonist-type ligand frameworks bear reexamination (Nock et al, 2003 and. Antagonist ligands are presumably not internalized, and therefore are not expected to residualize as effectively in tumor tissue when compared to agonist-based ligand frameworks.…”

“…Antagonist ligands are presumably not internalized, and therefore are not expected to residualize as effectively in tumor tissue when compared to agonist-based ligand frameworks. Studies using 99m Tc-Demobesin1 ([ 99m Tc-N 4 0-1 ,bzlg 0 ,D-Phe 6 ,LeuNHEt 13 ,des-Met 14 ]BBN(6-14)) demonstrated very high affinity and selectivity for the GRPR with pronounced accumulation and retention of radioactivity in human tumor xenografts in rodents (Nock et al, 2003 and. In addition, Maecke and co-workers have begun investigating another antagonist-like targeting vector, [DOTA-4-amino-1-carboxymethylpiperidine-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH 2 ], having high selectivity for the GRPr (Mansi et al, 2009 and2011).…”