Design, Synthesis, and Biological Evaluation of an Antagonist−Bombesin Analogue as Targeting Vector

Abstract

The gastrin releasing peptide receptor (GRP-R) is over-expressed on a number of tumors and cancer cell lines including pancreas, prostate, breast, gastrointestinal and small cell lung cancer (SCLC). Radiolabeled bombesin (BBN) analogues have exhibited high binding affinity and specificity to the GRP-R. A bombesin analogue with an antagonist targeting-vector at the C-terminus, DOTAaminohexanoyl-[D-Phe 6 , Leu-NHCH 2 CH 2 CH 3 13 , des Met 14 ] BBN [6][7][8][9][10][11][12][13][14] (1, "Bomproamide"), has been synthesized and displays high binding affinity (IC 50 = 1.36 ± 0.09 nM) against 125 I-Tyr 4 -BBN in in vitro competitive assays using PC-3 cells. Maximum internalization of 111 In-1 reached 14% in PC-3 cells after 45 minutes of incubation. Rapid (0.25-hour PI) and high (12.21 ± 3.2 %ID/g) pancreatic uptake of 111 In-1 was observed in healthy CF-1 mice and 90% of the activity was blocked by co-injection of 100 μg of BBN. Rapid (0.25-hour PI) and high uptake (6.90 ± 1.06 %ID/g) was observed in PC-3 prostate cancer xenografts in SCID mice, as well as visualized clearly in a SPECT/ CT study. These results support the use of a bombesin construct with an antagonist C-terminal vector as a candidate of choice for specific in vivo imaging of tumors over-expressing GRP-receptors.

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

“…Recent preclinical studies demonstrated that GRPr antagonists may be preferable to agonists for tumor targeting, yielding high tumor uptake and long tumor washout (23,34). Our data indicated that 18 F-BAY 86-4367 behaves as an antagonist for GRPr, making this peptide promising for further evaluation in a clinical trial.…”

N-Terminal Modifications Improve the Receptor Affinity and Pharmacokinetics of Radiolabeled Peptidic Gastrin-Releasing Peptide Receptor Antagonists: Examples of 68Ga- and 64Cu-Labeled Peptides for PET Imaging

“…5). Different retention times of the tracers in the tumor and pancreas have also been observed for other GRPr antagonists already studied (8)(9)(10)29,30), but this was not the case for GRPr agonists (16) for which pancreas uptake was found to be high over time. Recently, Liu et al (31) have coupled NODAGA to RM1 (antagonist) and to AMBA (agonist) and labeled the 2 conjugates with 64 Cu and 18 F-AlF.…”

“…Innovative developments using agonists hybridized with other targeting units such as a v b 3 integrins or hypoxia-targeting agents such as 2-nitroimidazoles (25). The successful pharmacokinetic performance of somatostatin-based antagonistic radiotracers preclinically (6,26,27) and clinically (28) led several research groups to develop GRPr antagonists, which indeed exhibit pharmacokinetics superior to agonists (7)(8)(9)(10)(29)(30)(31)(32). Despite these promising data with the first antagonists, there is no consensus that antagonists are superior to agonists targeting the GRPr (33,34).…”

Evaluation of a 1,4,7,10-Tetraazacyclododecane-1,4,7,10-Tetraacetic Acid–Conjugated Bombesin-Based Radioantagonist for the Labeling with Single-Photon Emission Computed Tomography, Positron Emission Tomography, and Therapeutic Radionuclides

“…During the reviewing process of this article, a paper was published describing another COOH-terminal-modified bombesin-based peptide conjugated to DOTA (40). The radiopeptide was not shown to have antagonistic properties but the tumor uptake was specific and reasonably high.…”