Synthesis and Evaluation of Bombesin Analogues Conjugated to Two Different Triazolyl‐Derived Chelators for ^99mTc Labeling

Abstract

Overexpression of the gastrin-releasing peptide receptor (GRPR) in a variety of human carcinomas has provided a means of diagnosis and treatment. Previously we reported a metabolically stable (N(α)His)Ac-βAla-βAla-[Cha(13),Nle(14)]BBS(7-14) analogue with high affinity for the GRPR. We have also shown that the biodistribution pattern of this fairly lipophilic, radiolabeled peptide can be enhanced by glycation, which is easily carried out by Cu(I)-catalyzed cycloaddition. Herein, we further elaborate this "click approach" in the synthesis of a new series of triazole-based chelating systems as alternatives to the (N(α)His)Ac chelator for labeling with the (99m)Tc(CO)(3) core. The bombesin analogues, containing these new chelating systems, were evaluated with regard to their synthesis and in vitro and in vivo properties, and were compared with their (N(α)His)Ac counterparts. The influence of the chelator on biodistribution properties was less than that of glycation, which clearly improved the tumor-to-background ratios.

New Insights in the Design of Bioactive Peptides and Chelating Agents for Imaging and Therapy in Oncology

“…Several chemical modifications have been introduced in the synthetic bombesin to stabilize the structure, to increase the binding affinity and to potentiate agonist or antagonist properties. Particularly, the methionine at the C-terminus (Met-14), sensitive to oxidation, and Leu-13 have been substituted with norleucine (Nle) and cyclohexylalanine (Cha), respectively, in order to improve the overall stability and binding affinity [ 53 ]. Other amino acids sensitive to endopeptidases, such as His-12/Leu-13 and Gly-11/His-12, have been substituted with non-natural Cha or statin (Sta) and N -methylglycine, respectively, to increase the in vivo stability [ 38 ].…”

Click-to-Chelate: Development of Technetium and Rhenium-Tricarbonyl Labeled Radiopharmaceuticals

“…Brans et al . have conjugated both variations of click ligands to the N-terminus of a tumor-targeting bombesin (BBS) derivative (Scheme 3; see below for the relevance of BBS in nuclear oncology) [29]. Radiolabeling of the two peptides with [ 99m Tc(CO) 3 ] + under standard conditions revealed a significantly lower radiolabeling yield for the peptide with the inverse click ligand (<60%) in comparison to the compound with the regular click ligand (>95%).…”

“…[38] Brans et al . [29], and Zhang et al . [39] have applied the click-to-chelate approach to tumor-targeting vectors of relevance in nuclear oncology and studied the biological characteristics of the 99m Tc-labeled conjugates.…”

Metal Complexes Containing Natural and Artificial Radioactive Elements and Their Applications

“…With that in mind, Huisgen click chemistry and monodentate phosphine ligands have been used for biomolecule incorporation on 99m Tc complexes [159]. Bombesin analogues were prepared by a “click approach”, using Cu(I)-catalyzed cycloaddition to obtain a new series of triazole-based chelating systems for labeling 99m Tc(CO) 3 moieties, which presented good biodistribution and improved tumor detection [160,161]. A bidentate ligand containing a bioactive pharmacophore, (2-methoxyphenyl)piperazine, has been prepared by this synthetic strategy, to further obtain a lipophilic technetium complex, potentially useful as a CNS imaging agent [162].…”