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

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 (NαHis)Ac‐βAla‐βAla‐[Cha13,Nle14]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 CuI‐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 (NαHis)Ac chelator for labeling with the 99mTc(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 (NαHis)Ac counterparts. The influence of the chelator on biodistribution properties was less than that of glycation, which clearly improved the tumor‐to‐background ratios. 99mTc conjugates are the bomb(esin)! The CuI‐catalyzed cycloaddition of an azide and an alkyne has proven to be a very successful conjugation reaction. We demonstrate the compatibility of this reaction with solid‐phase peptide synthesis for chelator conjugation, as well as for easy conjugation to glucose. The 99mTc(CO)3 radiolabeled bombesin analogue can be used to target the GRP receptor in PC‐3 cells with high affinity and selectivity.