Synthesis and Evaluation of Bombesin Derivatives on the Basis of Pan-Bombesin Peptides Labeled with Indium-111, Lutetium-177, and Yttrium-90 for Targeting Bombesin Receptor-Expressing Tumors

Bombesin receptors are overexpressed on a variety of human tumors like prostate, breast, and lung cancer. The aim of this study was to develop radiolabeled (Indium-111, Lutetium-177, and Yttrium-90) bombesin analogues with affinity to the three bombesin receptor subtypes for targeted radiotherapy. The following structures were synthesized: diethylenetriaminepentaacetic acid-γ-aminobutyric acid-[d-Tyr 6 , β-Ala 11 , Thi 13 , Nle 14 ] bombesin (6–14) (BZH1) and 1,4,7,10-tetraazacyclododecane- N,N′,N″,N ‴ -tetraacetic acid-γ-aminobutyric acid-[d-Tyr 6 , β-Ala 11 , Thi 13 , Nle 14 ] bombesin (6–14) (BZH2). [ 111 In]-BZH1 and in particular [ 90 Y]-BZH2 were shown to have high affinity to all three human bombesin receptor subtypes with binding affinities in the nanomolar range. In human serum metabolic cleavage was found between β-Ala 11 and His 12 with an approximate half-life of 2 hours. The metabolic breakdown was inhibited by EDTA and β-Ala 11 -His 12 (carnosine) indicating that carnosinase is the active enzyme. Both 111 In-labeled peptides were shown to internalize into gastrin-releasing peptide-receptor–positive AR4–2J and PC-3 cells with similar high rates, which were independent of the radiometal. The biodistribution studies of [ 111 In]-BZH1 and [ 111 In]-BZH2 ([ 177 Lu]-BZH2) in AR4–2J tumor-bearing rats showed specific and high uptake in gastrin-releasing peptide-receptor–positive organs and in the AR4–2J tumor. A fast clearance from blood and all of the nontarget organs except the kidneys was found. These radiopeptides were composed of the first pan-bombesin radioligands, which show great promise for the early diagnosis of tumors bearing not only gastrin-releasing peptide-receptors but also the other two bombesin receptor subtypes and may be of use in targeted radiotherapy of these tumors.