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-,gamma-aminobutyric acid- [D-Tyr(6),beta-Ala (11), Thi(13), Nle(14)] bombesin (6-14) (BZH1) and 1,4,7,10-tetraazacyclododecane-N,N',N,N' -tetraacetic acid-gamma-aminobutyric acid-[D-Tyr(6), beta-Ala(11), Thi(13), Nle(14)] bombesin (6-14) (BZH2). [In-111]-BZH1 and in particular [Y-90]-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 beta-Ala(11) and Hi(12) with an approximate half-life of 2 hours. The metabolic breakdown was inhibited by EDTA and beta-Ala(11)-His(12) (carnosine) indicating that carnosinase is the active enzyme. Both In-111-labeled peptides were shown to internalize into gastrinreleasing peptide-receptor-positive AR4-2J and PC-3 cells with similar high rates, which were independent of the radiometal. The biodistribution studies of [In-111]-BZH1 and [In-111]-BZH2 ([Lu-177]-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.