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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

¹ Division of Radiological Chemistry, Institute of Nuclear Medicine, Department of Radiology, University Hospital, Basel; and ² Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, Berne, Switzerland

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--aminobutyric acid-[D-Tyr⁶, ß-Ala¹¹, Thi¹³, Nle¹⁴] bombesin (6–14) (BZH1) and 1,4,7,10-tetraazacyclododecane-N,N',N'',N''' -tetraacetic acid--aminobutyric acid-[D-Tyr⁶, ß-Ala¹¹, Thi¹³, Nle¹⁴] bombesin (6–14) (BZH2). [¹¹¹In]-BZH1 and in particular [⁹⁰Y]-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 ß-Ala¹¹ and His¹² with an approximate half-life of 2 hours. The metabolic breakdown was inhibited by EDTA and ß-Ala¹¹-His¹² (carnosine) indicating that carnosinase is the active enzyme.

Both ¹¹¹In-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 [¹¹¹In]-BZH1 and [¹¹¹In]-BZH2 ([¹⁷⁷Lu]-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.

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