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.

Abstract

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-Tyr6, beta-Ala11, Thi13, Nle14] bombesin (6-14) (BZH1) and 1,4,7,10-tetraazacyclododecane-N,N',N",N"' -tetraacetic acid-gamma-aminobutyric acid-[D-Tyr6, beta-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 beta-Ala11 and His12 with an approximate half-life of 2 hours. The metabolic breakdown was inhibited by EDTA and beta-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.

• Authors: Hanwen Zhang, Jianhua Chen, Christian Waldherr, Karin Hinni, Beatrice Waser, Jean Claude Reubi, Helmut R Maecke
• Journal: Cancer research (Cancer Res) Vol. 64 Issue 18 Pg. 6707-15 (Sep 15 2004) ISSN: 0008-5472 [Print] United States
• PMID: 15374988 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Indium Radioisotopes
• Radioisotopes
• Radiopharmaceuticals
• Receptors, Bombesin
• Yttrium Radioisotopes
• Lutetium
• Bombesin

Topics

• Animals
• Bombesin (analogs & derivatives, chemical synthesis, pharmacokinetics, pharmacology)
• Drug Stability
• Humans
• Indium Radioisotopes (chemistry)
• Isotope Labeling (methods)
• Lutetium (chemistry)
• Male
• Pancreatic Neoplasms (diagnostic imaging, metabolism)
• Prostatic Neoplasms (diagnostic imaging, metabolism)
• Radioisotopes (chemistry)
• Radionuclide Imaging
• Radiopharmaceuticals (chemical synthesis, pharmacokinetics, pharmacology)
• Rats
• Receptors, Bombesin (biosynthesis, classification, metabolism)
• Tissue Distribution
• Yttrium Radioisotopes (chemistry)