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

Cancer Res. 2004 Sep 15;64(18):6707-15. doi: 10.1158/0008-5472.CAN-03-3845.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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