title: 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.affiliation: Division of Radiological Chemistry, Institute of Nuclear Medicine, Department of Radiology, University Hospital, Basel.
authors.forename: Hanwen
authors.initials: H
authors.lastname: Zhang
authors.forename: Jianhua
authors.initials: J
authors.lastname: Chen
authors.forename: Christian
authors.initials: C
authors.lastname: Waldherr
authors.forename: Karin
authors.initials: K
authors.lastname: Hinni
authors.forename: Beatrice
authors.initials: B
authors.lastname: Waser
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Reubi
authors.forename: Helmut R
authors.initials: HR
authors.lastname: Maecke
mesh_terms: D000818:Animals; D001839:Bombesin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D004355:Drug Stability; D006801:Humans; D007205:Indium Radioisotopes / Q000737:chemistry; D007553:Isotope Labeling / Q000379:methods; D008187:Lutetium / Q000737:chemistry; D008297:Male; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism*; D011868:Radioisotopes / Q000737:chemistry; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D018004:Receptors, Bombesin / Q000096:biosynthesis / Q000145:classification / Q000378:metabolism*; D014018:Tissue Distribution; D015021:Yttrium Radioisotopes / Q000737:chemistry
chemical_list: D007205:Indium Radioisotopes; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D018004:Receptors, Bombesin; D015021:Yttrium Radioisotopes; D008187:Lutetium; D001839:Bombesin