title: Gastrin releasing peptide receptor-directed radioligands based on a bombesin antagonist: synthesis, (111)in-labeling, and preclinical profile.
abstract: Novel bombesin (BBN) antagonists were synthesized by coupling the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) to H-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 (JMV594) through linkers of increasing number of (βAla)x residues (x = 1-3). Labeling with (111)In afforded the respective radiotracers in high purity and high specific activity. Bioconjugate affinity for the gastrin releasing peptide receptor (GRPR) as determined against [(125)I-Tyr(4)]BBN was high (IC50 values in the lower nanomolar range). Radioligands poorly internalized in PC-3 cells at 37 °C. Radiopeptides remained >60% intact 5 min after entering the bloodstream of healthy mice. After injection in SCID mice bearing human PC-3 xenografts all analogues showed high tumor uptake and rapid background clearance via the kidneys into urine. Interestingly, pancreatic uptake, albeit GRPR-specific, declined rapidly with time. (111)In-DOTA-(βAla)2-JMV594 achieved the highest tumor values among the group (17.0 ± 2.8%ID/g vs. 8-10%ID/g, respectively, at 4 h pi) indicating that the (βAla)2-linker favors in vivo interaction of radiopeptides with the GRPR.
authors: Molecular Radiopharmacy, INRASTES, National Center for Scientific Research "Demokritos", Ag. Paraskevi Attikis, GR-153 10 Athens, Greece.
authors: Panteleimon J
authors: PJ
authors: Marsouvanidis
authors: Berthold A
authors: BA
authors: Nock
authors: Bouchra
authors: B
authors: Hajjaj
authors: Jean-Alain
authors: JA
authors: Fehrentz
authors: Luc
authors: L
authors: Brunel
authors: Céline
authors: C
authors: M'Kadmi
authors: Linda
authors: L
authors: van der Graaf
authors: Eric P
authors: EP
authors: Krenning
authors: Theodosia
authors: T
authors: Maina
authors: Jean
authors: J
authors: Martinez
authors: Marion
authors: M
authors: de Jong
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001839:Bombesin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D005260:Female; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D006801:Humans; D007205:Indium Radioisotopes; D007553:Isotope Labeling; D008024:Ligands; D051379:Mice; D009842:Oligopeptides / Q000737:chemistry; D018004:Receptors, Bombesin / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D006573:Heterocyclic Compounds, 1-Ring; D007205:Indium Radioisotopes; D008024:Ligands; D009842:Oligopeptides; D018004:Receptors, Bombesin; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D001839:Bombesin