title: Evaluation of three different families of bombesin receptor radioantagonists for targeted imaging and therapy of gastrin releasing peptide receptor (GRP-R) positive tumors.
abstract: Two new classes of radiolabeled GRP receptor antagonists are studied and compared with the well-established statine-based receptor antagonist DOTA-4-amino-1-carboxymethylpiperidine-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 (RM2, 1; DOTA:1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; Sta:(3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid). The bombesin-based pseudopeptide DOTA-4-amino-1-carboxymethylpiperidine-d-Phe-Gln-Trp-Ala-Val-Gly-His-Leuψ(CHOH-CH2)-(CH2)2-CH3 (RM7, 2), and the methyl ester DOTA-4-amino-1-carboxymethylpiperidine-d-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-OCH3 (ARBA05, 3) analogues are labeled with (111)In and evaluated in vitro in PC-3 cell line and in vivo in PC-3 tumor-bearing nude mice. Antagonist potency was assessed by immunofluorescence-based receptor internalization and Ca(2+) mobilization assays. The conjugates showed good binding affinity, the IC50 value of 2 (3.2 ± 1.8 nM) being 2 and 10 times lower than 1 and 3. Compared to (111)In-1, (111)In-2 showed higher uptake in target tissues such as pancreas (1.5 ± 0.5%IA/g and 39.8 ± 9.3%IA/g at 4 h, respectively), whereas the compounds had similar tumor uptake (11.5 ± 2.4%IA/g and 11.8 ± 3.9%IA/g at 4h, respectively). The displacement of the radioligand in vivo was different in different receptor positive organs and depended on the displacing peptide.
authors.affiliation: Division of Radiological Chemistry, University Hospital Basel , Petersgraben 4, CH-4031 Basel, Switzerland.
authors.forename: Rosalba
authors.initials: R
authors.lastname: Mansi
authors.forename: Keelara
authors.initials: K
authors.lastname: Abiraj
authors.forename: Xuejuan
authors.initials: X
authors.lastname: Wang
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Tamma
authors.forename: Eleni
authors.initials: E
authors.lastname: Gourni
authors.forename: Renzo
authors.initials: R
authors.lastname: Cescato
authors.forename: Sandra
authors.initials: S
authors.lastname: Berndt
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Reubi
authors.forename: Helmut R
authors.initials: HR
authors.lastname: Maecke
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D007205:Indium Radioisotopes; D051379:Mice; D008856:Microscopy, Fluorescence; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000532:radiotherapy; D049268:Positron-Emission Tomography; D011869:Radioligand Assay; D018004:Receptors, Bombesin / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D007205:Indium Radioisotopes; D018004:Receptors, Bombesin; D002118:Calcium