title: [64Cu-NOTA-8-Aoc-BBN(7-14)NH2] targeting vector for positron-emission tomography imaging of gastrin-releasing peptide receptor-expressing tissues.
abstract: Radiolabeled peptides hold promise as diagnostic/therapeutic targeting vectors for specific human cancers. We report the design and development of a targeting vector, [(64)Cu-NOTA-8-Aoc-BBN(7-14)NH(2)] (NOTA = 1,4,7-triazacyclononane-1,4,7-triacetic acid, 8-Aoc = 8-aminooctanoic acid, and BBN = bombesin), having very high selectivity and affinity for the gastrin-releasing peptide receptor (GRPr). GRPrs are expressed on a variety of human cancers, including breast, lung, pancreatic, and prostate, making this a viable approach toward site-directed localization or therapy of these human diseases. In this study, [NOTA-X-BBN(7-14)NH(2)] conjugates were synthesized, where X = a specific pharmacokinetic modifier. The IC(50) of [NOTA-8-Aoc-BBN(7-14)NH(2)] was determined by a competitive displacement cell-binding assay in PC-3 human prostate cancer cells using (125)I-[Tyr(4)]-BBN as the displacement ligand. An IC(50) of 3.1 +/- 0.5 nM was obtained, demonstrating high binding affinity of [NOTA-8-Aoc-BBN] for the GRPr. [(64)Cu-NOTA-X-BBN] conjugates were prepared by the reaction of (64)CuCl(2) with peptides in buffered aqueous solution. In vivo studies of [(64)Cu-NOTA-8-Aoc-BBN(7-14)NH(2)] in tumor-bearing PC-3 mouse models indicated very high affinity of conjugate for the GRPr. Uptake of conjugate in tumor was 3.58 +/- 0.70% injected dose (ID) per g at 1 h postintravenous injection (p.i.). Minimal accumulation of radioactivity in liver tissue (1.58 +/- 0.40% ID per g, 1 h p.i.) is indicative of rapid renal-urinary excretion and suggests very high in vivo kinetic stability of [(64)Cu-NOTA-8-Aoc-BBN(7-14)NH(2)] with little or no in vivo dissociation of (64)Cu(2+) from the NOTA chelator. Kidney accumulation at 1 h p.i. was 3.79 +/- 1.09% ID per g. Molecular imaging studies in GRPr-expressing tumor models produced high-contrast, high-quality micro-positron-emission tomography images.
authors.affiliation: Department of Radiology, University of Missouri School of Medicine, Columbia, MO 65211, USA.
authors.forename: Adam F
authors.initials: AF
authors.lastname: Prasanphanich
authors.forename: Prasant K
authors.initials: PK
authors.lastname: Nanda
authors.forename: Tammy L
authors.initials: TL
authors.lastname: Rold
authors.forename: Lixin
authors.initials: L
authors.lastname: Ma
authors.forename: Michael R
authors.initials: MR
authors.lastname: Lewis
authors.forename: Jered C
authors.initials: JC
authors.lastname: Garrison
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Hoffman
authors.forename: Gary L
authors.initials: GL
authors.lastname: Sieckman
authors.forename: Said D
authors.initials: SD
authors.lastname: Figueroa
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Smith
mesh_terms: D000818:Animals; D001896:Boron Compounds; D045744:Cell Line, Tumor; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry / Q000302:isolation & purification / Q000493:pharmacokinetics; D006801:Humans; D008689:Methacrylates; D008768:Methylmethacrylates; D051379:Mice; D016513:Mice, SCID; D015394:Molecular Structure; D009369:Neoplasms / Q000175:diagnosis / Q000378:metabolism; D009928:Organ Specificity / Q000187:drug effects; D010446:Peptide Fragments / Q000737:chemistry / Q000302:isolation & purification / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D018004:Receptors, Bombesin / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C522549:64Cu-1,4,7-triazacyclononane-1,4,7-triacetic acid-8-aminooctanoic acid-bombesin(7-14)amide; D001896:Boron Compounds; D006573:Heterocyclic Compounds, 1-Ring; D008689:Methacrylates; D008768:Methylmethacrylates; D010446:Peptide Fragments; D018004:Receptors, Bombesin; C049495:Super-bond