title: Bombesin analogues for gastrin-releasing peptide receptor imaging.
abstract: OBJECTIVE
  The present study describes the design and development of a series of new bombesin (BBN) antagonist peptide ligands of the form [(64)Cu-(NO2A-X-D-Phe(6)-BBN(6-13)NHEt)], where Cu-64=a positron emitting radiometal; NO2A=1,4,7-triazacyclononane-1,4-diacetic acid; X=6-amino hexanoic acid, 8-amino octanoic acid or 9-Aminononanoic acid; and BBN(6-13)NHEt=Gln-Trp-Ala-Val-Gly-His-Leu-NHEt, an antagonist analogue of bombesin peptide for specific targeting of the gastrin-releasing peptide receptor (GRPR).
  
  
  METHODS
  [NO2A-X-D-Phe(6)-BBN(6-13)NHEt] conjugates were manually conjugated with NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid), and the resulting conjugates were labeled with (64)Cu to yield [(64)Cu-(NO2A-X-D-Phe(6)-BBN(6-13)NHEt)]. The metallated and nonmetallated conjugates were purified via reversed-phase high-performance liquid chromatography and characterized by electrospray ionization-mass spectrometry.
  
  
  RESULTS
  Competitive displacement binding assays displayed nanomolar binding affinities toward human GRPR for all of the newly formed peptide analogues. Biodistribution studies showed very high uptake and retention of tumor-associated radioactivity in PC-3 (a prostate tumor model known to express the GRPR) tumor-bearing rodent models. The radiolabeled conjugates also exhibited rapid urinary excretion and very high tumor to background ratios. Micro-positron emission tomography (PET) molecular imaging investigations showed clear visualization of tumors in female PC-3 tumor-bearing mice 15 h postinjection.
  
  
  CONCLUSIONS
  The biodistribution and molecular imaging study suggests that these conjugates can be considered as potential PET tracer candidates for the diagnosis of GRPR-positive tumors in human patients.
authors.affiliation: Department of Radiology, University of Missouri School of Medicine, Columbia, MO 65211, USA.
authors.forename: Prasant K
authors.initials: PK
authors.lastname: Nanda
authors.forename: Usha
authors.initials: U
authors.lastname: Pandey
authors.forename: Brienne N
authors.initials: BN
authors.lastname: Bottenus
authors.forename: Tammy L
authors.initials: TL
authors.lastname: Rold
authors.forename: Gary L
authors.initials: GL
authors.lastname: Sieckman
authors.forename: Ashley F
authors.initials: AF
authors.lastname: Szczodroski
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Hoffman
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Smith
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001839:Bombesin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D003301:Copper Radioisotopes; D005260:Female; D006571:Heterocyclic Compounds / Q000737:chemistry; D006573:Heterocyclic Compounds, 1-Ring; D006801:Humans; D008297:Male; D051379:Mice; D057054:Molecular Imaging / Q000379:methods*; D049268:Positron-Emission Tomography; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism; D021381:Protein Transport; D018004:Receptors, Bombesin / Q000378:metabolism*; D055114:X-Ray Microtomography
chemical_list: D003301:Copper Radioisotopes; D006571:Heterocyclic Compounds; D006573:Heterocyclic Compounds, 1-Ring; D018004:Receptors, Bombesin; C048993:1,4,7-triazacyclononane-N,N',N''-triacetic acid; D001839:Bombesin