title: PET of tumors expressing gastrin-releasing peptide receptor with an 18F-labeled bombesin analog.
abstract: The gastrin-releasing peptide receptor (GRPR) is overexpressed in human prostate cancer. Bombesin (BBN) is a neurotransmitter of 14 amino acids and binds with selectivity and with high affinity to GRPRs. We have synthesized a NOTA-conjugated bombesin derivative, NOTA-8-Aoc-BBN(7-14)NH(2), to label this analog with (18)F using the new Al(18)F method. In this study, the GRPR-targeting potential of (18)F-labeled NOTA-8-Aoc-BBN(7-14)NH(2) was studied using (68)Ga-NOTA-8-Aoc-BBN(7-14)NH(2) as a reference.
  
  
  METHODS
  The NOTA-conjugated bombesin analog was synthesized and radiolabeled with (68)Ga or (18)F. For (18)F labeling, we used our new 1-pot, 1-step method. The labeled product was purified by reversed-phase high-performance liquid chromatography. The log P values of the radiotracers were determined. The tumor-targeting characteristics of the compounds were assessed in mice with subcutaneously growing PC-3 xenografts. GRPR-binding specificity was studied by coinjection of an excess of unlabeled NOTA-8-Aoc-BBN(7-14)NH(2). Small-animal PET/CT images were acquired.
  
  
  RESULTS
  NOTA-8-Aoc-BBN(7-14)NH(2) could be efficiently labeled with (18)F or with (68)Ga. NOTA-8-Aoc-BBN(7-14)NH(2) was labeled with (18)F in a single step, with 50%-90% yield. Radiolabeling, including purification, was performed in 45 min and resulted in a specific activity of greater than 10 GBq/μmol. The log P values of (18)F- and (68)Ga-labeled NOTA-8-Aoc-BBN(7-14)NH(2) were -1.47 ± 0.05 and -1.98 ± 0.03, respectively. In mice, both radiolabeled compounds cleared rapidly from the blood (<0.07 percentage injected dose per gram at 1 h after injection), mainly via the kidneys. At 1 h after injection, the uptake of (18)F- and (68)Ga-labeled NOTA-8-Aoc-BBN(7-14)NH(2) in the PC-3 tumors was 2.15 ± 0.55 and 1.24 ± 0.26 percentage injected dose per gram, respectively. GRPR-binding specificity was demonstrated by reduced tumor uptake of radiolabeled NOTA-8-Aoc-BBN(7-14)NH(2) after coinjection of a 100-fold excess of unlabeled NOTA-8-Aoc-BBN(7-14)NH(2) peptide. The accumulation of (18)F-NOTA-8-Aoc-BBN(7-14)NH(2) in the subcutaneous PC-3 tumors could be visualized via small-animal PET.
  
  
  CONCLUSIONS
  NOTA-8-Aoc-BBN(7-14)NH(2) could be labeled rapidly and efficiently with (18)F using a 1-pot, 1-step method. Radiolabeled NOTA-8-Aoc-BBN(7-14)NH(2) specifically accumulated in the GRPR-expressing PC-3 tumors and should be evaluated clinically.
authors.affiliation: Department of Nuclear Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Dijkgraaf
authors.forename: Gerben M
authors.initials: GM
authors.lastname: Franssen
authors.forename: William J
authors.initials: WJ
authors.lastname: McBride
authors.forename: Christopher A
authors.initials: CA
authors.lastname: D'Souza
authors.forename: Peter
authors.initials: P
authors.lastname: Laverman
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Smith
authors.forename: David M
authors.initials: DM
authors.lastname: Goldenberg
authors.forename: Wim J G
authors.initials: WJ
authors.lastname: Oyen
authors.forename: Otto C
authors.initials: OC
authors.lastname: Boerman
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001839:Bombesin / Q000031:analogs & derivatives*; D045744:Cell Line, Tumor; D005462:Fluorine Radioisotopes; D006801:Humans; D007553:Isotope Labeling; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D049268:Positron-Emission Tomography / Q000379:methods*; D011471:Prostatic Neoplasms / Q000737:chemistry / Q000000981:diagnostic imaging*; D019275:Radiopharmaceuticals; D018004:Receptors, Bombesin / Q000032:analysis*; D014018:Tissue Distribution
chemical_list: D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D018004:Receptors, Bombesin; D001839:Bombesin