title: Preclinical comparison of Al18F- and 68Ga-labeled gastrin-releasing peptide receptor antagonists for PET imaging of prostate cancer.
abstract: Gastrin-releasing peptide receptor (GRPR) is overexpressed in human prostate cancer and is being used as a target for molecular imaging. In this study, we report on the direct comparison of 3 novel GRPR-targeted radiolabeled tracers: Al(18)F-JMV5132, (68)Ga-JMV5132, and (68)Ga-JMV4168 (JMV5132 is NODA-MPAA-βAla-βAla-[H-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2], JMV4168 is DOTA-βAla-βAla-[H-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2], and NODA-MPAA is 2-[4-(carboxymethyl)-7-{[4-(carboxymethyl)phenyl]methyl}-1,4,7-triazacyclononan-1-yl]acetic acid).
  
  
  METHODS
  The GRPR antagonist JMV594 (H-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2) was conjugated to NODA-MPAA for labeling with Al(18)F. JMV5132 was radiolabeled with (68)Ga and (18)F, and JMV4168 was labeled with (68)Ga for comparison. The inhibitory concentration of 50% values for binding GRPR of JMV4168, JMV5132, (nat)Ga-JMV4168, and (nat)Ga-JMV5132 were determined in a competition-binding assay using GRPR-overexpressing PC-3 tumors. The tumor-targeting characteristics of the compounds were assessed in mice bearing subcutaneous PC-3 xenografts. Small-animal PET/CT images were acquired, and tracer biodistribution was determined by ex vivo measurements.
  
  
  RESULTS
  JMV5132 was labeled with (18)F in a novel 1-pot, 1-step procedure within 20 min, without need for further purification and resulting in a specific activity of 35 MBq/nmol. Inhibitory concentration of 50% values (in nM) for GRPR binding of JMV5132, JMV4168, (nat)Ga-JMV5132, (nat)Ga-JMV4168, and Al(nat)F-JMV5132 were 6.8 (95% confidence intervals [CIs], 4.6-10.0), 13.2 (95% CIs, 5.9-29.3), 3.0 (95% CIs, 1.5-6.0), 3.2 (95% CIs, 1.8-5.9), and 10.0 (95% CIs, 6.3-16.0), respectively. In mice with subcutaneous PC-3 xenografts, all tracers cleared rapidly from the blood, exclusively via the kidneys for (68)Ga-JMV4168 and partially hepatobiliary for (68)Ga-JMV5132 and Al(18)F-JMV5132. Two hours after injection, the uptake of (68)Ga-JMV4168, (68)Ga-JMV5132, and Al(18)F-JMV5132 in PC-3 tumors was 5.96 ± 1.39, 5.24 ± 0.29, 5.30 ± 0.98 (percentage injected dose per gram), respectively. GRPR specificity was confirmed by significantly reduced tumor uptake of the 3 tracers after coinjection of a 100-fold excess of unlabeled JMV4168 or JMV5132. Small-animal PET/CT clearly visualized PC-3 tumors, with the highest resolution observed for Al(18)F-JMV5132.
  
  
  CONCLUSIONS
  JMV5132 could be rapidly and efficiently labeled with (18)F. Al(18)F-JMV5132, (68)Ga-JMV5132, and (68)Ga-JMV4168 all showed comparable high and specific accumulation in GRPR-positive PC-3 tumors. These new PET tracers are promising candidates for future clinical translation.
authors.affiliation: Department of Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands Department of Urology, Erasmus MC, Rotterdam, The Netherlands k.chatalic@erasmusmc.nl.
authors.forename: Kristell L S
authors.initials: KL
authors.lastname: Chatalic
authors.affiliation: Department of Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Gerben M
authors.initials: GM
authors.lastname: Franssen
authors.affiliation: Department of Urology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Wytske M
authors.initials: WM
authors.lastname: van Weerden
authors.affiliation: Immunomedics, Inc., Morris Plains, New Jersey; and.
authors.forename: William J
authors.initials: WJ
authors.lastname: McBride
authors.affiliation: Department of Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Laverman
authors.affiliation: Department of Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: de Blois
authors.affiliation: Institut des Biomolécules Max Mousseron, UMR 5247, CNRS-UM1-UM2, Montpellier, France.
authors.forename: Bouchra
authors.initials: B
authors.lastname: Hajjaj
authors.affiliation: Institut des Biomolécules Max Mousseron, UMR 5247, CNRS-UM1-UM2, Montpellier, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Brunel
authors.affiliation: Immunomedics, Inc., Morris Plains, New Jersey; and.
authors.forename: David M
authors.initials: DM
authors.lastname: Goldenberg
authors.affiliation: Institut des Biomolécules Max Mousseron, UMR 5247, CNRS-UM1-UM2, Montpellier, France.
authors.forename: Jean-Alain
authors.initials: JA
authors.lastname: Fehrentz
authors.affiliation: Institut des Biomolécules Max Mousseron, UMR 5247, CNRS-UM1-UM2, Montpellier, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Martinez
authors.affiliation: Department of Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Otto C
authors.initials: OC
authors.lastname: Boerman
authors.affiliation: Department of Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Marion
authors.initials: M
authors.lastname: de Jong
mesh_terms: D017607:Aluminum Compounds / Q000737:chemistry; D000818:Animals; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000737:chemistry / Q000493:pharmacokinetics; D005459:Fluorides / Q000737:chemistry; D005462:Fluorine Radioisotopes / Q000737:chemistry; D005710:Gallium Radioisotopes / Q000737:chemistry; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010455:Peptides / Q000737:chemistry / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging*; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics; D018004:Receptors, Bombesin / Q000037:antagonists & inhibitors*; D014018:Tissue Distribution; D051598:Whole Body Imaging
chemical_list: C000594844:68Ga-JMV4168; C000594843:68Ga-JMV5132; C000594842:Al18F-JMV5132; D017607:Aluminum Compounds; D056831:Coordination Complexes; D005462:Fluorine Radioisotopes; D005710:Gallium Radioisotopes; D010455:Peptides; D019275:Radiopharmaceuticals; D018004:Receptors, Bombesin; D005459:Fluorides; C032311:aluminum fluoride
keywords: 18F; prostate cancer; GRPR; PET; bombesin