title: GRPR-selective PET imaging of prostate cancer using [(18)F]-lanthionine-bombesin analogs.
abstract: The gastrin-releasing peptide receptor (GRPR) is overexpressed in a variety of human malignancies, including prostate cancer. Bombesin (BBN) is a 14 amino acids peptide that selectively binds to GRPR. In this study, we developed two novel Al(18)F-labeled lanthionine-stabilized BBN analogs, designated Al(18)F-NOTA-4,7-lanthionine-BBN and Al(18)F-NOTA-2,6-lanthionine-BBN, for positron emission tomography (PET) imaging of GRPR expression using xenograft prostate cancer models. (Methyl)lanthionine-stabilized 4,7-lanthionine-BBN and 2,6-lanthionine-BBN analogs were conjugated with a NOTA chelator and radiolabeled with Al(18)F using the aluminum fluoride strategy. Al(18)F-NOTA-4,7-lanthionine-BBN and Al(18)F-NOTA-2,6-lanthionine-BBN was labeled with Al(18)F with good radiochemical yield and specific activity>30 GBq/μmol for both radiotracers. The logD values measured for Al(18)F-NOTA-4,7-lanthionine-BBN and Al(18)F-NOTA-2,6-lanthionine-BBN were -2.14 ± 0.14 and -2.34 ± 0.15, respectively. In athymic nude PC-3 xenografts, at 120 min post injection (p.i.), the uptake of Al(18)F-NOTA-4,7-lanthionine-BBN and Al(18)F-NOTA-2,6-lanthionine-BBN in prostate cancer (PC-3) mouse models was 0.82 ± 0.23% ID/g and 1.40 ± 0.81% ID/g, respectively. An excess of unlabeled ɛ-aminocaproic acid-BBN(7-14) (300-fold) was co-injected to assess GRPR binding specificity. Tumor uptake of Al(18)F-NOTA-4,7-lanthionine-BBN and Al(18)F-NOTA-2,6-lanthionine-BBN in PC-3 tumors was evaluated by microPET (μPET) imaging at 30, 60 and 120 min p.i. Blocking studies showed decreased uptake in PC-3 bearing mice. Stabilized 4,7-lanthionine-BBN and 2,6-lanthionine-BBN peptides were rapidly and successfully labeled with (18)F. Both tracers may have potential for GRPR-positive tumor imaging.
authors: Department of Urology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: G
authors: G
authors: Carlucci
authors: Lanthio Pharma, Groningen, The Netherlands.
authors: A
authors: A
authors: Kuipers
authors: Department of Urology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: H J K
authors: HJ
authors: Ananias
authors: Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: D
authors: D
authors: de Paula Faria
authors: Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: R A J O
authors: RA
authors: Dierckx
authors: Surgical Research Laboratory, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: W
authors: W
authors: Helfrich
authors: Lanthio Pharma, Groningen, The Netherlands.
authors: R
authors: R
authors: Rink
authors: Lanthio Pharma, Groningen, The Netherlands; Department of Molecular Genetics, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, The Netherlands.
authors: G N
authors: GN
authors: Moll
authors: Department of Urology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: I J
authors: IJ
authors: de Jong
authors: Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. Electronic address: p.h.elsinga@umcg.nl.
authors: P H
authors: PH
authors: Elsinga
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D000818:Animals; D001839:Bombesin / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D049268:Positron-Emission Tomography; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D018004:Receptors, Bombesin / Q000378:metabolism*; D013440:Sulfides / Q000493:pharmacokinetics; D014018:Tissue Distribution; D055114:X-Ray Microtomography
chemical_list: D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D018004:Receptors, Bombesin; D013440:Sulfides; C001520:lanthionine; D000409:Alanine; D001839:Bombesin
keywords: Al(18)F; Bombesin; GRPR; PC-3; PET; Stability