title: Theranostic Perspectives in Prostate Cancer with the Gastrin-Releasing Peptide Receptor Antagonist NeoBOMB1: Preclinical and First Clinical Results.
abstract: We recently introduced the potent gastrin-releasing peptide receptor (GRPR) antagonist68Ga-SB3 (68Ga-DOTA-p-aminomethylaniline-diglycolic acid-DPhe-Gln-Trp-Ala-Val-Gly-His-Leu-NHEt), showing excellent tumor localizing efficacy in animal models and in patients. By replacement of the C-terminal Leu13-Met14-NH2dipeptide of SB3 by Sta13-Leu14-NH2, the novel GRPR antagonist NeoBOMB1 was generated and labeled with different radiometals for theranostic use. We herein report on the biologic profile of resulting67/68Ga-,111In-, and177Lu-NeoBOMB1 radioligands in GRPR-expressing cells and mouse models. The first evidence of prostate cancer lesion visualization in men using68Ga-NeoBOMB1 and PET/CT is also presented.
  
  
  METHODS
  NeoBOMB1 was radiolabeled with67/68Ga,111In, and177Lu according to published protocols. The respective metalated speciesnatGa-,natIn-, andnatLu-NeoBOMB1 were also synthesized and used in competition binding experiments against [125I-Tyr4]BBN in GRPR-positive PC-3 cell membranes. Internalization of67Ga-,111In-, and177Lu-NeoBOMB1 radioligands was studied in PC-3 cells at 37°C, and their metabolic stability in peripheral mouse blood was determined by high-performance liquid chromatography analysis of blood samples. Biodistribution was performed by injecting a67Ga-,111In-, or177Lu-NeoBOMB1 bolus (74, 74, or 370 kBq, respectively, 100 μL, 10 pmol total peptide ± 40 nmol Tyr4-BBN: for in vivo GRPR blockade) in severe combined immunodeficiency mice bearing PC-3 xenografts. PET/CT images with68Ga-NeoBOMB1 were acquired in prostate cancer patients.
  
  
  RESULTS
  NeoBOMB1 andnatGa-,natIn-, andnatLu-NeoBOMB1 bound to GRPR with high affinity (half maximal inhibitory concentration, 1-2 nM).67Ga-,111In-, and177Lu-NeoBOMB1 specifically and strongly bound on the cell membrane of PC-3 cells displaying low internalization, as expected for receptor antagonists. They showed excellent metabolic stability in peripheral mouse blood (>95% intact at 5 min after injection). After injection in mice, all 3 (67Ga-,111In-, and177Lu-NeoBOMB1) showed comparably high and GRPR-specific uptake in the PC-3 xenografts (e.g., 30.6 ± 3.9, 28.6 ± 6.0, and >35 percentage injected dose per gram at 4 h after injection, respectively), clearing from background predominantly via the kidneys. During a translational study in prostate cancer patients,68Ga-NeoBOMB1 rapidly localized in pathologic lesions, achieving high-contrast imaging.
  
  
  CONCLUSIONS
  The GRPR antagonist radioligands67Ga-,111In-, and177Lu-NeoBOMB1, independent of the radiometal applied, have shown comparable behavior in prostate cancer models, in favor of future theranostic use in GRPR-positive cancer patients. Such translational prospects were further supported by the successful visualization of prostate cancer lesions in men using68Ga-NeoBOMB1 and PET/CT.
authors: Molecular Radiopharmacy, INRASTES, National Center for Scientific Research "Demokritos", Athens, Greece nock_berthold.a@hotmail.com.
authors: Berthold A
authors: BA
authors: Nock
authors: Molecular Radiopharmacy, INRASTES, National Center for Scientific Research "Demokritos", Athens, Greece.
authors: Aikaterini
authors: A
authors: Kaloudi
authors: Molecular Radiopharmacy, INRASTES, National Center for Scientific Research "Demokritos", Athens, Greece.
authors: Emmanouil
authors: E
authors: Lymperis
authors: Molecular Radiopharmacy, INRASTES, National Center for Scientific Research "Demokritos", Athens, Greece.
authors: Athina
authors: A
authors: Giarika
authors: Theranostics Center for Molecular Radiotherapy and Molecular Imaging, Zentralklinik, Bad Berka, Germany.
authors: Harshad R
authors: HR
authors: Kulkarni
authors: Theranostics Center for Molecular Radiotherapy and Molecular Imaging, Zentralklinik, Bad Berka, Germany.
authors: Ingo
authors: I
authors: Klette
authors: Theranostics Center for Molecular Radiotherapy and Molecular Imaging, Zentralklinik, Bad Berka, Germany.
authors: Aviral
authors: A
authors: Singh
authors: Department of Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands; and.
authors: Eric P
authors: EP
authors: Krenning
authors: Department of Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands; and.|Department of Radiology, Erasmus MC, Rotterdam, The Netherlands.
authors: Marion
authors: M
authors: de Jong
authors: Molecular Radiopharmacy, INRASTES, National Center for Scientific Research "Demokritos", Athens, Greece.
authors: Theodosia
authors: T
authors: Maina
authors: Theranostics Center for Molecular Radiotherapy and Molecular Imaging, Zentralklinik, Bad Berka, Germany.
authors: Richard P
authors: RP
authors: Baum
mesh_terms: D000818:Animals; D001839:Bombesin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000528:radiation effects; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D010865:Pilot Projects; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000532:radiotherapy*; D011868:Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics / Q000627:therapeutic use; D018004:Receptors, Bombesin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000068936:Theranostic Nanomedicine / Q000379:methods*; D014018:Tissue Distribution; D016896:Treatment Outcome
chemical_list: D011868:Radioisotopes; D019275:Radiopharmaceuticals; D018004:Receptors, Bombesin; D001839:Bombesin
keywords: PET; SPECT; gastrin releasing peptide receptor antagonist; molecular tumor imaging; prostate cancer; radionuclide therapy; theranostic applications