title: Preclinical and first clinical experience with the gastrin-releasing peptide receptor-antagonist [⁶⁸Ga]SB3 and PET/CT.
abstract: OBJECTIVE
  Gastrin-releasing peptide receptors (GRPR) represent attractive targets for tumor diagnosis and therapy because of their overexpression in major human cancers. Internalizing GRPR agonists were initially proposed for prolonged lesion retention, but a shift of paradigm to GRPR antagonists has recently been made. Surprisingly, radioantagonists, such as [(99m)Tc]DB1 ((99m)Tc-N4'-DPhe(6),Leu-NHEt(13)]BBN(6-13)), displayed better pharmacokinetics than radioagonists, in addition to their higher inherent biosafety. We introduce here [(68)Ga]SB3, a [(99m)Tc]DB1 mimic-carrying, instead of the (99m)Tc-binding tetraamine, the chelator DOTA for labeling with the PET radiometal (68)Ga.
  
  
  METHODS
  Competition binding assays of SB3 and [(nat)Ga]SB3 were conducted against [(125)I-Tyr(4)]BBN in PC-3 cell membranes. Blood samples collected 5 min postinjection (pi) of the [(67)Ga]SB3 surrogate in mice were analyzed using high-performance liquid chromatography (HPLC) for degradation products. Likewise, biodistribution was performed after injection of [(67)Ga]SB3 (37 kBq, 100 μL, 10 pmol peptide) in severe combined immunodeficiency (SCID) mice bearing PC-3 xenografts. Eventually, [(68)Ga]SB3 (283 ± 91 MBq, 23 ± 7 nmol) was injected into 17 patients with breast (8) and prostate (9) cancer. All patients had disseminated disease and had received previous therapies. PET/CT fusion images were acquired 60-115 min pi.
  
  
  RESULTS
  SB3 and [(nat)Ga]SB3 bound to the human GRPR with high affinity (IC50: 4.6 ± 0.5 nM and 1.5 ± 0.3 nM, respectively). [(67)Ga]SB3 displayed good in vivo stability (>85 % intact at 5 min pi). [(67)Ga]SB3 showed high, GRPR-specific and prolonged retention in PC-3 xenografts (33.1 ± 3.9%ID/g at 1 h pi - 27.0 ± 0.9%ID/g at 24 h pi), but much faster clearance from the GRPR-rich pancreas (≈160%ID/g at 1 h pi to <17%ID/g at 24 h pi) in mice. In patients, [(68)Ga]SB3 elicited no adverse effects and clearly visualized cancer lesions. Thus, 4 out of 8 (50 %) breast cancer and 5 out of 9 (55 %) prostate cancer patients showed pathological uptake on PET/CT with [(68)Ga]SB3.
  
  
  CONCLUSIONS
  [(67)Ga]SB3 showed excellent pharmacokinetics in PC-3 tumor-bearing mice, while [(68)Ga]SB3 PET/CT visualized lesions in about 50 % of patients with advanced and metastasized prostate and breast cancer. We expect imaging with [(68)Ga]SB3 to be superior in patients with primary breast or prostate cancer.
authors.affiliation: Molecular Radiopharmacy, INRASTES, NCSR "Demokritos", Ag. Paraskevi Attikis, 15310, Athens, Greece. maina_thea@hotmail.com.
authors.forename: Theodosia
authors.initials: T
authors.lastname: Maina
authors.affiliation: Department of Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Bergsma
authors.affiliation: Molecular Radiotherapy and Molecular Imaging, Zentralklinik, Bad Berka, Germany.
authors.forename: Harshad R
authors.initials: HR
authors.lastname: Kulkarni
authors.affiliation: Molecular Radiotherapy and Molecular Imaging, Zentralklinik, Bad Berka, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Mueller
authors.affiliation: Molecular Radiopharmacy, INRASTES, NCSR "Demokritos", Ag. Paraskevi Attikis, 15310, Athens, Greece.
authors.forename: David
authors.initials: D
authors.lastname: Charalambidis
authors.affiliation: Department of Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Krenning
authors.affiliation: Molecular Radiopharmacy, INRASTES, NCSR "Demokritos", Ag. Paraskevi Attikis, 15310, Athens, Greece.
authors.forename: Berthold A
authors.initials: BA
authors.lastname: Nock
authors.affiliation: Department of Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands.|Department of Radiology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Marion
authors.initials: M
authors.lastname: de Jong
authors.affiliation: Molecular Radiotherapy and Molecular Imaging, Zentralklinik, Bad Berka, Germany.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Baum
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001839:Bombesin / Q000031:analogs & derivatives*; D001943:Breast Neoplasms / Q000000981:diagnostic imaging*; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000737:chemistry / Q000493:pharmacokinetics*; D005260:Female; D005710:Gallium Radioisotopes; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D009842:Oligopeptides / Q000737:chemistry / Q000493:pharmacokinetics*; D000072078:Positron Emission Tomography Computed Tomography; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging*; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D018004:Receptors, Bombesin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: C000612948:68Ga-SB3; D056831:Coordination Complexes; D005710:Gallium Radioisotopes; D009842:Oligopeptides; D019275:Radiopharmaceuticals; D018004:Receptors, Bombesin; D001839:Bombesin
keywords: 68Ga radiotracer; Breast cancer; Gastrin-releasing peptide receptor antagonist; PET/CT tumor imaging; Prostate cancer