title: Evaluation of cobalt-labeled octreotide analogs for molecular imaging and auger electron-based radionuclide therapy.
abstract: The somatostatin receptor, which is overexpressed by many neuroendocrine tumors, is a well-known target for molecular imaging and peptide receptor radionuclide therapy. Recently, (57)Co-labeled DOTATOC, an octreotide analog, was shown to have the highest affinity yet found for somatostatin receptor subtype 2. The aim of this study was to evaluate the biologic effects of novel cobalt-labeled octreotide analogs targeting the somatostatin receptor to identify promising candidates for molecular imaging and Auger electron-based radionuclide therapy.
  
  
  METHODS
  Cobalt-labeled DOTATATE, DOTATOC, and DOTANOC were prepared with (57)Co or (58m)Co for SPECT or Auger electron-based therapy, respectively. The cellular uptake and intracellular distribution of the radioligands were characterized with the pancreatic tumor cell line AR42J in vitro, including assessment of the therapeutic effects of (58m)Co-DOTATATE via DNA double-strand break and proliferation assays. Comparisons with the therapeutic effects of (111)In- and (177)Lu-DOTATATE were also performed. Tumor uptake and normal tissue uptake were characterized in a subcutaneous pancreatic tumor mouse model.
  
  
  RESULTS
  All 3 cobalt-conjugated peptides resulted in time-dependent and receptor-specific uptake, with a high level (≥88%) of cellular internalization in vitro of the total cell-associated radioactivity. The DNA double-strand break yield showed a dose-dependent increase with activity, whereas cell survival showed a dose-dependent decrease. (58m)Co-DOTATATE was significantly more efficient in cell killing per cumulated decay than (111)In- and (177)Lu-DOTATATE. The in vivo pharmacokinetic studies showed a high level of receptor-specific tumor uptake.
  
  
  CONCLUSIONS
  All cobalt-labeled radioligands showed a high level of receptor-specific uptake both in vitro and in vivo in tumor-bearing mice. Furthermore, (58m)Co-DOTATATE showed considerable therapeutic effects in vitro and, thus, could be an effective agent for eradicating disseminated tumor cells and micrometastases.
authors.affiliation: PET & Cyclotron Unit, Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark Institute of Clinical Research, University of Southern Denmark, Odense, Denmark Helge.Thisgaard@rsyd.dk.
authors.forename: Helge
authors.initials: H
authors.lastname: Thisgaard
authors.affiliation: PET & Cyclotron Unit, Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark.
authors.forename: Birgitte Brinkmann
authors.initials: BB
authors.lastname: Olsen
authors.affiliation: PET & Cyclotron Unit, Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark.
authors.forename: Johan Hygum
authors.initials: JH
authors.lastname: Dam
authors.affiliation: Biomedical Laboratory, University of Southern Denmark, Odense, Denmark; and.
authors.forename: Peter
authors.initials: P
authors.lastname: Bollen
authors.affiliation: Lundbeckfonden Center of Excellence NanoCAN and Molecular Oncology Group, Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Jan
authors.initials: J
authors.lastname: Mollenhauer
authors.affiliation: PET & Cyclotron Unit, Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.
authors.forename: Poul Flemming
authors.initials: PF
authors.lastname: Høilund-Carlsen
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000528:radiation effects; D003037:Cobalt Radioisotopes / Q000627:therapeutic use; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D004583:Electrons; D005260:Female; D051379:Mice; D057054:Molecular Imaging / Q000379:methods*; D015282:Octreotide / Q000031:analogs & derivatives / Q000627:therapeutic use*; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology / Q000532:radiotherapy; D011878:Radiotherapy / Q000379:methods*; D051381:Rats; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed
chemical_list: D003037:Cobalt Radioisotopes; D015282:Octreotide
keywords: 177Lu; 58mCo; Auger electrons; DOTATATE; radionuclide therapy