title: In Vivo Evaluation of ¹⁸F-SiFAlin-Modified TATE: A Potential Challenge for ⁶⁸Ga-DOTATATE, the Clinical Gold Standard for Somatostatin Receptor Imaging with PET.
abstract: Radiolabeled peptides for tumor imaging with PET that can be produced with kits are currently in the spotlight of radiopharmacy and nuclear medicine. The diagnosis of neuroendocrine tumors in particular has been a prime example for the usefulness of peptides labeled with a variety of different radionuclides. Among those, (68)Ga and (18)F stand out because of the ease of radionuclide introduction (e.g., (68)Ga isotope) or optimal nuclide properties for PET imaging (slightly favoring the (18)F isotope). The in vivo properties of good manufacturing practice-compliant, newly developed kitlike-producible (18)F-SiFA- and (18)F-SiFAlin- (SiFA = silicon-fluoride acceptor) modified TATE derivatives were compared with the current clinical gold standard (68)Ga-DOTATATE for high-quality imaging of somatostatin receptor-bearing tumors.
  
  
  METHODS
  SiFA- and SiFAlin-derivatized somatostatin analogs were synthesized and radiolabeled using cartridge-based dried (18)F and purified via a C18 cartridge (radiochemical yield 49.8% ± 5.9% within 20-25 min) without high-performance liquid chromatography purification. Tracer lipophilicity and stability in human serum were tested in vitro. Competitive receptor binding affinity studies were performed using AR42J cells. The most promising tracers were evaluated in vivo in an AR42J xenograft mouse model by ex vivo biodistribution and in vivo PET/CT imaging studies for evaluation of their pharmacokinetic profiles, and the results were compared with those of the current clinical gold standard (68)Ga-DOTATATE.
  
  
  RESULTS
  Synthetically easily accessible (18)F-labeled silicon-fluoride acceptor-modified somatostatin analogs were developed. They exhibited high binding affinities to somatostatin receptor-positive tumor cells (1.88-14.82 nM). The most potent compound demonstrated comparable pharmacokinetics and an even slightly higher absolute tumor accumulation level in ex vivo biodistribution studies as well as higher tumor standardized uptake values in PET/CT imaging than (68)Ga-DOTATATE in vivo. The radioactivity uptake in nontumor tissue was higher than for (68)Ga-DOTATATE.
  
  
  CONCLUSIONS
  The introduction of the novel SiFA building block SiFAlin and of hydrophilic auxiliaries enables a favorable in vivo biodistribution profile of the modified TATE peptides, resulting in high tumor-to-background ratios although lower than those observed with (68)Ga-DOTATATE. As further advantage, the SiFA methodology enables a kitlike labeling procedure for (18)F-labeled peptides advantageous for routine clinical application.
authors.affiliation: Division of Molecular Imaging and Radiochemistry, Department of Clinical Radiology and Nuclear Medicine, Medical Faculty Mannheim of Heidelberg University, Mannheim, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Niedermoser
authors.affiliation: McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Canada.
authors.forename: Joshua
authors.initials: J
authors.lastname: Chin
authors.affiliation: Division of Biomedical Chemistry, Department of Clinical Radiology and Nuclear Medicine, Medical Faculty Mannheim of Heidelberg University, Mannheim, Germany schirrma@ualberta.ca Bjoern.Waengler@medma.uni-heidelberg.de.
authors.forename: Carmen
authors.initials: C
authors.lastname: Wängler
authors.affiliation: McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Canada.
authors.forename: Alexey
authors.initials: A
authors.lastname: Kostikov
authors.affiliation: McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Canada Division of Oncological Imaging, Department of Oncology, University of Alberta, Edmonton, AB, Canada.
authors.forename: Vadim
authors.initials: V
authors.lastname: Bernard-Gauthier
authors.affiliation: Division of Nuclear Medicine, Department of Clinical Radiology and Nuclear Medicine, Medical Faculty Mannheim of Heidelberg University, Mannheim, Germany; and.
authors.forename: Nils
authors.initials: N
authors.lastname: Vogler
authors.affiliation: McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Canada Concordia-PERFORM Centre, Concordia University, Montreal, Canada.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Soucy
authors.affiliation: Division of Oncological Imaging, Department of Oncology, University of Alberta, Edmonton, AB, Canada.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: McEwan
authors.affiliation: McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Canada Division of Oncological Imaging, Department of Oncology, University of Alberta, Edmonton, AB, Canada.
authors.forename: Ralf
authors.initials: R
authors.lastname: Schirrmacher
authors.affiliation: Division of Molecular Imaging and Radiochemistry, Department of Clinical Radiology and Nuclear Medicine, Medical Faculty Mannheim of Heidelberg University, Mannheim, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Wängler
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D003952:Diagnostic Imaging; D005459:Fluorides / Q000737:chemistry; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D005710:Gallium Radioisotopes / Q000737:chemistry*; D051379:Mice; D009368:Neoplasm Transplantation; D018358:Neuroendocrine Tumors / Q000000981:diagnostic imaging; D015282:Octreotide / Q000031:analogs & derivatives; D009942:Organometallic Compounds / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000737:chemistry; D051381:Rats; D017481:Receptors, Somatostatin / Q000737:chemistry*; D012825:Silicon / Q000737:chemistry; D014018:Tissue Distribution; D014057:Tomography, X-Ray Computed
chemical_list: D005462:Fluorine Radioisotopes; D005710:Gallium Radioisotopes; D009942:Organometallic Compounds; D010455:Peptides; D019275:Radiopharmaceuticals; D017481:Receptors, Somatostatin; C513399:gallium Ga 68 dotatate; D005459:Fluorides; D015282:Octreotide; D012825:Silicon
keywords: 18F-SiFAlin-TATE; 68Ga-DOTATATE; PET; kitlike 18F labeling; somatostatin receptor imaging