title: Radiosynthesis and Preclinical Evaluation of18F-Fluoroglycosylated Octreotate for Somatostatin Receptor Imaging.
abstract: Short synthetic octapeptide analogs derived from the native somatostatin peptides SST-14 and SST-28, namely, octreotate (TATE) or octreotide (TOC), bind with high affinity to somatostatin receptors (sstr), mainly to subtypes 2 and 5, which are expressed in high density on neuroendocrine tumors (NET). Therefore, radiolabeled TATE or TOC derivatives represent highly valuable imaging probes for NET diagnosis by positron emission tomography (PET). The aim of our study was the development of an18F-labeled octreotate analog as an alternative radiotracer for the clinically established68Ga-DOTATOC and68Ga-DOTATATE. We applied our previously developed method based on copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) to the radiosynthesis of18F-fluoroglycosylated TATE ([18F]FGlc-TATE). [18F]FGlc-TATE was obtained in high yields of 19-22% (non-decay-corrected, referred to [18F]fluoride) and in high specific activities of 32-106 GBq/μmol. [18F]FGlc-TATE showed high affinity to sstr expressed on AR42J cells (IC50= 4.2 nM) with fast and high internalization, and a beneficial logD7.4of -1.8. In AR42J tumor bearing nude mice, [18F]FGlc-TATE showed high and specific tumor uptake of 5.6%ID/g at 60 min post-injection, as determined by blocking experiments using octreotide, and fast clearance from other organs, resulting in excellent tumor-to-blood ratios increasing from 9 to 17 from 30 to 60 min post-injection. Small animal PET studies revealed high uptake of [18F]FGlc-TATE in the tumor which could be blocked with octreotide by >99%. Overall, [18F]FGlc-TATE revealed excellent in vitro and in vivo properties and is therefore a viable alternative18F-labeled radiopeptide for imaging somatostatin receptor-positive tumors by PET.
authors.affiliation: Molecular Imaging and Radiochemistry, Department of Nuclear Medicine, Friedrich Alexander University Erlangen-Nürnberg (FAU) , Schwabachanlage 6, 91054 Erlangen, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Maschauer
authors.affiliation: Molecular Imaging and Radiochemistry, Department of Nuclear Medicine, Friedrich Alexander University Erlangen-Nürnberg (FAU) , Schwabachanlage 6, 91054 Erlangen, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Heilmann
authors.affiliation: Biomedical Chemistry, Department of Clinical Radiology and Nuclear Medicine Medical Faculty Mannheim of Heidelberg University , Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.
authors.forename: Carmen
authors.initials: C
authors.lastname: Wängler
authors.affiliation: Medical Isotope Cyclotron Facility, Department of Oncology, University of Alberta , 11560 University Avenue, Edmonton, Alberta T6G 1Z2, Canada.
authors.forename: Ralf
authors.initials: R
authors.lastname: Schirrmacher
authors.affiliation: Molecular Imaging and Radiochemistry, Department of Nuclear Medicine, Friedrich Alexander University Erlangen-Nürnberg (FAU) , Schwabachanlage 6, 91054 Erlangen, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Prante
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D005462:Fluorine Radioisotopes; D006031:Glycosylation; D006801:Humans; D008297:Male; D051379:Mice; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D011854:Radiochemistry; D017481:Receptors, Somatostatin / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D005462:Fluorine Radioisotopes; D010456:Peptides, Cyclic; D017481:Receptors, Somatostatin