title: Improved radiosynthesis and preliminary in vivo evaluation of a (18)F-labeled glycopeptide-peptoid hybrid for PET imaging of neurotensin receptor 2.
abstract: The neurotensin receptor 2 (NTS2) is an attractive target for cancer imaging, as it is overexpressed in a variety of tumor types including prostate, pancreas and breast carcinoma. The aim of this study was the development of the first NTS2 subtype selective (18)F-labeled radioligand for imaging NTS2 expression in vivo by positron emission tomography (PET). The radiosynthesis of glycopeptoid (18)F-4 was realized by copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC), applying the prosthetic group 6-deoxy-6-[(18)F]fluoroglucosyl azide for (18)F-fluoroglycosylation of the alkyne-terminated NT(8-13) analog Pra-N-Me-Arg-Arg-Pro-N-homo-Tyr-Ile-Leu-OH. The binding affinity of the peptide-peptoid 4 for NTS2 was 7nM with excellent subtype selectivity over NTS1 (260-fold). In vitro autoradiography studies of rat brain slices confirmed the high selectivity of (18)F-4 for NTS2. Biodistribution experiments using HT29 and PC3 tumor-bearing nude mice revealed high renal and only moderate tumor uptake, while PET imaging experiments revealed specific binding of (18)F-4 in NTS2-positive tumors. As (18)F-4 displayed high stability in vitro but fast degradation in vivo, future work will focus on the development of metabolically more stable NT(8-13) analogs.
authors.affiliation: Department of Nuclear Medicine, Molecular Imaging and Radiochemistry, Friedrich Alexander University Erlangen-Nürnberg (FAU), Schwabachanlage 6, D-91054 Erlangen, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Maschauer
authors.affiliation: Department of Chemistry and Pharmacy, Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University Erlangen-Nürnberg (FAU), Schuhstraße 19, 91052 Erlangen, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Greff
authors.affiliation: Department of Chemistry and Pharmacy, Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University Erlangen-Nürnberg (FAU), Schuhstraße 19, 91052 Erlangen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Einsiedel
authors.affiliation: Department of Nuclear Medicine, Molecular Imaging and Radiochemistry, Friedrich Alexander University Erlangen-Nürnberg (FAU), Schwabachanlage 6, D-91054 Erlangen, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Ott
authors.affiliation: Department of Nuclear Medicine, Molecular Imaging and Radiochemistry, Friedrich Alexander University Erlangen-Nürnberg (FAU), Schwabachanlage 6, D-91054 Erlangen, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Tripal
authors.affiliation: Department of Chemistry and Pharmacy, Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University Erlangen-Nürnberg (FAU), Schuhstraße 19, 91052 Erlangen, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Hübner
authors.affiliation: Department of Chemistry and Pharmacy, Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University Erlangen-Nürnberg (FAU), Schuhstraße 19, 91052 Erlangen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Gmeiner
authors.affiliation: Department of Nuclear Medicine, Molecular Imaging and Radiochemistry, Friedrich Alexander University Erlangen-Nürnberg (FAU), Schwabachanlage 6, D-91054 Erlangen, Germany. Electronic address: olaf.prante@uk-erlangen.de.
authors.forename: Olaf
authors.initials: O
authors.lastname: Prante
mesh_terms: D000818:Animals; D001345:Autoradiography; D060326:Chemistry Techniques, Synthetic; D004355:Drug Stability; D005260:Female; D005462:Fluorine Radioisotopes; D006020:Glycopeptides / Q000737:chemistry; D019073:HT29 Cells; D006801:Humans; D007553:Isotope Labeling; D008819:Mice, Nude; D034444:Peptoids / Q000737:chemistry*; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics*; D018028:Receptors, Neurotensin / Q000032:analysis* / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D005462:Fluorine Radioisotopes; D006020:Glycopeptides; C490985:NTSR2 protein, human; D034444:Peptoids; D019275:Radiopharmaceuticals; D018028:Receptors, Neurotensin
keywords: Cancer imaging; Fluorine-18; Neurotensin; Neurotensin receptor 2; PET; Peptoid; Positron emission tomography