title: (18)F-Labeled 1,4-Dioxa-8-azaspiro[4.5]decane Derivative: Synthesis and Biological Evaluation of a σ1 Receptor Radioligand with Low Lipophilicity as Potent Tumor Imaging Agent.
abstract: We report the syntheses and evaluation of series of novel piperidine compounds with low lipophilicity as σ1 receptor ligands. 8-(4-(2-Fluoroethoxy)benzyl)-1,4-dioxa-8-azaspiro[4.5]decane (5a) possessed high affinity (K(i) = 5.4 ± 0.4 nM) for σ1 receptors and selectivity for σ2 receptors (30-fold) and the vesicular acetylcholine transporter (1404-fold). [(18)F]5a was prepared using a one-pot, two-step labeling procedure in an automated synthesis module, with a radiochemical purity of >95%, and a specific activity of 25-45 GBq/μmol. Cellular association, biodistribution, and autoradiography with blocking experiments indicated specific binding of [(18)F]5a to σ1 receptors in vitro and in vivo. Small animal positron emission tomography (PET) imaging using mouse tumor xenograft models demonstrated a high accumulation in human carcinoma and melanoma. Treatment with haloperidol significantly reduced the accumulation of the radiotracer in tumors. These findings suggest that radiotracer with suitable lipophilicity and appropriate affinity for σ1 receptors could be used for tumor imaging.
authors.affiliation: †Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, POB 510119, D-01314 Dresden, Germany.|‡Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Xie
authors.affiliation: †Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, POB 510119, D-01314 Dresden, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Bergmann
authors.affiliation: †Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, POB 510119, D-01314 Dresden, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Kniess
authors.affiliation: †Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, POB 510119, D-01314 Dresden, Germany.
authors.forename: Winnie
authors.initials: W
authors.lastname: Deuther-Conrad
authors.affiliation: †Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, POB 510119, D-01314 Dresden, Germany.|§Technische Universität Dresden, Department of Chemistry and Food Chemistry, D-01062 Dresden, Germany.
authors.forename: Constantin
authors.initials: C
authors.lastname: Mamat
authors.affiliation: †Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, POB 510119, D-01314 Dresden, Germany.
authors.forename: Christin
authors.initials: C
authors.lastname: Neuber
authors.affiliation: ‡Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China.
authors.forename: Boli
authors.initials: B
authors.lastname: Liu
authors.affiliation: †Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, POB 510119, D-01314 Dresden, Germany.|§Technische Universität Dresden, Department of Chemistry and Food Chemistry, D-01062 Dresden, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Steinbach
authors.affiliation: †Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, POB 510119, D-01314 Dresden, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Brust
authors.affiliation: †Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, POB 510119, D-01314 Dresden, Germany.|§Technische Universität Dresden, Department of Chemistry and Food Chemistry, D-01062 Dresden, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Pietzsch
authors.affiliation: ‡Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Jia
mesh_terms: D000473:Alkanes / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D001692:Biological Transport; D001921:Brain / Q000000981:diagnostic imaging; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D004355:Drug Stability; D005260:Female; D005462:Fluorine Radioisotopes; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000473:pathology; D049268:Positron-Emission Tomography / Q000379:methods*; D011854:Radiochemistry; D051381:Rats; D013141:Spiro Compounds / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: C000601953:8-(4-(2-fluoroethoxy)benzyl)-1,4-dioxa-8-azaspiro(4.5)decane; D000473:Alkanes; D005462:Fluorine Radioisotopes; D008024:Ligands; D013141:Spiro Compounds; C012867:decane