title: Synthesis and evaluation of novel (18)F-labeled spirocyclic piperidine derivatives as σ1 receptor ligands for positron emission tomography imaging.
abstract: A series of spirocyclic piperidine derivatives were designed and synthesized as σ1 receptor ligands. In vitro competition binding assays showed that 1'-(4-(2-fluoroethoxy)benzyl)-3H-spiro[2-benzofuran-1,4'-piperidine] (19) possessed high σ1 receptor affinity (Ki = 0.79 nM) and excellent σ1/σ2 subtype selectivity (350-fold) as well as high σ1/VAChT selectivity (799-fold). The radiolabeled compound [(18)F]19 was synthesized by substitution of the tosylate precursor 24 with [(18)F]fluoride, with an isolated radiochemical yield of 35-60%, a radiochemical purity of >99%, and a specific activity of 30-55 GBq/μmol. Biodistribution studies in imprinting control region mice indicated that [(18)F]19 displayed excellent initial brain uptake and slow washout. Ex vivo autoradiography in Sprague-Dawley rats demonstrated high accumulation of the radiotracer in brain areas known to express high levels of σ1 receptors. Micro positron emission tomography imaging and blocking studies confirmed the specific binding of [(18)F]19 to σ1 receptors in vivo.
authors.affiliation: Key Laboratory of Radiopharmaceuticals Beijing Normal University, Ministry of Education, College of Chemistry, Beijing Normal University , Beijing 100875, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Xia
authors.initials: X
authors.lastname: Wang
authors.forename: Jinming
authors.initials: J
authors.lastname: Zhang
authors.forename: Winnie
authors.initials: W
authors.lastname: Deuther-Conrad
authors.forename: Fang
authors.initials: F
authors.lastname: Xie
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Zhang
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.forename: Jinping
authors.initials: J
authors.lastname: Qiao
authors.forename: Mengchao
authors.initials: M
authors.lastname: Cui
authors.forename: Jörg
authors.initials: J
authors.lastname: Steinbach
authors.forename: Peter
authors.initials: P
authors.lastname: Brust
authors.forename: Boli
authors.initials: B
authors.lastname: Liu
authors.forename: Hongmei
authors.initials: H
authors.lastname: Jia
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D004355:Drug Stability; D005462:Fluorine Radioisotopes; D057927:Hydrophobic and Hydrophilic Interactions; D007553:Isotope Labeling; D008024:Ligands; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D010880:Piperidines / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D051381:Rats; D017480:Receptors, sigma / Q000378:metabolism*; D013141:Spiro Compounds / Q000737:chemistry*
chemical_list: D005462:Fluorine Radioisotopes; D008024:Ligands; D010880:Piperidines; D017480:Receptors, sigma; D013141:Spiro Compounds