title: Synthesis and evaluation of a 18F-labeled spirocyclic piperidine derivative as promising σ1 receptor imaging agent.
abstract: Several spirocyclic piperidine derivatives were designed and synthesized as σ1 receptor ligands. In vitro competition binding assays showed that the fluoroalkoxy analogues with small substituents possessed high affinity towards σ1 receptors and subtype selectivity. Particularly for ligand 1'-((6-(2-fluoroethoxy)pyridin-3-yl)methyl)-3H-spiro[2-benzofuran-1,4'-piperidine] (2), high σ1 receptor affinity (Ki=2.30 nM) and high σ1/σ2 subtype selectivity (142-fold) as well as high σ1/VAChT selectivity (234-fold) were observed. [18F]2 was synthesized using an efficient one-pot, two-step reaction method in a home-made automated synthesis module, with an overall isolated radiochemical yield of 8-10%, a radiochemical purity of higher than 99%, and specific activity of 56-78GBq/μmol. Biodistribution studies of [18F]2 in ICR mice indicated high initial brain uptake and a relatively fast washout. Administration of haloperidol, compound 1 and different concentrations of SA4503 (3, 5, or 10 μmol/kg) 5 min prior to injection of [18F]2 significantly decreased the accumulation of radiotracer in organs known to contain σ1 receptors. Ex vivo autoradiography in Sprague-Dawley rats demonstrated high accumulation of radiotracer in brain areas with high expression of σ1 receptors. These encouraging results prove that [18F]2 is a suitable candidate for σ1 receptor imaging with PET in humans.
authors.affiliation: Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Chen
authors.affiliation: Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Wang
authors.affiliation: Nuclear Medicine Department, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Jin-Ming
authors.initials: JM
authors.lastname: Zhang
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, 04318 Leipzig, Germany.
authors.forename: Winnie
authors.initials: W
authors.lastname: Deuther-Conrad
authors.affiliation: Nuclear Medicine Department, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Zhang
authors.affiliation: PET Center, Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China.
authors.forename: Jia-Jun
authors.initials: JJ
authors.lastname: Ye
authors.affiliation: Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China.
authors.forename: Meng-Chao
authors.initials: MC
authors.lastname: Cui
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, 04318 Leipzig, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Steinbach
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, 04318 Leipzig, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Brust
authors.affiliation: Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China.
authors.forename: Bo-Li
authors.initials: BL
authors.lastname: Liu
authors.affiliation: Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China. Electronic address: hmjia@bnu.edu.cn.
authors.forename: Hong-Mei
authors.initials: HM
authors.lastname: Jia
mesh_terms: D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D005462:Fluorine Radioisotopes / Q000737:chemistry; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D057054:Molecular Imaging; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis* / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000032:analysis* / Q000378:metabolism*; D013141:Spiro Compounds / Q000737:chemistry*
chemical_list: D005462:Fluorine Radioisotopes; D010880:Piperidines; D019275:Radiopharmaceuticals; D017480:Receptors, sigma; D013141:Spiro Compounds
keywords: (18)F; Imaging agent; PET; Sigma-1 receptors; Spirocyclic piperidine derivatives