title: Distinctive in vivo kinetics of the new σ1 receptor ligands (R)-(+)- and (S)-(-)-18F-fluspidine in porcine brain.
abstract: Because of their involvement in growth and survival signaling cascades, the σ(1) receptors (σ(1)Rs) represent a novel target for the treatment of cancer and several brain diseases such as depression and neurodegeneration. From a series of σ1R-specific (18)F-fluoroalkylated spirocyclic piperidines, we have chosen (18)F-fluspidine for detailed investigation of the in vivo kinetics of the (R)-(+)- and (S)-(-)-enantiomers to identify their potential for imaging in humans.
  
  
  METHODS
  Enantiopure tosylate precursors for radiolabeling were obtained using chiral preparative high-performance liquid chromatography and used for radiosynthesis of both (18)F-fluspidine enantiomers by nucleophilic substitution with K-(18)F-F-Kryptofix 222-carbonate complex in a synthesis module. Brain pharmacokinetics were investigated by dynamic PET studies in piglets under baseline and blocking conditions using the highly selective σ1R agonist SA4503. Standardized uptake values (SUVs) were calculated for 24 MR-defined brain regions. Total distribution volume (V(T)) and binding potentials (k3'/k4) of (S)-(-)- and (R)-(+)-(18)F-fluspidine were estimated. Furthermore, V(T) values were estimated by graphical analysis using Logan plots.
  
  
  RESULTS
  The (S)- and (R)-tosylates were obtained in excellent enantiomeric purities (>98% and >96% enantiomeric excess, respectively). (S)-(-)- and (R)-(+)-(18)F-fluspidine were synthesized within approximately 70 min (radiochemical yield, 35%-45%; specific activity, 650-870 GBq/μmol; radiochemical purity, >99%). Both radiotracers displayed different brain uptake kinetics. Although the initial brain uptake was similar, the SUV at the end of the study differed significantly (P < 0.05), with (R)-(+)-(18)F-fluspidine showing about 60%-150% higher values. Administration of SA4503 reduced SUV almost equally for both radiotracers by approximately 65%. Furthermore, k(3)' was significantly decreased under blocking conditions in almost all regions ((S)-(-)-(18)F-fluspidine, -90%-95%; (R)-(+)-(18)F-fluspidine, -70%-90%) whereas effects on k(4) differed according to the particular brain region. V(T) estimated by both graphical analysis using Logan plots and full nonlinear kinetic analysis revealed significant inhibition for both radiotracers under blocking conditions.
  
  
  CONCLUSIONS
  Both (S)-(-)- and (R)-(+)-(18)F-fluspidine appear to be suitable for σ1R imaging in humans. The different pharmacokinetics of (S)-(-)-(18)F-fluspidine and (R)-(+)-(18)F-fluspidine may have the potential for application in the diagnostics of different pathologic conditions.
authors: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Leipzig, Germany p.brust@hzdr.de.
authors: Peter
authors: P
authors: Brust
authors: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Leipzig, Germany.
authors: Winnie
authors: W
authors: Deuther-Conrad
authors: Department of Nuclear Medicine and IFB Adiposity Diseases, Universität Leipzig, Leipzig, Germany.
authors: Georg
authors: G
authors: Becker
authors: Department of Nuclear Medicine and IFB Adiposity Diseases, Universität Leipzig, Leipzig, Germany.
authors: Marianne
authors: M
authors: Patt
authors: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Leipzig, Germany.
authors: Cornelius K
authors: CK
authors: Donat
authors: Department of Chemistry, University of Missouri, Columbia, Missouri.
authors: Shannon
authors: S
authors: Stittsworth
authors: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Leipzig, Germany.
authors: Steffen
authors: S
authors: Fischer
authors: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Leipzig, Germany.
authors: Achim
authors: A
authors: Hiller
authors: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Leipzig, Germany.
authors: Barbara
authors: B
authors: Wenzel
authors: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Leipzig, Germany.
authors: Sladjana
authors: S
authors: Dukic-Stefanovic
authors: Department of Nuclear Medicine and IFB Adiposity Diseases, Universität Leipzig, Leipzig, Germany.
authors: Swen
authors: S
authors: Hesse
authors: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Leipzig, Germany.
authors: Jörg
authors: J
authors: Steinbach
authors: Department of Pharmaceutical and Medicinal Chemistry, Westfälische Wilhelms-Universität Münster, Münster, Germany; and.
authors: Bernhard
authors: B
authors: Wünsch
authors: Department of Chemistry, University of Missouri, Columbia, Missouri MU Research Reactor, University of Missouri, Columbia, Missouri.
authors: Susan Z
authors: SZ
authors: Lever
authors: Department of Nuclear Medicine and IFB Adiposity Diseases, Universität Leipzig, Leipzig, Germany.
authors: Osama
authors: O
authors: Sabri
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000493:pharmacokinetics*; D001921:Brain / Q000000981:diagnostic imaging*; D002851:Chromatography, High Pressure Liquid; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D007700:Kinetics; D008024:Ligands; D010880:Piperidines / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography / Q000379:methods; D017480:Receptors, sigma / Q000737:chemistry*; D013237:Stereoisomerism; D013552:Swine; D013997:Time Factors
chemical_list: C558383:1'-benzyl-3-(2-fluoroethyl)-3H-spiro((2)benzofuran-1,4'-piperidine); D001572:Benzofurans; D005462:Fluorine Radioisotopes; D008024:Ligands; D010880:Piperidines; D017480:Receptors, sigma
keywords: cancer; depression; positron emission tomography; sigma receptor; steroids