title: Synthesis, radiofluorination and pharmacological evaluation of a fluoromethyl spirocyclic PET tracer for central σ1 receptors and comparison with fluoroalkyl homologs.
abstract: The spirocyclic σ(1) receptor ligand 1 (1'-benzyl-3-(fluoromethyl)-3H-spiro[[2]benzofuran-1,4'-piperidine]) was prepared in four steps starting from methoxy derivative 5. Due to its high σ(1) affinity (K(i)=0.74nM) and selectivity against several other relevant targets, 1 was investigated as (18)F-labeled PET tracer and its biological properties were compared with those of homologous fluoroalkyl derivatives 2-4. The fluoromethyl derivative 1 was faster metabolized in vitro than homologs 2-4. In contrast to the radiosynthesis of [(18)F]2-4, the nucleophilic substitution of the tosylate 15 using the K[(18)F]F-K(222)-carbonate complex required heating to 150°C in DMSO to achieve high labeling efficiencies. Whereas radiometabolites of [(18)F]2-4 were not detected in vivo in the brain of mice, two radiometabolites of [(18)F]1 were found. Analysis of ex vivo autoradiography images provided rather low target-to-nontarget ratio for [(18)F]1 compared with [(18)F]2-4. [(18)F]1 showed a fast uptake in the brain, which decreased continuously over time. The brain-to-plasma ratio of the radiotracer [(18)F]1 was only exceeded by the fluoroethyl tracer [(18)F]2.
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig, Institute of Radiopharmacy, Division of Neuroradiopharmaceuticals, Permoserstraße-15, D-04318 Leipzig, Germany.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Maisonial
authors.forename: Eva
authors.initials: E
authors.lastname: Grosse Maestrup
authors.forename: Christian
authors.initials: C
authors.lastname: Wiese
authors.forename: Achim
authors.initials: A
authors.lastname: Hiller
authors.forename: Dirk
authors.initials: D
authors.lastname: Schepmann
authors.forename: Steffen
authors.initials: S
authors.lastname: Fischer
authors.forename: Winnie
authors.initials: W
authors.lastname: Deuther-Conrad
authors.forename: Jörg
authors.initials: J
authors.lastname: Steinbach
authors.forename: Peter
authors.initials: P
authors.lastname: Brust
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging; D005462:Fluorine Radioisotopes / Q000737:chemistry; D007553:Isotope Labeling; D008024:Ligands; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051381:Rats; D017480:Receptors, sigma / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D005462:Fluorine Radioisotopes; D008024:Ligands; D019275:Radiopharmaceuticals; D017480:Receptors, sigma; D013141:Spiro Compounds