Fluorinated PET Tracers for Molecular Imaging of σ1Receptors in the Central Nervous System.
At first the role of σ1receptors in various neurological, psychiatric and neurodegenerative disorders is discussed. In the second part, the principle of positron emission tomography (PET ) is described and the known fluorinated PET tracers for labeling of σ1receptors are presented. The third part focuses on fluoroalkyl substituted spirocyclic PET tracers, which represent the most promising class of fluorinated PET tracers reported so far. The homologous fluoroalkyl derivatives 12-15 show high σ1affinity (Ki= 0.59-1.4 nM) and high selectivity over the σ2subtype (408-1331-fold). The enantiomers of the fluoroethyl derivative fluspidine 13 were prepared and pharmacologically characterized. Whereas the (S)-configured enantiomer (S)-13 (Ki= 2.3 nM) is 4-fold less active than the (R)-enantiomer (R)-13 (Ki= 0.57 nM), (S)-13 is metabolically more stable. The interactions of (S)-13 and (R)-13 with the σ1receptor were analyzed at the molecular level using the 3D homology model. In an automated radiosynthesis [18F](S)-13 and [18F](R)-13 were prepared by nucleophilic substitution of the tosylates (S)-17 and (R)-17 with K[18F]F in high radiochemical yield, high radiochemical purity and short reaction time. Application of both enantiomers [18F](S)-13 and [18F](R)-13 to mice and piglets led to fast uptake into the brain, but [18F](R)-13 did not show washout from the brain indicating a quasi-irreversible binding. Both radiotracers [18F](S)-13 and [18F](R)-13 were able to label regions in the mouse and piglet brain with high σ1receptor density. The specific binding of the enantiomeric tracers [18F](S)-13 and [18F](R)-13 could be replaced by the selective σ1ligand SA4503.
Institute of Pharmaceutical and Medicinal Chemistry, Westfälische Wilhelms-Universität Münster, Corrensstraße 48, D-48149, Münster, Germany.
Frauke
F
Weber
Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Permoserstraße 15, D-04318, Leipzig, Germany.
Peter
P
Brust
Molecular Simulations Engineering (MOSE) Laboratory, Department of Engineering and Architecture (DEA), University of Trieste, Via Valerio 6, 34127, Trieste, Italy.
Erik
E
Laurini
Molecular Simulations Engineering (MOSE) Laboratory, Department of Engineering and Architecture (DEA), University of Trieste, Via Valerio 6, 34127, Trieste, Italy.|National Interuniversity Consortium for Material Science and Technology (INSTM), Research Unit MOSE-DEA, University of Trieste, Via Valerio 6, 32127, Trieste, Italy.
Sabrina
S
Pricl
Institute of Pharmaceutical and Medicinal Chemistry, Westfälische Wilhelms-Universität Münster, Corrensstraße 48, D-48149, Münster, Germany. wuensch@uni-muenster.de.|Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), University Münster, Münster, Germany. wuensch@uni-muenster.de.
Bernhard
B
Wünsch
D000818:Animals; D002490:Central Nervous System / Q000378:metabolism*; D005462:Fluorine Radioisotopes / Q000378:metabolism; D057054:Molecular Imaging / Q000379:methods; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals / Q000378:metabolism; D017480:Receptors, sigma / Q000378:metabolism*; D000097605:Sigma-1 Receptor
D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor
Enantioselective kinetics; Ligand receptor interaction; Neuroimaging; Non-covalent quasi irreversible binding; PET , synthesis; Radiosynthesis; σ1 receptors