Asymmetric Synthesis of Spirocyclic 2-Benzopyrans for Positron Emission Tomography of σ1 Receptors in the Brain.
Sharpless asymmetric dihydroxylation of styrene derivative 6 afforded chiral triols (R)-7 and (S)-7, which were cyclized with tosyl chloride in the presence of Bu2SnO to provide 2-benzopyrans (R)-4 and (S)-4 with high regioselectivity. The additional hydroxy moiety in the 4-position was exploited for the introduction of various substituents. Williamson ether synthesis and replacement of the Boc protective group with a benzyl moiety led to potent σ1 ligands with high σ1/σ2-selectivity. With exception of the ethoxy derivative 16, the (R)-configured enantiomers represent eutomers with eudismic ratios of up to 29 for the ester (R)-18. The methyl ether (R)-15 represents the most potent σ1 ligand of this series of compounds, with a Ki value of 1.2 nM and an eudismic ratio of 7. Tosylate (R)-21 was used as precursor for the radiosynthesis of [18F]-(R)-20, which was available by nucleophilic substitution with K[18F]F K222 carbonate complex. The radiochemical yield of [18F]-(R)-20 was 18%-20%, the radiochemical purity greater than 97% and the specific radioactivity 175-300 GBq/µmol. Although radiometabolites were detected in plasma, urine and liver samples, radiometabolites were not found in brain samples. After 30 min, the uptake of the radiotracer in the brain was 3.4% of injected dose per gram of tissue and could be reduced by coadministration of the σ1 antagonist haloperidol. [18F]-(R)-20 was able to label those regions of the brain, which were reported to have high density of σ1 receptors.
Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstraße 48, Münster D-48149, Germany.
Katharina
K
Holl
Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstraße 48, Münster D-48149, Germany.
Dirk
D
Schepmann
Helmholtz-Zentrum Dresden-Rossendorf, Institut für Radiopharmazeutische Krebsforschung, Forschungsstelle Leipzig, Abteilung Neuroradiopharmaka, Permoserstraße 15, Leipzig D-04318, Germany.
Steffen
S
Fischer
Helmholtz-Zentrum Dresden-Rossendorf, Institut für Radiopharmazeutische Krebsforschung, Forschungsstelle Leipzig, Abteilung Neuroradiopharmaka, Permoserstraße 15, Leipzig D-04318, Germany.
Friedrich-Alexander
FA
Ludwig
Helmholtz-Zentrum Dresden-Rossendorf, Institut für Radiopharmazeutische Krebsforschung, Forschungsstelle Leipzig, Abteilung Neuroradiopharmaka, Permoserstraße 15, Leipzig D-04318, Germany.
Achim
A
Hiller
Helmholtz-Zentrum Dresden-Rossendorf, Institut für Radiopharmazeutische Krebsforschung, Forschungsstelle Leipzig, Abteilung Neuroradiopharmaka, Permoserstraße 15, Leipzig D-04318, Germany.
Cornelius K
CK
Donat
Helmholtz-Zentrum Dresden-Rossendorf, Institut für Radiopharmazeutische Krebsforschung, Forschungsstelle Leipzig, Abteilung Neuroradiopharmaka, Permoserstraße 15, Leipzig D-04318, Germany.
Winnie
W
Deuther-Conrad
Helmholtz-Zentrum Dresden-Rossendorf, Institut für Radiopharmazeutische Krebsforschung, Forschungsstelle Leipzig, Abteilung Neuroradiopharmaka, Permoserstraße 15, Leipzig D-04318, Germany.
Peter
P
Brust
Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstraße 48, Münster D-48149, Germany. wuensch@uni-muenster.de.
Bernhard
B
Wünsch