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 Bu
2SnO to provide 2-benzopyrans
(R)-4 and
(S)-4 with high
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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 Bu
2SnO 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 σ
1 ligands with high σ
1/σ
2-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 σ
1 ligand of this series of compounds, with a K
i 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 σ
1 antagonist haloperidol. [
18F]-
(R)-
20 was able to label those regions of the brain, which were reported to have high density of σ
1 receptors.
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