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Pharmaceuticals 2014, 7(1), 78-112; doi:10.3390/ph7010078
Article

Asymmetric Synthesis of Spirocyclic 2-Benzopyrans for Positron Emission Tomography of σ1 Receptors in the Brain

1, 1, 2, 2, 2, 2, 2, 2 and 1,*
1 Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstraße 48, Münster D-48149, Germany 2 Helmholtz-Zentrum Dresden-Rossendorf, Institut für Radiopharmazeutische Krebsforschung, Forschungsstelle Leipzig, Abteilung Neuroradiopharmaka, Permoserstraße 15, Leipzig D-04318, Germany
* Author to whom correspondence should be addressed.
Received: 17 December 2013 / Revised: 15 January 2014 / Accepted: 16 January 2014 / Published: 22 January 2014
(This article belongs to the Special Issue Radiopharmaceutical Chemistry between Imaging and Radioendotherapy)
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Abstract

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 σ12-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.
Keywords: 2-benzopyrans; Sharpless Asymmetric Dihydroxylation; spirocycles; σ affinity; radiochemistry; positron emission tomography; autoradiography; organ distribution 2-benzopyrans; Sharpless Asymmetric Dihydroxylation; spirocycles; σ affinity; radiochemistry; positron emission tomography; autoradiography; organ distribution
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Holl, K.; Schepmann, D.; Fischer, S.; Ludwig, F.-A.; Hiller, A.; Donat, C.K.; Deuther-Conrad, W.; Brust, P.; Wünsch, B. Asymmetric Synthesis of Spirocyclic 2-Benzopyrans for Positron Emission Tomography of σ1 Receptors in the Brain. Pharmaceuticals 2014, 7, 78-112.

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