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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 (CC BY 3.0).
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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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