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

Pharmaceuticals

Katharina Holl¹  Dirk Schepmann¹  Steffen Fischer²  Friedrich-Alexander Ludwig²  Achim Hiller²  Cornelius K. Donat²  Winnie Deuther-Conrad²  Peter Brust² 

[1] Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstraße 48, Münster D-48149, Germany;Helmholtz-Zentrum Dresden-Rossendorf, Institut für Radiopharmazeutische Krebsforschung, Forschungsstelle Leipzig, Abteilung Neuroradiopharmaka, Permoserstraße 15, Leipzig D-04318, Germany

关键词: 2-benzopyrans;    Sharpless Asymmetric Dihydroxylation;    spirocycles;    σ affinity;    radiochemistry;    positron emission tomography;    autoradiography;    organ distribution;   

DOI  :  10.3390/ph7010078

来源: mdpi

【 摘 要 】

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 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 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.

【 授权许可】

CC BY   
© 2014 by the authors; licensee MDPI, Basel, Switzerland.