[<sup>18</sup>F]Fluspidine—A PET Tracer for Imaging of σ<sub>1</sub> Receptors in the Central Nervous System
σ<sub>1</sub> receptors play a crucial role in various neurological and neurodegenerative diseases including pain, psychosis, Alzheimer’s disease, and depression. Spirocyclic piperidines represent a promising class of potent σ<sub>1</sub> receptor ligands. The relationship be...
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| Format: | Article |
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MDPI AG
2024-01-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/17/2/166 |
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| author | Friedrich-Alexander Ludwig Erik Laurini Judith Schmidt Sabrina Pricl Winnie Deuther-Conrad Bernhard Wünsch |
| author_facet | Friedrich-Alexander Ludwig Erik Laurini Judith Schmidt Sabrina Pricl Winnie Deuther-Conrad Bernhard Wünsch |
| author_sort | Friedrich-Alexander Ludwig |
| collection | DOAJ |
| description | σ<sub>1</sub> receptors play a crucial role in various neurological and neurodegenerative diseases including pain, psychosis, Alzheimer’s disease, and depression. Spirocyclic piperidines represent a promising class of potent σ<sub>1</sub> receptor ligands. The relationship between structural modifications and σ<sub>1</sub> receptor affinity and selectivity over σ<sub>2</sub> receptors led to the 2-fluoroethyl derivative fluspidine (<b>2</b>, <i>K</i><sub>i</sub> = 0.59 nM). Enantiomerically pure (<i>S</i>)-configured fluspidine ((<i>S</i>)-<b>2</b>) was prepared by the enantioselective reduction of the α,β-unsaturated ester <b>23</b> with NaBH<sub>4</sub> and the enantiomerically pure co-catalyst (<i>S</i>,<i>S</i>)-<b>24</b>. The pharmacokinetic properties of both fluspidine enantiomers (<i>R</i>)-<b>2</b> and (<i>S</i>)-<b>2</b> were analyzed in vitro. Molecular dynamics simulations revealed very similar interactions of both fluspidine enantiomers with the σ<sub>1</sub> receptor protein, with a strong ionic interaction between the protonated amino moiety of the piperidine ring and the COO<sup>-</sup> moiety of glutamate 172. The <sup>18</sup>F-labeled radiotracers (<i>S</i>)-[<sup>18</sup>F]<b>2</b> and (<i>R</i>)-[<sup>18</sup>F]<b>2</b> were synthesized in automated syntheses using a TRACERlab FX FN synthesis module. High radiochemical yields and radiochemical purity were achieved. Radiometabolites were not found in the brains of mice, piglets, and rhesus monkeys. While both enantiomers revealed similar initial brain uptake, the slow washout of (<i>R</i>)-[<sup>18</sup>F]<b>2</b> indicated a kind of irreversible binding. In the first clinical trial, (<i>S</i>)-[<sup>18</sup>F]<b>2</b> was used to visualize σ<sub>1</sub> receptors in the brains of patients with major depressive disorder (MDD). This study revealed an increased density of σ<sub>1</sub> receptors in cortico-striato-(para)limbic brain regions of MDD patients. The increased density of σ<sub>1</sub> receptors correlated with the severity of the depressive symptoms. In an occupancy study with the PET tracer (<i>S</i>)-[<sup>18</sup>F]<b>2</b>, the selective binding of pridopidine at σ<sub>1</sub> receptors in the brain of healthy volunteers and HD patients was shown. |
| first_indexed | 2024-03-07T22:17:33Z |
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| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-07T22:17:33Z |
| publishDate | 2024-01-01 |
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| spelling | doaj.art-0a3bc1da7d3848428725bd959f3c6d572024-02-23T15:30:33ZengMDPI AGPharmaceuticals1424-82472024-01-0117216610.3390/ph17020166[<sup>18</sup>F]Fluspidine—A PET Tracer for Imaging of σ<sub>1</sub> Receptors in the Central Nervous SystemFriedrich-Alexander Ludwig0Erik Laurini1Judith Schmidt2Sabrina Pricl3Winnie Deuther-Conrad4Bernhard Wünsch5Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Helmholtz-Zentrum Dresden-Rossendorf, D-04318 Leipzig, GermanyMolecular Biology and Nanotechnology Laboratory (MolBNL@UniTS), DEA, University of Trieste, 34127 Trieste, ItalyInstitut für Pharmazeutische und Medizinische Chemie, Universität Münster, Corrensstraße 48, D-48149 Münster, GermanyMolecular Biology and Nanotechnology Laboratory (MolBNL@UniTS), DEA, University of Trieste, 34127 Trieste, ItalyInstitute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Helmholtz-Zentrum Dresden-Rossendorf, D-04318 Leipzig, GermanyInstitut für Pharmazeutische und Medizinische Chemie, Universität Münster, Corrensstraße 48, D-48149 Münster, Germanyσ<sub>1</sub> receptors play a crucial role in various neurological and neurodegenerative diseases including pain, psychosis, Alzheimer’s disease, and depression. Spirocyclic piperidines represent a promising class of potent σ<sub>1</sub> receptor ligands. The relationship between structural modifications and σ<sub>1</sub> receptor affinity and selectivity over σ<sub>2</sub> receptors led to the 2-fluoroethyl derivative fluspidine (<b>2</b>, <i>K</i><sub>i</sub> = 0.59 nM). Enantiomerically pure (<i>S</i>)-configured fluspidine ((<i>S</i>)-<b>2</b>) was prepared by the enantioselective reduction of the α,β-unsaturated ester <b>23</b> with NaBH<sub>4</sub> and the enantiomerically pure co-catalyst (<i>S</i>,<i>S</i>)-<b>24</b>. The pharmacokinetic properties of both fluspidine enantiomers (<i>R</i>)-<b>2</b> and (<i>S</i>)-<b>2</b> were analyzed in vitro. Molecular dynamics simulations revealed very similar interactions of both fluspidine enantiomers with the σ<sub>1</sub> receptor protein, with a strong ionic interaction between the protonated amino moiety of the piperidine ring and the COO<sup>-</sup> moiety of glutamate 172. The <sup>18</sup>F-labeled radiotracers (<i>S</i>)-[<sup>18</sup>F]<b>2</b> and (<i>R</i>)-[<sup>18</sup>F]<b>2</b> were synthesized in automated syntheses using a TRACERlab FX FN synthesis module. High radiochemical yields and radiochemical purity were achieved. Radiometabolites were not found in the brains of mice, piglets, and rhesus monkeys. While both enantiomers revealed similar initial brain uptake, the slow washout of (<i>R</i>)-[<sup>18</sup>F]<b>2</b> indicated a kind of irreversible binding. In the first clinical trial, (<i>S</i>)-[<sup>18</sup>F]<b>2</b> was used to visualize σ<sub>1</sub> receptors in the brains of patients with major depressive disorder (MDD). This study revealed an increased density of σ<sub>1</sub> receptors in cortico-striato-(para)limbic brain regions of MDD patients. The increased density of σ<sub>1</sub> receptors correlated with the severity of the depressive symptoms. In an occupancy study with the PET tracer (<i>S</i>)-[<sup>18</sup>F]<b>2</b>, the selective binding of pridopidine at σ<sub>1</sub> receptors in the brain of healthy volunteers and HD patients was shown.https://www.mdpi.com/1424-8247/17/2/166σ<sub>1</sub> receptor ligandsσ<sub>1</sub>:σ<sub>2</sub> selectivitystructure–affinity relationshipsenantioselective synthesispharmacokineticslogD<sub>7.4</sub> value |
| spellingShingle | Friedrich-Alexander Ludwig Erik Laurini Judith Schmidt Sabrina Pricl Winnie Deuther-Conrad Bernhard Wünsch [<sup>18</sup>F]Fluspidine—A PET Tracer for Imaging of σ<sub>1</sub> Receptors in the Central Nervous System Pharmaceuticals σ<sub>1</sub> receptor ligands σ<sub>1</sub>:σ<sub>2</sub> selectivity structure–affinity relationships enantioselective synthesis pharmacokinetics logD<sub>7.4</sub> value |
| title | [<sup>18</sup>F]Fluspidine—A PET Tracer for Imaging of σ<sub>1</sub> Receptors in the Central Nervous System |
| title_full | [<sup>18</sup>F]Fluspidine—A PET Tracer for Imaging of σ<sub>1</sub> Receptors in the Central Nervous System |
| title_fullStr | [<sup>18</sup>F]Fluspidine—A PET Tracer for Imaging of σ<sub>1</sub> Receptors in the Central Nervous System |
| title_full_unstemmed | [<sup>18</sup>F]Fluspidine—A PET Tracer for Imaging of σ<sub>1</sub> Receptors in the Central Nervous System |
| title_short | [<sup>18</sup>F]Fluspidine—A PET Tracer for Imaging of σ<sub>1</sub> Receptors in the Central Nervous System |
| title_sort | sup 18 sup f fluspidine a pet tracer for imaging of σ sub 1 sub receptors in the central nervous system |
| topic | σ<sub>1</sub> receptor ligands σ<sub>1</sub>:σ<sub>2</sub> selectivity structure–affinity relationships enantioselective synthesis pharmacokinetics logD<sub>7.4</sub> value |
| url | https://www.mdpi.com/1424-8247/17/2/166 |
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