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[ 18 F]Fluspidine-A PET Tracer for Imaging of σ 1 Receptors in the Central Nervous System.

التفاصيل البيبلوغرافية
العنوان: [ 18 F]Fluspidine-A PET Tracer for Imaging of σ 1 Receptors in the Central Nervous System.
المؤلفون: Ludwig FA; Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Helmholtz-Zentrum Dresden-Rossendorf, D-04318 Leipzig, Germany., Laurini E; Molecular Biology and Nanotechnology Laboratory (MolBNL@UniTS), DEA, University of Trieste, 34127 Trieste, Italy., Schmidt J; Institut für Pharmazeutische und Medizinische Chemie, Universität Münster, Corrensstraße 48, D-48149 Münster, Germany., Pricl S; Molecular Biology and Nanotechnology Laboratory (MolBNL@UniTS), DEA, University of Trieste, 34127 Trieste, Italy.; Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 90-136 Lodz, Poland., Deuther-Conrad W; Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Helmholtz-Zentrum Dresden-Rossendorf, D-04318 Leipzig, Germany., Wünsch B; Institut für Pharmazeutische und Medizinische Chemie, Universität Münster, Corrensstraße 48, D-48149 Münster, Germany.; GRK 2515, Chemical Biology of Ion Channels (Chembion), Universität Münster, Corrensstraße 48, D-48149 Münster, Germany.
المصدر: Pharmaceuticals (Basel, Switzerland) [Pharmaceuticals (Basel)] 2024 Jan 28; Vol. 17 (2). Date of Electronic Publication: 2024 Jan 28.
نوع المنشور: Journal Article; Review
اللغة: English
بيانات الدورية: Publisher: MDPI Country of Publication: Switzerland NLM ID: 101238453 Publication Model: Electronic Cited Medium: Print ISSN: 1424-8247 (Print) Linking ISSN: 14248247 NLM ISO Abbreviation: Pharmaceuticals (Basel) Subsets: PubMed not MEDLINE
أسماء مطبوعة: Original Publication: Basel, Switzerland : MDPI, c2004-
مستخلص: σ 1 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 1 receptor ligands. The relationship between structural modifications and σ 1 receptor affinity and selectivity over σ 2 receptors led to the 2-fluoroethyl derivative fluspidine ( 2 , K i = 0.59 nM). Enantiomerically pure ( S )-configured fluspidine (( S )- 2 ) was prepared by the enantioselective reduction of the α,β-unsaturated ester 23 with NaBH 4 and the enantiomerically pure co-catalyst ( S , S )- 24 . The pharmacokinetic properties of both fluspidine enantiomers ( R )- 2 and ( S )- 2 were analyzed in vitro. Molecular dynamics simulations revealed very similar interactions of both fluspidine enantiomers with the σ 1 receptor protein, with a strong ionic interaction between the protonated amino moiety of the piperidine ring and the COO - moiety of glutamate 172. The 18 F-labeled radiotracers ( S )-[ 18 F] 2 and ( R )-[ 18 F] 2 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 ( R )-[ 18 F] 2 indicated a kind of irreversible binding. In the first clinical trial, ( S )-[ 18 F] 2 was used to visualize σ 1 receptors in the brains of patients with major depressive disorder (MDD). This study revealed an increased density of σ 1 receptors in cortico-striato-(para)limbic brain regions of MDD patients. The increased density of σ 1 receptors correlated with the severity of the depressive symptoms. In an occupancy study with the PET tracer ( S )-[ 18 F] 2 , the selective binding of pridopidine at σ 1 receptors in the brain of healthy volunteers and HD patients was shown.
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معلومات مُعتمدة: Pilot applications), T.2.8 Centro Nazionale di Ricerca in Hihg-Performance Computing, Big Data, and Quantum Computing; WU 176 Deutsche Forschungsgemeinschaft
فهرسة مساهمة: Keywords: automated radiosynthesis; biodistribution; biotransformation; enantioselective synthesis; increased σ1 receptor density; irreversible binding of (R)-[18F]2; ligand–σ1 receptor interactions; logD7.4 value; major depressive disorder; molecular dynamics simulations; occupancy study with pridopidine; pharmacokinetics; plasma protein binding; radiometabolites; radiosynthesis; structure–affinity relationships; σ1 receptor ligands; σ1:σ2 selectivity
تواريخ الأحداث: Date Created: 20240224 Latest Revision: 20240227
رمز التحديث: 20240227
مُعرف محوري في PubMed: PMC10892410
DOI: 10.3390/ph17020166
PMID: 38399380
قاعدة البيانات: MEDLINE
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