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Synthesis and Pharmacological Evaluation of Fluorinated Quinoxaline-Based κ-Opioid Receptor (KOR) Agonists Designed for PET Studies |
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| Authors: | Dr Giovanni Tangherlini Dr Frederik Börgel Dr Dirk Schepmann Dr Samuel Slocum Prof Tao Che Dr Stefan Wagner Dr Katrin Schwegmann Dr Sven Hermann Dr Nadine Mykicki Prof Karin Loser Prof Bernhard Wünsch |
| Affiliation: | 1. Institut für Pharmazeutische und Medizinische Chemie, Universität Münster, Corrensstraße 48, 48149 Münster, Germany
Cells-in-Motion Cluster of Excellence (EXC 1003-CiM), Westfälische Wilhelms-Universität Münster, 48149 Münster, Germany;2. Institut für Pharmazeutische und Medizinische Chemie, Universität Münster, Corrensstraße 48, 48149 Münster, Germany;3. Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599 USA;4. Department of Anesthesiology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110 USA;5. Department of Nuclear Medicine, University Hospital Münster, Albert-Schweitzer-Campus 1, Building A1, 48149 Münster, Germany;6. European Institute for Molecular Imaging (EIMI), University of Münster, Waldeyerstraße 15, 48149 Münster, Germany;7. Department of Dermatology, University of Münster, von-Esmarch-Str. 58, 48149 Münster, Germany;8. Cells-in-Motion Cluster of Excellence (EXC 1003-CiM), Westfälische Wilhelms-Universität Münster, 48149 Münster, Germany Department of Dermatology, University of Münster, von-Esmarch-Str. 58, 48149 Münster, Germany CRC1009 Breaking Barriers and CRC-TR 128 Multiple Sclerosis, University of Münster, von-Esmarch-Str. 58, 48149 Münster, Germany |
| Abstract: | κ-Opioid receptors (KORs) play a predominant role in pain alleviation, itching skin diseases, depression and neurodegenerative disorders such as multiple sclerosis. Therefore, imaging of KOR by a fluorinated PET tracer was envisaged. Two strategies were followed to introduce a F atom into the very potent class of cis,trans-configured perhydroquinoxalines. Whereas the synthesis of fluoroethyltriazole 2 has already been reported, fluoropyrrolidines 14 (1-2-(3,4-dichlorophenyl)acetyl]-8-(R)-3-fluoropyrrolidin-1-yl]-perhydroquinoxalines) were prepared by SN2 substitution of a cyclic sulfuric acid derivative with hydroxypyrrolidine and subsequent transformation of the OH moiety into a F substituent. Fluoropyrrolidines 14 showed similar low-nanomolar KOR affinity and selectivity to the corresponding pyrrolidines, but the corresponding alcohols were slightly less active. In the cAMP and β-arrestin assay, 14b (proton at the 4-position) exhibited similar KOR agonistic activity as U-50,488. The fluoro derivatives 14b and 14c (CO2CH3 at the 4-position) revealed KOR-mediated anti-inflammatory activity as CD11c and the IFN-γ production were reduced significantly in mouse and human dendritic cells. Compounds 14b and 14-c also displayed anti-inflammatory and immunomodulatory activity in mouse and human T cells. The PET tracer 18F]- 2 was prepared by 1,3-dipolar cycloaddition. In vivo, 18F]- 2 did not label KOR due to very fast elimination kinetics. Nucleophilic substitution of a mesylate precursor provided 18F]- 14c . Unfortunately, defluorination of 18F]- 14c occurred in vivo, which was analyzed in detail by in vitro studies. |
| Keywords: | anti-inflammatory activity effector cells fluorine opioid receptor agonists perhydroquinoxaline PET tracers |