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Synthesis and Pharmacological Evaluation of Fluorinated Quinoxaline‐Based κ‐Opioid Receptor (KOR) Agonists Designed for PET Studies
Author(s) -
Tangherlini Giovanni,
Börgel Frederik,
Schepmann Dirk,
Slocum Samuel,
Che Tao,
Wagner Stefan,
Schwegmann Katrin,
Hermann Sven,
Mykicki Nadine,
Loser Karin,
Wünsch Bernhard
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000502
Subject(s) - chemistry , in vivo , stereochemistry , substituent , pharmacology , medicine , microbiology and biotechnology , biology
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 S N 2 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 (CO 2 CH 3 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 [ 18 F]‐ 2 was prepared by 1,3‐dipolar cycloaddition. In vivo, [ 18 F]‐ 2 did not label KOR due to very fast elimination kinetics. Nucleophilic substitution of a mesylate precursor provided [ 18 F]‐ 14c . Unfortunately, defluorination of [ 18 F]‐ 14c occurred in vivo, which was analyzed in detail by in vitro studies.