Journal
CHEMMEDCHEM
Volume 15, Issue 19, Pages 1834-1853Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.202000502
Keywords
anti-inflammatory activity; effector cells; fluorine; opioid receptor agonists; perhydroquinoxaline; PET tracers
Categories
Funding
- Deutsche Forschungsgemeinschaft (DFG) [SFB-TR 128, SFB 1009, 817/5-1, FF-2016-11]
- Interdisciplinary Center for Clinical Research (IZKF) [Lo2/004/16]
- Interdisciplinary Center for Clinical Research (IZKF core unit PIX)
- NIDA [PO1 DA035764]
- Projekt DEAL
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kappa-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 fluoroethyltriazole2has already been reported, fluoropyrrolidines14(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. Fluoropyrrolidines14showed similar low-nanomolar KOR affinity and selectivity to the corresponding pyrrolidines, but the corresponding alcohols were slightly less active. In the cAMP and beta-arrestin assay,14b(proton at the 4-position) exhibited similar KOR agonistic activity as U-50,488. The fluoro derivatives14band14c(CO(2)CH(3)at the 4-position) revealed KOR-mediated anti-inflammatory activity as CD11c and the IFN-gamma production were reduced significantly in mouse and human dendritic cells. Compounds14band14-calso displayed anti-inflammatory and immunomodulatory activity in mouse and human T cells. The PET tracer [F-18]-2was prepared by 1,3-dipolar cycloaddition. In vivo, [F-18]-2did not label KOR due to very fast elimination kinetics. Nucleophilic substitution of a mesylate precursor provided [F-18]-14c. Unfortunately, defluorination of [F-18]-14coccurred in vivo, which was analyzed in detail byin vitrostudies.
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