Synthesis and Pharmacological Evaluation of Fluorinated Quinoxaline-Based κ-Opioid Receptor (KOR) Agonists Designed for PET Studies

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.