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

Abstract

k-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,transconfigured 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 antiinflammatory 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.

The Kappa Opioid Receptor: A Promising Therapeutic Target for Multiple Pathologies

“…Additional studies have provided further evidence that KOR agonists promote remyelination and recovery in mouse models of MS. Tangherlini et al (2019) synthesised a series of quinoxaline-based KOR agonists and showed that two of these KOR agonists ameliorated EAE paralysis in mice. Tangherlini et al (2020) also observed that treatment with KOR agonists reduced immune cell infiltration into the CNS. They also confirmed that immunomodulatory effects of these compounds depended on the presence of KOR ( Tangherlini et al, 2020 ).…”

“… Tangherlini et al (2020) also observed that treatment with KOR agonists reduced immune cell infiltration into the CNS. They also confirmed that immunomodulatory effects of these compounds depended on the presence of KOR ( Tangherlini et al, 2020 ). Oral administration of a plant-derived peptide called [T20K]kalata B1 also reduced demyelination and improved functional EAE behavioural scores (level of paralysis) in mice.…”

“…Recent studies have shown that activation of KOR may be an effective strategy for promoting remyelination and functional recovery in preclinical models of MS. Several key papers supporting the therapeutic potential of KOR agonists as remyelinating agents have recently been published ( Du et al, 2016 ; Mei et al, 2016 ; Thell et al, 2016 ; Tangherlini et al, 2019 ; Tangherlini et al, 2020 ; Denny et al, 2021 ; Paton et al, 2021 ).…”

Evaluation of Specific Binding of [11C]RTI-97 to Kappa Opioid Receptor by Autoradiography and PET Imaging in Rat

“…25,26 Thus, characterization of KOR radiopharmaceuticals with antagonism properties and high target specificity is still desirable. 27 A few years ago, we developed KOR radiotracers derived from JDTic [(3R)-7-hydroxy-N-((1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide] established as the most potent and selective KOR antagonist reported so far (Figure 1). 28,29 Among them, the N-…”

“…Among them, [ 11 C]­GR103545, [ 11 C]­EKAP, and [ 11 C]­LY2795050 have been assessed in clinical trials. [ 11 C]­GR103545 displayed slow binding kinetics and ultrapotency leading to the risk of side effects such as dysphoria, sedation, and psychosis due to its KOR agonist property. , The novel KOR agonist [ 11 C]­EKAP was recently reported to display faster tissue kinetics than [ 11 C]­GR103545 in test–retest reproducibility studies. − [ 11 C]­LY2795050, identified as a KOR antagonist with short-term effects, was shown to possess favorable brain uptake, pharmacokinetic properties, and binding profiles but poor stability and moderate KOR selectivity. − The analogue [ 11 C]/[ 18 F]­LY2459989 recently evaluated in nonhuman primates was suggested to display a similar in vivo behavior. , Thus, characterization of KOR radiopharmaceuticals with antagonism properties and high target specificity is still desirable …”