![]() Nucleophilic substitution of mesylate precursor 19 provided 14c. In vivo, 2 did not label KOR due to very fast elimination kinetics. The PET tracer 2 was prepared by 1,3‐dipolar cycloaddition. 14b and 14c displayed also anti‐inflammatory and immunomodulatory activity on mouse and human T cells. The fluoro derivatives 14b and 14c revealed KOR‐mediated anti‐inflammatory activity as CD11c and the IFN‐γ production were reduced significantly in mouse and human dendritic cells. In the cAMP and β‐arrestin assay, 14b exhibited similar KOR agonistic activity as U‐50,488. The fluoropyrrolidines 14 showed similar low‐nanomolar KOR affinity and selectivity as the pyrrolidines 1, but the alcohols 12 were slightly less active. Whereas the synthesis of fluoroethyltriazole 2 was already reported, fluoropyrrolidines 14 were prepared by an SN2 substitution of cyclic sulfuric acid derivative 10 with hydroxypyrrolidine and subsequent transformation of the OH moiety into a F‐substituent. Two strategies were followed to introduce a F‐atom into the very potent class of cis,trans‐configured perhydroquinoxalines. Therefore, imaging of KOR by a fluorinated PET tracer was envisaged. Κ‐Opioid receptors (KOR) play a predominant role in pain alleviation, itching skin diseases, depression and neurodegenerative disorders such as multiple sclerosis.
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