Fluorinated and [18F]fluorinated morphinan based opioid ligands.
It is well documented in the literature that opioid receptors modulate a large number of physiological functions (pain perception, breathing, mood, gastrointestinal motility and etc.). Natural opiates and 4,5α-epoxymorphinan derivatives obtained by their chemical modification, which are frequently referred to as semi-synthetic opioids, are among the most important types of opioid ligands. On the other hand, fluorinated compounds have a remarkable record in medicinal chemistry providing developmental candidates for therapeutic applications. The reasons are very similar steric impact of hydrogen and fluorine along with the influence of substituting fluorine for hydrogen in the molecules of exogenous compounds on their lipophilicity, metabolism, conformational and other properties. This review focuses on the functionalization of 4,5α-epoxymorphinans and their derivatives via substitutions with fluorine or fluorine-containing groups in a search for improved pharmacological profile opioid ligands and 18F-containing opioid receptor radioligands for PET. These functionalizations are typically associated with either the substituents at C(3)-O, C(6)-O, and N(17) positions of the 4,5α-epoxymorphinan core or at C(7) in the thebaine based Diels-Alder type adducts. The syntheses resulted in preparations of both single fluorinated derivatives or short sets of the compounds and the families of the fluorine-containing opioids allowing, in principle, the structure-activity relationship studies.