Synthesis and Biological Evaluation of N-Substituted Quinolinimides, as Potential Ligands for in Vivo Imaging Studies of $δ$-Opioid Receptors

We report here the syntheses of N-substituted quinolinimide derivatives displaying sufficient affinity and high selectivity for $δ$-opioid receptors. Among 9-subsituted derivatives, one showed much higher selectivity for the 6 receptor in binding assays than the 6 antagonist methylnaltrindole (6: Ki = 42 nM; $μ$/$δ$ and K/6 > 238 on rat brain membranes) and antagonist properties. This compound was labeled with carbon-11 (t1/2 = 20.4 min) as a potential radioligand for the noninvasive assessment of $δ$ opioid receptors in vivo with positron emission tomography (PET). A high yielding radiosynthesis of [11C]-6, based on the [11C]methyl introduction on the pyridine moiety by a Stille reaction, was described (radiochemical yield = 60 ± 10%, specific activities = 0.8 to 1.5 Ci/$μ$mol). The in vivo pharmacological profile in rats indicated that the radiotracer crossed the blood-brain barrier but was not stable and underwent rapid degradation in both plasma and brain. No specific binding was consequently revealed.