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 delta-opioid receptors. Among 9-subsituted derivatives, one showed much higher selectivity for the delta receptor in binding assays than the delta antagonist methylnaltrindole (6: K-i = 42 nM; mu/delta and kappa/delta > 238 on rat brain membranes) and antagonist properties. This compound was labeled with carbon-11 (t(1/2) = 20.4 min) as a potential radioligand for the noninvasive assessment of delta opioid receptors in vivo with positron emission tomography (PET). A high yielding radiosynthesis of [C-11]-6, based on the [C-11]methyl introduction on the pyridine moiety by a Stille reaction, was described (radiochemical yield = 60 +/- 10%, specific activities = 0.8 to 1.5 Ci/mu 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.