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

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journal contribution
posted on 2007-03-21, 00:00 authored by Thomas Bourdier, Géraldine Poisnel, Martine Dhilly, Jérôme Delamare, Joël Henry, Danièle Debruyne, Louisa Barré
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 δ receptor in binding assays than the δ antagonist methylnaltrindole (6:  Ki = 42 nM; μ/δ and κ/δ > 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/μmol). 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.