Synthesis and biological evaluation of N-substituted quinolinimides, as potential ligands for in vivo imaging studies of delta-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: Ki = 42 nM; micro/delta and kappa/delta > 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 delta 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/micromol). 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.
Bourdier
Thomas
T
Groupe de Développements Méthodologiques en Tomographie par Emission de Positons, DSV/DRM UMR CEA 2E, Université de Caen Basse Normandie, Centre Cyceron, 15 Boulevard Henri Becquerel, Caen, France.
Poisnel
Géraldine
G
Dhilly
Martine
M
Delamare
Jérôme
J
Henry
Joël
J
Debruyne
Danièle
D
Barré
Louisa
L
D000818:Animals; D001665:Binding Sites; D001812:Blood-Brain Barrier; D001921:Brain / Q000000981:diagnostic imaging*; D002250:Carbon Radioisotopes; D007094:Imides / Q000737:chemistry*; D008024:Ligands; D008297:Male; D011806:Quinolinium Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D014018:Tissue Distribution
D002250:Carbon Radioisotopes; D007094:Imides; D008024:Ligands; D011806:Quinolinium Compounds; D019275:Radiopharmaceuticals; D017465:Receptors, Opioid, delta