We report here the syntheses of
N-substituted quinolinimide derivatives displaying sufficient affinity and highse
lectivity for
-opioid receptors. Among 9-subsituted derivatives, one showed much higher se
lectivity for the
receptor in binding assays than the
antagonist methylnaltrindo
le (
6:
Ki = 42 nM;
/
and
/
> 238 on ratbrain membranes) and antagonist properties. This compound was labe
led with carbon-11 (
t1/2 = 20.4 min) as apotential radioligand for the noninvasive assessment of
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 moietyby a Stil
le reaction, was described (radiochemical yield = 60 ± 10%, specific activities = 0.8 to 1.5 Ci/
mol).The in vivo pharmacological profi
le in rats indicated that the radiotracer crossed the blood-brain barrier but wasnot stab
le and underwent rapid degradation in both plasma and brain. No specific binding was consequentlyrevea
led.