[11C]WAY 100635: a radioligand for imaging 5-HT1A receptors with positron emission tomography

The potent and selective 5-HT1A antagonist WAY 100635 (N-[2-]4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2- pyridinyl)cyclohexanecarboxamide) was radiolabeled with 11C in high specific activity, and the in vivo properties of this radioligand were assessed in the brains of rats and monkeys. Following i.v. tail vein injection in rats, [11C]WAY 100635 rapidly penetrated into brain tissue and was retained over a 30-90 min time period in a manner consistent with the known distribution of 5-HT1A receptors. Pretreatment of rats with the selective 5-HT1A agonist (+/-)-8-OH-DPAT effectively blocked the retention of radioactivity in brain regions known to contain high densities of 5-HT1A receptors. The hippocampus-to-cerebellum radioactivity concentration ratio reached a maximum of 16:1 at 60 min post injection. Following i.v. injection of [11C]WAY 100635 in rhesus monkeys, the concentrations of radioactivity in brain regions were consistent with the reported distribution of 5-HT1A receptors in primates, and the frontal cortex-to-cerebellum ratio reached 5.5:1 at 80 min post injection. Pretreatment of the monkeys with (+/-)-8-OH-DPAT reduced this ratio to 1.4:1, and injection of (+/-)-8-OH-DPAT 20 min after the injection of [11C]WAY 100635 significantly displaced frontal cortex binding. The in vivo properties of [11C]WAY 100635 in rats and monkeys strongly support the future utility of this radioligand for imaging 5-HT1A receptors using positron emission tomography (PET).