Drugs acting on the 5-HT 1A receptor are used in the treatment of depression, generalized anxiety disorder, and schizophrenia. This study investigated 5-HT 1A receptor occupancy by the 5-HT 1A agonist drugs flesinoxan (a highly selective probe for the 5-HT 1A receptor) and ziprasidone (a novel atypical antipsychotic drug). Using a within-subject design, 14 healthy volunteers each received two positron emission tomography scans using the selective 5-HT 1A antagonist radiotracer [ 11 C]WAY-100635. One scan constituted a baseline, while the other followed either 1 mg flesinoxan or 40 mg ziprasidone orally. In addition, rats were pretreated with intravenous flesinoxan at doses ranging from 0.001 to 5 mg/kg then [ 11 C]WAY-100635 binding measured ex vivo. Cerebral cortical and hippocampal regions of interest, and cerebellar reference regions were sampled to estimate 5-HT 1A receptor occupancy (inferred from reductions in specific radioligand binding). In man, occupancy was not significant despite volunteers experiencing side effects consistent with central serotonergic activity. The mean cerebral cortex occupancy (71 SD) for flesinoxan was 8.7% (713%), and for ziprasidone 4.6% (717%). However, in rats, flesinoxan achieved significant and dose-related occupancy (17-57%) at 0.25 mg/kg and above. We conclude that 5-HT 1A receptor agonists produce detectable occupancy only at higher doses that would produce unacceptable levels of side effects in man, although lower doses are sufficient to produce pharmacological effects. The development of agonist radiotracers may increase the sensitivity of detecting agonist binding, as 5-HT 1A antagonists bind equally to low-and high-affinity receptor states, while agonists bind preferentially to the high-affinity state.

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1. Nineteen healthy male volunteers participated in a double-blind, six-way, crossover study. With a separation of 1 week between sessions, volunteers received randomly one oral dose of each of the following compounds: 3 or 10 mg of the dopamine (DA2) receptor antagonist and serotonin (5HT1A) agonist DU 29894, 1 mg flesinoxan, 400 mg sulpiride, 3 mg haloperidol or placebo. 2. To assess the dopamine (DA2) antagonistic activity of the different compounds, plasma levels of prolactin were assessed at pre-dose, 0.5, 1, 2, 3, 4, 6 and 24 h post-dose. To assess the serotonin (5HT1A) agonistic activity, plasma levels of ACTH, cortisol and growth hormone were assessed at the same time-points as well as body temperature; the latter was also assessed 8 h post-dose. Plasma levels of DU 29894 were assessed at pre-dose and 2, 3, 4 and 24 h post-dose. 3. Sulpiride, haloperidol and both doses of 3 mg and 10 mg DU 29894 produced statistically significant increases in prolactin levels. The increase produced by 3 mg was roughly equivalent to that produced by 3 mg haloperidol whereas the increase produced by 10 mg DU 29894 was significantly larger. 4. Only 10 mg DU 29894 and 1 mg flesinoxan produced statistically significant increases in ACTH, cortisol and growth hormone. All compounds either showed a significant attenuation of the normal day time increase of body temperature (3 mg DU 29894, haloperidol and sulpiride) or a true significant decrease in body temperature (10 mg DU 29894 and flesinoxan).(ABSTRACT TRUNCATED AT 250 WORDS)

5-HT1A receptor agonists consistently reduce neuroleptic induced catalepsy in rats. A serotonin-dopamine interaction has been proposed to underlie this effect. Specifically, 5-HT1A receptor agonists may reduce the activity of serotonergic projections that inhibit dopaminergic nigrostriatal neurones, therefore increasing dorsal striatal dopamine levels and partially overcoming the neuroleptic blockade of D2 receptors. We tested the hypothesis that 5-HT1A receptor agonists increase striatal dopamine release in man using PET scanning with the selective D2 receptor radioligand [11C]raclopride, which is sensitive to endogenous dopamine levels. Six healthy volunteers received two PET scans, one after placebo, the other after 1 mg flesinoxan, a selective 5-HT1A receptor agonist. Binding potential values for striatal subdivisions were determined using a simplified reference tissue model. We did not find any difference in striatal [11C]raclopride binding between conditions, even though flesinoxan lead to typical 5-HT1A receptor agonist side effects and produced elevation of growth hormone in five of the six subjects. Our results suggest that the anticataleptic effect of 5-HT1A receptor agonists is not mediated by striatal dopamine release, and indicates a need for further research with other suitable 5-HT1A receptor agonists.