Bengt Andrée

Serotonin transporter genotype is associated with cognitive performance but not regional 5-HT1A receptor binding in humans

The human serotonin transporter (5-HTT) gene is one of the most extensively studied in psychiatry. A functional polymorphism in the promoter region of the 5-HTT gene (5-HTTLPR) has been associated with several psychiatric disorders as well as anxiety-related personality traits. In search of a mechanistic understanding of the functional implications of 5-HTTLPR, the influence of this polymorphism on regional 5-HT1A receptor density has previously been examined in two positron emission tomography (PET) studies in humans, yielding, however, contradictory results. In the present study, 54 control subjects were examined with [11C]WAY 100635 PET and a battery of cognitive tests. Regional binding potential (BP) of [11C]WAY 100635 to 5-HT1A receptor was calculated for the dorsal raphe nuclei, the hippocampus, the anterior cingulate, the insula, the temporal cortex and the frontal cortex. The influence of 5-HTTLPR genotype on regional 5-HT1A BP and cognitive performance was investigated. No differences in 5-HT1A receptor density between carriers and non-carriers of the S allele were found. Thus, we could not replicate any of the previously reported associations between 5-HTTLPR and 5-HT1A density. There was, however, a highly significant association between 5-HTTLPR genotype and performance in Wisconsin Card Sorting Test; carriers of the S allele had a superior performance compared to the LL carriers. These observations suggest that functional implications of the 5-HTTLPR polymorphism are not likely to be mediated by differences in 5-HT1A expression levels and that other biomarkers must be considered for future investigations at phenotype level.

Pindolol binding to 5-HT1A receptors in the human brain confirmed with positron emission tomography

Abstract The augmentation effect of (–)pindolol as used in combination with SSRI to treat major depression has been ascribed to blocking of dorsal raphe nucleus cell body 5-HT autoreceptors. In this study, the radioligand [carbonyl-11C]WAY-100635 and positron emission tomography were used to establish whether pindolol at a clinical dose level (10 mg s.o.d.) occupies 5-HT1A receptors in the human brain in vivo. Three healthy males were recruited and each subject was used as his own control. The 5-HT1A receptor occupancy was calculated for the frontal and temporal cortex and the raphe nuclei, using and a ratio analysis with the cerebellar cortex as the reference region. Maximal pindolol plasma concentration was reached within 3 h after drug administration. Two hours after pindolol administration, the regional 5-HT1A receptor occupancy was within the range 7–21% in the three subjects. The study confirms that the 5-HT1A-receptor may be a clinically significant target for pindolol.

Positron emission tomographic analysis of dose-dependent MDL 100,907 binding to 5-hydroxytryptamine-2A receptors in the human brain.

Selective 5-hydroxytryptamine-2A (5-HT2A) antagonism has been proposed as a mechanism of atypical antipsychotic drug action. MDL 100,907, a new selective 5-HT2A receptor antagonist, has high affinity in vitro for 5-HT2A receptors and is being developed as a potential antipsychotic drug. In this study, neocortical 5-HT2A receptor occupancy was measured in six healthy male volunteers after placebo and escalating single doses (1-72 mg) of MDL 100,907 using positron emission tomography and the nonspecific radioligand [11C]N-methylspiperone ([11C]NMSP). Receptor occupancy was calculated using a ratio-equilibrium analysis, assuming that maximal radioligand binding inhibition represents 100% 5-HT2A receptor occupancy. Plasma concentrations of MDL 100,907 were measured with high-pressure liquid chromatography. The pharmacokinetic parameters area under the curve and peak plasma concentration increased linearly with dose, with rapid absorption and a 6- to 9-hour elimination half-life. The neocortical binding of [11C]NMSP was inhibited dose-dependently. After administration of 6 mg of MDL 100,907 the inhibition was 70%, corresponding to a 5-HT2A receptor occupancy of 90%. The calculated maximal inhibition was 77%. These observations indicate that MDL 100,907 passes the blood-brain barrier and binds to 5-HT2A receptors in a saturable manner in the living human brain. Repeated doses of MDL 100,907, 10 mg/day or more, should induce a sustained 5-HT2A receptor occupancy in most patients. Thus, MDL 100,907 provides a suitable tool to evaluate the potential of selective 5-HT2A receptor antagonism in the treatment of schizophrenia.

PET-Determination of Robalzotan (NAD-299) Induced 5-HT1A Receptor Occupancy in the Monkey Brain

The serotonin 5-hydroxytryptamine-1A (5-HT1A) receptor subtype is of central interest in research, particularly in the area of pathophysiology and pharmacological treatment of psychiatric disorders. Robalzotan (generic name for NAD-299) is a new putative drug that binds with high selectivity and affinity to 5-HT1A-receptors in the rodent brain in vitro and in vivo. The aim of this positron emission tomography study was to determine 5-HT1A receptor occupancy in the cynomolgus monkey brain in vivo after IV injection of robalzotan. Two healthy monkeys were examined with Positron Emission Tomography (PET) and the radioligand [carbonyl-11C]WAY-100635, the first after IV administration of 2 μg/kg and 20 μg/kg, and the second after 10 μg/kg and 100 μg/kg IV. 5-HT1A receptor occupancy was calculated using an equilibrium-ratio analysis. Robalzotan occupied 5-HT1A receptors in a dose-dependent and saturable manner. The highest 5-HT1A receptor occupancy (70–80%) was attained after 100 μg/kg. The relationship between robalzotan drug concentration and 5-HT1A receptor occupancy could be described by a hyperbolic function, which can be used to guide the selection of appropriate doses for the initial studies in man. The study further corroborates that quantitative neuroimaging of receptor binding has potentials for the evaluation and dose finding of new CNS drugs.

Central 5-HT2A and D2 dopamine receptor occupancy after sublingual administration of ORG 5222 in healthy men

Abstract It has been suggested that a combined blockade of 5-HT2A and D2-dopamine receptors improves efficacy and reduces the risk for extrapyramidal symptoms when treating schizophrenic patients with antipsychotic drugs. ORG 5222 is a new potential anti-psychotic drug which has high affinity for 5-HT2A, D2-dopamine and α1 adrenergic receptors in vitro. The objective of this study was to examine if ORG 5222 occupies 5-HT2A and D2-dopamine receptors in human subjects in vivo. Central receptor occupancy was measured by positron emission tomography (PET) in three healthy subjects after sublingual administration of 100 μg ORG 5222. [11C]N-methylspiperone ([11C] NMSP) was the radioligand used to measure 5-HT2A receptor binding in the neocortex and [11C]raclopride to measure D2-dopamine receptor binding in the striatum. The 5-HT2A occupancy was 15–30% and the D2-dopamine receptor occupancy was 12–23%. The study confirms that ORG 5222 binds to 5-HT2A and D2-dopamine receptors in human brain. Since receptor occupancy of ORG 5222 is rather low, doses higher than 100 μg are suggested in future clinical trials to evaluate the antipsychotic drug effect of ORG 5222.