Antipsychotics possessing antidepressive efficacy increase G<Subscript>olf</Subscript> protein in rat striatum

Rationale Paliperidone ER is a novel antipsychotic drug in an extended-release (ER) formulation. As with all antipsychotics, careful dose setting is necessary to avoid side effects. Objectives In this study, we measured striatal and extrastriatal dopamine D₂ receptor occupancy during paliperidone ER treatment in patients with schizophrenia using positron emission tomography (PET) to compare regional occupancy and to estimate the optimal dose. Materials and methods Thirteen male patients with schizophrenia participated in this 6-week multiple-dose study. Six of them took 3 mg of paliperidone ER per day, four took 9 mg, and three took 15 mg. Two to 6 weeks after first drug intake, two PET scans, one with [¹¹C]raclopride and one with [¹¹C]FLB 457, were performed in each patient on the same day. The relationship between the dose or plasma concentration of paliperidone and dopamine D₂ receptor occupancy was calculated. Results The dopamine D₂ receptor occupancies in the striatum measured with [¹¹C]raclopride and the temporal cortex measured with [¹¹C]FLB 457 were 54.2–85.5% and 34.5–87.3%, respectively. ED₅₀ values of the striatum and temporal cortex were 2.38 and 2.84 mg/day, respectively. There was no significant difference in dopamine D₂ receptor occupancy between the striatum and the temporal cortex. Conclusions The data from this study suggest that paliperidone ER at 6–9 mg provides an estimated level of dopamine D₂ receptor occupancy between 70–80% and that the magnitude of dopamine D₂ receptor occupancy is similar between the striatum and temporal cortex.     

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

It has been suggested that a combined blockade of 5-HT_2A 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-HT_2A, D₂-dopamine and α₁ adrenergic receptors in vitro. The objective of this study was to examine if ORG 5222 occupies 5-HT_2A 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-HT_2A receptor binding in the neocortex and [¹¹C]raclopride to measure D₂-dopamine receptor binding in the striatum. The 5-HT_2A occupancy was 15–30% and the D₂-dopamine receptor occupancy was 12–23%. The study confirms that ORG 5222 binds to 5-HT_2A 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. Received: 9 September 1996 / Final version: 2 January 1997     

No regional difference in dopamine D2 receptor occupancy by the second-generation antipsychotic drug risperidone in humans: a positron emission tomography study

The effects of antipsychotic drugs have generally been considered to be mediated by blockade of dopamine D2 receptors. The concept of limbic and cortical selectivity of second-generation antipsychotics, i.e. higher dopamine D2 receptor occupancy in the cerebral cortices than in the striatum, has been suggested to explain their clinical efficacy with lower incidence of extrapyramidal side-effects. In this study, regional distribution of dopamine D2 receptor occupancy by risperidone was determined in order to elucidate the limbic and cortical selectivity of second-generation antipsychotics. Striatal and extrastriatal dopamine D2 receptor binding at baseline and after oral administration of 2 mg risperidone were measured in ten healthy men by positron emission tomography (PET) using different tracers with different affinity for the receptors, [11C]raclopride and [11C]FLB 457, respectively. Striatal and extrastriatal occupancies of dopamine D2 receptors were calculated for each brain region. Occupancies of dopamine D2 receptors were about 70% and 60% in the striatum and extrastriatum, respectively. A simulation study showed that non-negligible specific binding in the reference region (cerebellum), could cause systemic underestimation of occupancy in [11C]FLB 457 PET studies, indicating that occupancies in both the striatum and extrastriatum may not have differed. Among the extrastriatal regions including limbic and neocortical regions, no significant regional differences in dopamine D2 receptor occupancy were observed. Thus, limbic and cortical selectivity was not observed by one of the second-generation antipsychotics, risperidone.     

Evaluation of SCH 39166 as PET ligand for central D1 dopamine receptor binding and occupancy in man

SCH 39166 is the first selective D₁-dopamine receptor antagonist developed for clinical trials in schizophrenia. SCH 39166 was evaluated as a radioligand for PET, labeled with¹¹C, and as a D₁-dopamine receptor antagonist after single oral doses in healthy men. After intravenous injection of [¹¹C]SCH 39166 distribution of radioactivity in brain grossly reflected D₁-dopamine receptor density. The putamen to cerebellum ratio at equilibrium was low (1.54±0.18 SD), which makes [¹¹C]SCH 39166 less suitable as a radioligand for applied PET studies. Saturability of specific binding was demonstrated after IV injection of [¹¹C]SCH 39166 with low specific radioactivity. Stereospecificity of binding was examined using the stereoisomer [¹¹C]SCH 39165. D₁-Receptor occupancy was demonstrated with [¹¹C]SCH 39166 2 h after administration of single oral doses of unlabeled SCH 39166 to each of three healthy subjects (25, 100 and 400 mg). There was a substantial reduction of specific [¹¹C]SCH 39166 uptake in the putamen after all doses. Single oral doses of 100 mg induced approximately 70% D₁-dopamine receptor occupancy in the basal ganglia, which should be sufficient to investigate the antipsychotic potential of D₁-dopamine receptor antagonism in clinical studies.     

Selective D1- and D2-dopamine receptor blockade both induces akathisia in humans — a PET study with [11C]SCH 23390 and [11C]raclopride

Pharmacological effects were recorded and time course for receptor binding in brain was followed by positron emission tomography after IV injection of the selective D₁-dopamine receptor antagonist SCH 23390 in four healthy subjects in doses of 310–810 µg. Akathisia, the syndrome of motor restlessness, appeared after the three highest doses. The akathisia was transient and occurred only when [¹¹C]SCH 23390 binding in the basal ganglia was at a high level with a central D₁-dopamine receptor occupancy of 45–59%. The D₂-dopamine receptor antagonist [¹¹C]raclopride was injected IV into 20 healthy subjects and 13 schizophrenic patients. Akathisia appeared in 14 healthy subjects and 7 patients and coincided with maximal [¹¹C]raclopride binding in the basal ganglia. The findings for [¹¹C]raclopride and [¹¹C]SCH 23390 are the first demonstration of a relationship between time courses for radioligand binding in the human brain and simultaneously induced pharmacological effects.     

Oral administration of NNC 756 — a placebo controlled PET study of D1-dopamine receptor occupancy and pharmacodynamics in man

NNC 756 is a new benzazepine with high affinity and selectivity for D₁-dopamine receptors. In a double-blind, placebo controlled, cross-over study, positron emission tomography and the radioligand [¹¹C]SCH 23390 were used to determine central D₁-do-pamine receptor occupancy after a single oral dose of 80 mg NNC 756 in three healthy men. NNC 756 induced 75, 66 and 47% occupancy of D₁-dopamine receptors in the putamen of at 1.5 h after drug administration and 46, 36 and 24% after 7.5 h. There was a hyperbolic relationship between the occupancy values and the serum concentrations. The K_i value for the hyperbola was 6.4 ng/ml (±SD 1.4). The occupancy at 1.5 h is on the same level as that shown to induce effects in animal models for prediction of antipsychotic effect. Restlessness (akathisia) appeared in two subjects and nausea in one subject at time of peak drug concentration in serum. The oral dose level of 80 mg should be appropriate to investigate the potential antipsychotic effect of NNC 756.     

PET examination of [11C]NNC 687 and [11C]NNC 756 as new radioligands for the D1-dopamine receptor

The benzazepines NNC 687 and NNC 756 have in animal studies been described as selective D₁-dopamine receptor antagonists. Both compounds have been labeled with¹¹C for examination by positron emission tomography (PET). In the present study central receptor binding was studied in monkeys and healthy men. After IV injection of both radioligands in Cynomolgus monkeys radioactivity accumulated markedly in the striatum, a region with a high density of D₁-dopamine receptors. This striatal uptake was displaced by high doses of the selective D₁-antagonist SCH 23390 (2 mg/kg) but not by the 5HT₂-antagonist ketanserin (1.5 mg/kg) or the selective D₂-antagonist raclopride (3 mg/kg). The cortical uptake after injection of [¹¹C]NNC 687 was not reduced in displacement experiments with ketanserin. The cortical uptake of [¹¹C]NNC 756 was reduced in displacement and protection experiments with ketanserin by 24–28% (1.5 mg/kg), whereas no reduction could be demonstrated on striatal uptake. In healthy males both compounds accumulated markedly in the striatum. For [¹¹C]NNC 687 the ratio of radioactivity in the putamen to cerebellum was about 1.5. For [¹¹C]NNC 756 the ratio was about 5. This ratio of 5 for [¹¹C]NNC 756 is the highest obtained so far for PET radioligands for the D₁-dopamine receptor.     

Autoradiographic localisation of D3-dopamine receptors in the human brain using the selective D3-dopamine receptor agonist (+)-[3H]PD 128907

The selective D₃-dopamine receptor agonist 4aR,10bR-(+)-trans-3,4,4a,10b-tetrahydro-4-[N-propyl-2,3-³H]-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol ([³H]PD 128907) was used to visualise D₃-dopamine receptors in whole hemisphere cryosections from post-mortem human brain. [³H]PD 128907 has an 18- to 40-fold selectivity for D₃- over D₂-dopamine receptors as compared to a 7- to 24-fold selectivity of the more commonly used ligand [³H]7-OH-DPAT. [³H]PD 128907 accumulated markedly in the nucleus accumbens and in the ventral parts of caudate nucleus and putamen, with a slightly heterogeneous (patch-matrix like) distribution. The binding in the lateral parts of caudate nucleus and putamen was much less dense. No binding was obtained in any other regions. A very high proportion of [³H]PD 128907 was specifically bound, as judged from the low binding remaining in the presence of the D₂/D₃-dopamine receptor antagonist raclopride. This gives the ligand a potential for the detection of low density D₃-dopamine receptors in the human brain. The binding obtained with [³H]PD 128907 was qualitatively similar to that using [³H]7-OH-DPAT in the presence of GTP. However, [³H]7-OH-DPAT labelled, in contrast to [³H]PD 128907, also D₃-dopamine receptors in neocortex. The new compound [³H]PD 128907 appears to be a suitable radioligand for autoradiographic examination of the D₃-dopamine receptor localisation in the human brain, and should also be useful for pharmacological studies of this receptor subtype. Received: 20 November 1995/Final version: 2 May 1996     

Increased [3H] raclopride binding sites in postmortem brains from schizophrenic violent suicide victims

The specific binding of the D₂-dopamine receptor antagonist radioligand [³H] raclopride was quantitated in the postmortem caudate and frontal cortex from schizophrenic suicide victims and control subjects. In schizophrenic suicides the density of binding sites (B_max) was higher (40%,P<0.05) in the caudate, whereas it did not change in the cortex as compared to those in controls. The apparent dissociation constants (K _d ) were also found increased both in caudate (24%) and cortex (75%) from schizophrenics, but these apparent decreases in receptor affinity did not reach statistical significance. The mean B_max value in drug-free schizophrenic suicides (n=3) did not differ from the B_max value in neuroleptic drug-treated schizophrenics (n=7) but it was found increased in respect to control subjects (n=9). No differences in [³H] raclopride binding were observed between non-schizophrenic suicide victims (n=4) and matched controls (n=4), suggesting that the modifications of D₂-dopamine receptors in schizophrenia are not related to suicide.     

Non-uniform blockade of intrastriatal D<Subscript>2</Subscript>/D<Subscript>3</Subscript> receptors by risperidone and amisulpride

Rationale Atypical antipsychotic drugs have been shown to preferentially affect extrastriatal (mesolimbic) D₂/D₃ receptors over those within the striatum (nigrostriatal). The striatum does not contain exclusively nigrostriatal dopamine tracts, however. The caudate nucleus and ventral parts of the striatum primarily contain limbic and associative dopamine pathways more relevant to psychosis. Objectives We tested the hypothesis that two pharmacologically distinct atypical antipsychotic drugs, amisulpride and risperidone, would preferentially occupy of D₂/D₃ dopamine receptors in limbic and associative regions of the striatum. Methods Eight amisulpride-treated patients, six risperidone-treated patients and six age- and sex-matched healthy controls were recruited. Dynamic SPET studies were performed after bolus injection of [¹²³I]epidepride. Binding potential (BP) images were generated using a modified Logan method and aligned between subjects. Regions of interest (ROIs) were placed around head of caudate and putamen bilaterally on an average BP map derived from aligned control images. These ROIs were then applied user-independently to the BP maps for each subject to calculate BP for head of caudate and putamen. Mean occupancy of D₂/D₃ receptors in each ROI was determined by reference to the drug-free healthy volunteer group. Occupancy values for head of caudate and putamen were compared using paired Student’s t test. Results D₂/D₃ receptor occupancy was 42% in caudate and 31% in putamen for risperidone (t=5.9, df=11, p=0.0001) and 51% in caudate and 37% in putamen for amisulpride (t=11.1, df=15, p<0.0001). Conclusions Amisulpride and risperidone both show selective occupancy for limbic and associative D₂/D₃ receptors within the striatum.     

5-HT2 and D2 dopamine receptor occupancy in the living human brain

It has been suggested that a combined blockade of 5-HT₂ and D₂ dopamine receptors may be superior to D₂ dopamine antagonists alone in the treatment of schizophrenia. Risperidone, which has a high affinity for 5-HT₂ and D₂ dopamine receptors in vitro, is a new antipsychotic drug that has been developed according to this hypothesis. The aim of this study was to examine if risperidone indeed induces 5-HT₂ and D₂ dopamine receptor occupancy in vivo in humans. Central receptor occupancy was examined by positron emission tomography (PET) in three healthy men after oral administration of 1 mg risperidone. [¹¹C]N-methylspiperone ([¹¹C]NMSP) was used as a radioligand for determination of 5-HT₂ receptor occupancy in the neocortex. Both an equilibrium ratio analysis and a kinetic three-compartmental analysis indicated a 5-HT₂ receptor occupancy about 60%. [¹¹C]raclopride was used as a radioligand for determination of D₂ dopamine receptor occupancy in the striatum and the calculated occupancy was about 50%. This is the first quantitative determination of 5-HT₂ receptor occupancy induced by an antipsychotic drug in the living human brain. The results indicate that 5-HT₂ receptor occupancy should be very high at the dose level of 4–10 mg risperidone daily, as suggested for clinical use. Risperidone is thus an appropriate compound for clinical evaluation of the benefit of combined 5-HT₂ and D₂ dopamine receptor blockade in the treatment of schizophrenia.This paper was presented in part at the XVIIIth C.I.N.P. Congress, Nice, France, 28th June-2nd July 1992.     

PET analysis of human dopamine receptor subtypes using 11C-SCH 23390 and 11C-raclopride

Tracer doses of ¹¹C-SCH 23390 and ¹¹C-raclopride, selective D1-dopamine and D2-dopamine receptor antagonists, respectively, were injected intravenously into three healthy male volunteers and two drug-treated schizophrenic patients. Regional radioactivity in brain and plasma was followed during 1 h by positron emission tomography (PET). After injection of both ligands a high accumulation of radioactivity was observed in the dopamine-rich caudate putamen. Experiments with ¹¹C-SCH 23390, but not ¹¹C-raclopride, showed a conspicuous accumulation of radioactivity also in the neocortex. None of the ligands accumulated in the dopamine-poor cerebellum. Specific binding of ¹¹C-raclopride in the putamen was reduced by more than 80% in schizophrenic patients treated with antipsychotic doses of sulpiride or cis(Z)-flupentixol decanoate. ¹¹C-SCH 23390 binding was slightly reduced in both the cortex and the putamen after treatment with cis(Z)-flupentixol decanoate but not after sulpiride. The results indicate that clinical antipsychotic drug treatment with sulpiride and cis(Z)-flupentixol decanoate causes a substantial blockade of D2-dopamine receptors in the basal ganglia but has only a minor effect on D1-dopamine receptors.     

In vivo affinity of [<Superscript>18</Superscript>F]fallypride for striatal and extrastriatal dopamine D<Subscript>2</Subscript> receptors in nonhuman primates

Rationale [¹⁸F]Fallypride is a new and promising radiotracer, suitable for imaging D₂ receptors with Positron Emission Tomography (PET) in both striatal and extrastriatal regions. The high signal to noise ratio of [¹⁸F]fallypride has been attributed to its high affinity for D₂ receptors (K_D of 0.03 nM, measured in vitro at room temperature).Objectives We sought to further characterize this tracer in terms of its in vivo affinity, possible affinity differences between brain regions and dependence of in vitro affinity on temperature.Methods PET scans were performed in baboons over a wide range of concentrations to measure the in vivo K_D of [¹⁸F]fallypride in striatal and extrastriatal regions. Several analytical approaches were used, including nonlinear kinetic modeling and equilibrium methods. Also, in vitro assays were performed at 22 and 37°C.Results No significant differences in the in vivo K_D were detected between regions. In vivo K_D of [¹⁸F]fallypride was 0.22±0.05 nM in striatum, 0.17±0.05 nM in thalamus, and 0.21±0.07 nM in hippocampus. These values were intermediate between in vitro K_D measured at 22 (0.04±0.03 nM) and 37 degrees (2.03±1.07 nM).Conclusion The in vivo affinity of [¹⁸F]fallypride was not as high as previously estimated from in vitro values. This property might contribute to the favorable kinetic properties of the tracer. The in vivo affinity was similar between striatal and extrastriatal regions. This result indicates that the measured regional in vivo affinities of this tracer are not affected by putative regional differences in endogenous dopamine, and that [¹⁸F]fallypride is an appropriate tool to provide unbiased estimates of the occupancy of D₂ receptors by antipsychotic drugs in striatal and extrastriatal regions.     

Occupancy of striatal and extrastriatal dopamine D2/D3 receptors by olanzapine and haloperidol.

There have been conflicting reports as to whether olanzapine produces lower occupancy of striatal dopamine D(2)/D(3) receptor than typical antipsychotic drugs and preferential occupancy of extrastriatal dopamine D(2)/D(3) receptors. We performed [(18)F] fallypride PET studies in six schizophrenic subjects treated with olanzapine and six schizophrenic subjects treated with haloperidol to examine the occupancy of striatal and extrastriatal dopamine receptors by these antipsychotic drugs. [(18)F] setoperone PET studies were performed in seven olanzapine-treated subjects to determine 5-HT(2A) receptor occupancy. Occupancy of dopamine D(2)/D(3) receptors by olanzapine was not significantly different from that seen with haloperidol in the putamen, ventral striatum, medial thalamus, amygdala, or temporal cortex, that is, 67.5-78.2% occupancy; olanzapine produced no preferential occupancy of dopamine D(2)/D(3) receptors in the ventral striatum, medial thalamus, amygdala, or temporal cortex. There was, however, significantly lower occupancy of substantia nigra/VTA dopamine D(2)/D(3) receptors in olanzapine-treated compared to haloperidol-treated subjects, that is, 40.2 vs 59.3% (p=0.0014, corrected for multiple comparisons); in olanzapine-treated subjects, the substantia nigra/VTA was the only region with significantly lower dopamine D(2)/D(3) receptor occupancy than the putamen, that is, 40.2 vs 69.2% (p<0.001, corrected for multiple comparison). Occupancy of 5-HT(2A) receptors was 85-93% in the olanzapine- treated subjects. The results of this study demonstrated that olanzapine does not produce preferential occupancy of extrastriatal dopamine D(2)/D(3) receptors but does spare substantia nigra/VTA receptors. Sparing of substantia nigra/VTA dopamine D(2)/D(3) receptor occupancy may contribute to the low incidence of extrapyramidal side effects in olanzapine-treated patients.     

Low striatal and extra-striatal D2 receptor occupancy during treatment with the atypical antipsychotic sertindole

RATIONALE: Sertindole is a new atypical antipsychotic drug. Preclinical pharmacology suggests that sertindole has a preferential effect on the activity of limbic and cortical dopaminergic neurons. Clinical trials have shown antipsychotic efficacy and very few extrapyramidal symptoms (EPS) with sertindole at 20 mg/day. OBJECTIVES: This positron emission tomography (PET) study aimed to measure D(2) receptor occupancy in striatal and extra-striatal regions induced by clinically representative doses of sertindole in patients with schizophrenia. METHOD: Four stabilized schizophrenic out-patients received sertindole 20 mg/day for 6-8 weeks. PET was performed using [(11)C]raclopride to measure D(2) receptor occupancy in the striatum and [(11)C]FLB457 to measure occupancy in the neocortex and thalamus, i.e. regions with very low D(2) receptor density.RESULTS: Striatal D(2) receptor occupancy was 52-68%. Similar occupancies were found in the thalamus, and the temporal and frontal cortices. CONCLUSIONS: Sertindole appears efficacious at a low D(2) receptor occupancy, comparable to that produced by clozapine. This finding could explain the low risk of EPS. The functional limbic selectivity of sertindole was not reflected in regional differences in receptor occupancy.     

Cortical glutamate–dopamine interaction and ketamine-induced psychotic symptoms in man

Rationale The noncompetitive glutamate N-methyl-d-aspartate receptor antagonist ketamine induces transient psychotic symptoms in man. Involvement of dopaminergic mechanisms in these effects has been suggested. Objectives The purpose of this article is to study the effects of ketamine on extrastriatal dopamine receptor availability in healthy subjects and extracellular dopamine levels in rat cortex. Materials and methods The effect of computer-driven subanesthetic ketamine infusion on cortical dopamine release was studied in healthy male subjects using a controlled study design. Dopamine D2/D3 receptor availability was quantified using positron emission tomography (PET) and [¹¹C]FLB 457. A conventional region of interest-based analysis and voxel-based analysis was applied to the PET data. The ketamine-induced cortical dopamine release in rats was studied using in vivo microdialysis. Results Ketamine infusion reduced significantly the [¹¹C]FLB 457 binding potential (BP) in the posterior cingulate/retrosplenial cortices, suggestive of increased dopamine release. This brain imaging finding was further supported by a microdialysis experiment in rats showing that ketamine increased the extracellular dopamine concentration by up to 200% in the retrosplenial cortex. Ketamine-induced psychotic symptoms were associated with changes in the [¹¹C]FLB 457 BP in the dorsolateral prefrontal and anterior cingulate cortices. Conclusions Our results suggest that cortical dopaminergic mechanisms have a role in the emergence of ketamine-induced psychosis-like symptoms in man. The glutamate–dopamine interaction in the posterior cingulate during ketamine infusion is well in line with the recent functional and structural imaging studies suggesting involvement of this cortical area in the development of schizophrenic psychosis.     

Evaluation of dopamine D2/D3 and serotonin 5-HT2A receptor occupancy for a novel antipsychotic, lurasidone, in conscious common marmosets using small-animal positron emission tomography

Rationale

Lurasidone is a novel antipsychotic drug with potent binding affinity for dopamine D₂ and serotonin (5-hydroxytryptamine, 5-HT)_2A, 5-HT₇, and 5-HT_1A receptors. Previous pharmacological studies have revealed that lurasidone exhibits a preferable profile (potent antipsychotic activity and lower incidence of catalepsy) to other antipsychotic drugs, although the contribution of receptor subtypes to this profile remains unclear.

Objectives

To compare target engagements of lurasidone with those of an atypical antipsychotic, olanzapine, we performed evaluation of dopamine D₂/D₃ and serotonin 5-HT_2A receptor occupancy in vivo by positron emission tomography (PET) with conscious common marmosets.

Methods

We measured brain receptor occupancies in conscious common marmosets after oral administrations of lurasidone or olanzapine by PET with [¹¹C]raclopride and [¹¹C]R-(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine methanol (MDL 100907) for D₂/D₃ and 5-HT_2A receptors, respectively.

Results

Increases in brain D₂/D₃ receptor occupancies of both lurasidone and olanzapine, which reached >80 % at maximum, were observed in the striatum with significant correlations to plasma drug levels. However, lurasidone showed lower 5-HT_2A receptor occupancy in the frontal cortex within the same dose range, while olanzapine showed broadly comparable 5-HT_2A and D₂/D₃ receptor occupancies.

Conclusions

Compared with olanzapine, lurasidone preferentially binds to D₂/D₃ receptors rather than 5-HT_2A receptors in common marmosets. These results suggest that the contribution of in vivo 5-HT_2A receptor blocking activity to the pharmacological profile of lurasidone might differ from olanzapine in terms of the low risk of extrapyramidal syndrome and efficacy against negative symptoms.     

Striatal dopamine D<Subscript>2</Subscript> receptors in medication-naive patients with major depressive disorder as assessed with [<Superscript>11</Superscript>C]raclopride PET

Rationale Among other monoamine neurotransmitters, dopamine is implicated in the pathophysiology of major depression. Experimental studies suggest the involvement of the mesolimbic dopamine system in the mechanism of action of antidepressant drugs. Previous in vivo imaging studies have studied striatal dopamine D₂ receptor availability in depression but the results are equivocal thus far. Objective To study the striatal and thalamic dopamine D₂ receptor availability in drug-naive patients with major depression was the aim of this study. Materials and methods Caudate, putamen, and thalamic dopamine D₂ receptor availability was estimated using positron emission tomography and [¹¹C]raclopride in 25 treatment-seeking drug-free patients (of whom 24 were drug-naive) with major depression (primary care patients) as well as in 19 demographically similar healthy control subjects. Receptor availability was expressed as the binding potential (BP_ND), and analyses were carried out based on both regional and voxel-level BP_ND estimates. Results No statistically significant differences in [¹¹C]raclopride BP_ND were observed between the groups either in the caudate nucleus (+1.7%, CI −4.8% to +8.3%), putamen (−1.0%, CI −7.2% to 5.1%), thalamus (−2.4%, CI −8.7% to 4.0%), or ventral striatum (−3.8%, CI −9.3% to +1.6%). In the patients, depressive symptoms were not associated with [¹¹C]raclopride BP_ND in any region. Conclusions The findings in this sample of treatment-seeking, drug-naive and predominantly first-episode patients with major depression do not support the involvement of striatal dopamine D₂ receptors in the pathophysiology of the illness, but do not exclude the potential importance of dopaminergic mechanisms in antidepressant drug action.     

Imaging Nicotine- and Amphetamine-Induced Dopamine Release in Rhesus Monkeys with [11C]PHNO vs [11C]raclopride PET

The radiotracer [¹¹C]PHNO may have advantages over other dopamine (DA) D₂/D₃ receptor ligands because, as an agonist, it measures high-affinity, functionally active D₂/D₃ receptors, whereas the traditionally used radiotracer [¹¹C]raclopride measures both high- and low-affinity receptors. Our aim was to take advantage of the strength of [¹¹C]PHNO for measuring the small DA signal induced by nicotine, which has been difficult to measure in preclinical and clinical neuroimaging studies. Nicotine- and amphetamine-induced DA release in non-human primates was measured with [¹¹C]PHNO and [¹¹C]raclopride positron emission tomography (PET) imaging. Seven adult rhesus monkeys were imaged on a FOCUS 220 PET scanner after injection of a bolus of [¹¹C]PHNO or [¹¹C]raclopride in three conditions: baseline; preinjection of nicotine (0.1 mg/kg bolus+0.08 mg/kg infusion over 30 min); preinjection of amphetamine (0.4 mg/kg, 5 min before radiotracer injection). DA release was measured as change in binding potential (BP_ND). Nicotine significantly decreased BP_ND in the caudate (7±8%), the nucleus accumbens (10±7%), and in the globus pallidus (13±15%) measured with [¹¹C]PHNO, but did not significantly decrease BP_ND in the putamen or the substantia nigra or in any region when measured with [¹¹C]raclopride. Amphetamine significantly reduced BP_ND in all regions with both radiotracers. In the striatum, larger amphetamine-induced changes were detected with [¹¹C]PHNO compared with [¹¹C]raclopride (52–64% vs 33–35%, respectively). We confirmed that [¹¹C]PHNO is more sensitive than [¹¹C]raclopride to nicotine- and amphetamine-induced DA release. [¹¹C]PHNO PET may be more sensitive to measuring tobacco smoking-induced DA release in human tobacco smokers.     

Occupancy of dopamine D2 and D3 and serotonin 5-HT1A receptors by the novel antipsychotic drug candidate, cariprazine (RGH-188), in monkey brain measured using positron emission tomography

Rationale

Cariprazine is a novel antipsychotic drug candidate that exhibits high selectivity and affinity to dopamine D₃ and D₂ receptors and moderate affinity to serotonin 5-HT_1A receptors. Targeting receptors other than D₂ may provide a therapeutic benefit for both positive and negative symptoms associated with schizophrenia. Positron emission tomography (PET) can be used as a tool in drug development to assess the in vivo distribution and pharmacological properties of a drug.

Objectives

The objective of this study was to determine dopamine D₂/D₃ and serotonin 5-HT_1A receptor occupancy in monkey brain after the administration of cariprazine.

Methods

We examined three monkeys using the following PET radioligands: [¹¹C]MNPA (an agonist at D₂ and D₃ receptors), [¹¹C]raclopride (an antagonist at D₂ and D₃ receptors), and [¹¹C]WAY-100635 (an antagonist at 5-HT_1A receptors). During each experimental day, the first PET measurement was a baseline study, the second after a low dose of cariprazine, and the third after the administration of a high dose.

Results

We found that cariprazine occupied D₂/D₃ receptors in a dose-dependent and saturable manner, with the lowest dose occupying ~5% of receptors and the highest dose showing more than 90% occupancy. 5-HT_1A receptor occupancy was considerably lower compared with D₂/D₃ occupancy at the same doses, with a maximal value of ~30% for the raphe nuclei.

Conclusions

We conclude that cariprazine binds preferentially to dopamine D₂/D₃ rather than to serotonin 5-HT_1A receptors in monkey brain. These findings can be used to guide the selection of cariprazine dosing in humans.