Dopamine D2 receptor occupancy in vivo by the novel atypical antipsychotic olanzapine — a123 IBZM single photon emission tomography (SPET) study

We have studied striatal D₂ dopamine binding in schizophrenic patients treated with the novel atypical antipsychotic drug, olanzapine.¹²³I iodobenzamide (IBZM) single photon emission tomography (SPET) was used to estimate striatal dopamine D₂ receptor binding in vivo. Patients were recruited from a prospective, double blind controlled trial of olanzapine versus haloperidol treatment. In vivo striatal D₂ binding data from olanzapine treated patients (n=6) were compared with previously reported data from typical antipsychotic responsive (n=10); clozapine (n=10); and risperidone (n=6) treated patient groups. Mean % Brief Psychiatric Rating Scale score (BPRS) improvement following olanzapine treatment was 49% (SD 44). The hypothesis that clinical improvement in olanzapine treated patients would be associated with higher mean striatal D₂ binding of¹²³I IBZM (reflecting lower levels of D₂ occupancy) than typical antipsychotic (1.25±0.05) or risperidone (1.24±0.04) treatment was confirmed. Olanzapine treated patients had similar levels of striatal D₂ binding in vivo (1.41±0.06) as those treated with clozapine (1.49±0.04). This preliminary evidence suggests olanzapine is another atypical antipsychotic drug in which therapeutic response is not associated with a high degree of striatal D₂ receptor occupancy in vivo.     

A positron emission tomography (PET) study of cerebral dopamine D<Subscript>2</Subscript> and serotonine 5-HT<Subscript>2A</Subscript> receptor occupancy in patients treated with cyamemazine (Tercian)

Rationale Cyamemazine (Tercian) is an antipsychotic drug with anxiolytic properties. Recently, an in vitro study showed that cyamemazine possesses high affinity for serotonin 5-HT_2A receptors, which was fourfold higher than its affinity for dopamine D₂ receptors (Hameg et al. 2003).Objectives The aim of this study is to confirm these previous data in vivo in patients treated with clinically relevant doses of Tercian.Methods Eight patients received 37.5, 75, 150 or 300 mg/day of Tercian depending on their symptomatology. Dopamine D₂ and serotonin 5-HT_2A receptor occupancies (RO) were assessed at steady-state plasma levels of cyamemazine with positron emission tomography (PET), using [¹¹C]raclopride and [¹¹C]N-methyl-spiperone, respectively. The effective plasma level of the drug leading to 50% of receptor occupancy was estimated by fitting RO with plasma levels of cyamemazine at the time of the PET scan.Results Cyamemazine induced near saturation of 5-HT_2A receptors (RO=62.1–98.2%) in the frontal cortex even at low plasma levels of the drug. On the contrary, occupancy of striatal D₂ receptors increased with plasma levels, and no saturation was obtained even at high plasma levels (RO=25.2–74.9%). The effective plasma level of cyamemazine leading to 50% of D₂ receptor occupancy was fourfold higher than that for 5-HT_2A receptors. Accordingly, individual 5-HT_2A/D₂ RO ratios ranged from 1.26 to 2.68. No patients presented relevant increased prolactin levels, and only mild extrapyramidal side effects were noticed on Simpson and Angus Scale.Conclusion This in vivo binding study conducted in patients confirms previous in vitro findings indicating that cyamemazine has a higher affinity for serotonin 5-HT_2A receptors compared to dopamine D₂ receptors. In the dose range 37.5–300 mg, levels of dopamine D₂ occupancy remained below the level for motor side effects observed with typical antipsychotics and is likely to explain the low propensity of the drug to induce extrapyramidal side effects.     

Clozapine binds preferentially to cortical D1-like dopamine receptors in the primate brain: a PET study

Rationale The D₁-like dopamine receptors have been suggested to play a role in the pathophysiology and treatment of schizophrenia. Previous positron emission tomography studies have demonstrated that the atypical antipsychotic clozapine occupies D₁-like dopamine receptors in the striatum in clozapine-treated patients. Objectives The aim of the present study was to compare striatal and cortical D₁-like dopamine receptor occupancy by clozapine in the primate brain. Methods Three monkeys were each examined three times at the same day with the radioligand (+)−[¹¹C]NNC 112. The first measurement was at baseline conditions, the second after 1.5 mg/kg and the third after 6 mg/kg clozapine IV. To compare regional levels of nonspecific binding in brain regions, an additional monkey was examined using the inactive enantiomer (−)−[¹¹C]NNC 112. Receptor occupancy was calculated using both the equilibrium–ratio analysis and the simplified reference tissue model. Results After 1.5 mg/kg the D₁-like dopamine receptor occupancy ranged from 30 to 38% in the striatum, whereas the range was 51 to 57% in the frontal cortex. After 6.0 mg/kg the occupancy was 53 to 64% in the striatum and 63 to 83% in the frontal cortex. The differences between striatal and cortical D₁-like receptors occupancy were between 12 and 25%. The study with (−)−[¹¹C]NNC 112 did not show regional differences in nonspecific binding that might explain the regional differences in occupancy. Conclusions The higher D₁-like dopamine receptor occupancy in the frontal cortex may reflect a different distribution of the D₁ and D₅ dopamine receptor subtypes among brain regions and different affinity of clozapine for the two subtypes. The finding supports the suggestion that binding to D₁-like dopamine receptors may explain clozapine’s atypical drug actions.     

Previous treatment as a confounding variable in studies with novel antipsychotics: two cases of high dopamine-2 receptor occupancy with quetiapine

Previous treatment can be a confounding variable in studies with novel antipsychotics. Quetiapine is a new antipsychotic substance with a low affinity for dopamine-2 (D₂) receptors. Preliminary SPECT and PET investigations revealed only a low striatal D₂ receptor occupancy rate. However, we present two cases of high striatal D2 receptor occupancy (51% and 71%) measured with ¹²³I IBZM SPECT during quetiapine monotherapy. Both patients had previously received continuous treatment with typical neuroleptics. We present evidence that the previous antipsychotic therapy influenced D₂ receptor binding of ¹²³I IBZM during quetiapine treatment weeks after cessation of typical neuroleptics. This might be of importance for the design of clinical trials and brain imaging studies in the future. Received: 14 April 1997 /Final version: 14 May 1997     

Dose dependent occupancy of central dopamine D2 receptors by the novel neuroleptic CP-88,059-01: a study using positron emission tomography and11C-raclopride

Positron emission tomography (PET) and¹¹C-raclopride were used to measure the occupancy of central dopamine D₂ receptors by a new neuroleptic, CP-88,059-1. In a double blind dose escalation study, seven healthy male subjects received a predose of between 2 mg and 60 mg CP-88,059-1, 5 h before PET scanning. One additional subject was assigned to placebo predose. Receptor occupancy was defined as the percentage reduction in binding potential compared with that seen in the subject predosed with placebo and with that seen in seven unmedicated normal volunteers previously studied. Binding of¹¹C-raclopride decreased in a dose dependent manner, and 85% dopamine D₂ receptor occupancy was achieved with the highest dose of CP-88,059-1. The findings confirm that brain dopamine D₂ receptors are blocked by CP-88,059-1 and suggest that an effective antipsychotic dose will be between 20 mg and 40 mg. The study highlights the potential of positron emission tomography in the preclinical evaluation of new drugs.     

In vivo occupancy of dopamine D2 receptors by antipsychotic drugs and novel compounds in the mouse striatum and olfactory tubercles

Interaction with dopamine D₂-like receptors plays a major role in the therapeutic effects of antipsychotic drugs. We examined in vivo dopamine D₂ receptor occupancy of various established and potential antipsychotics in mouse striatum and olfactory tubercles 1 h after administration of the compound, using [³H]nemonapride as a ligand. All the compounds reduced in vivo binding of [³H]nemonapride in the striatum. When administered systemically, conventional antipsychotics, D₂ antagonists, nemonapride (ID₅₀: 0.034 mg/kg), eticlopride (0.047), haloperidol (0.11) and raclopride (0.11) potently inhibited [³H]nemonapride binding. The ‘atypical’ antipsychotics, risperidone (0.18), ziprasidone (0.38), aripiprazole (1.6), olanzapine (0.99), and clozapine (11.1) were less potent for occupying D₂-like receptors. New compounds, displaying marked agonism at 5-HT_1A receptors in addition to D₂ receptor affinity, exhibited varying D₂ receptor occupancy: bifeprunox (0.25), SLV313 (0.78), SSR181507 (1.6) and sarizotan (6.7). ID₅₀ values for inhibition of [³H]nemonapride binding in the striatum correlated with those in the olfactory tubercles (r=0.95, P<0.0001). These values also correlated with previously-reported in vitro affinity of the compounds at rat D₂ receptors (r=0.85, P=0.0001) and with inhibition of apomorphine-induced climbing in mice (r=0.79 P=0.0005). In contrast, there was no significant correlation between ID₅₀ values herein and previously-reported ED₅₀ values for catalepsy in mice. These data indicate that: (1) there is no difference in D₂ receptor occupancy in limbic versus striatal regions between most classical and atypical or potential antipsychotics; and (2) high occupancy of D₂ receptors can be dissociated from catalepsy, if the drugs also activate 5-HT_1A receptors. Taken together, these data support the strategy of simultaneously targeting D₂ receptor blockade and 5-HT_1A receptor activation for new antipsychotics.     

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.     

Striatal D2 dopamine receptor binding characteristics in vivo in patients with alcohol dependence

Striatal D₂ dopamine receptor characteristics of nine male patients with alcohol dependence abstinent for 1–68 weeks and eight healthy male volunteers were studied in vivo with positron emission tomography. The selective D₂ receptor ligand [¹¹C]raclopride and equilibrium model was used for D₂ receptor density (B_max) and affinity (K_d) measurements. A trend for a decreased striatal D₂ receptor density and for reduced D₂ receptor affinity was observed in patients with alcohol dependence. These parameters were not statistically significantly different between alcoholics and controls, but the ratio between D₂ receptor density and affinity (B_max/K_d or the striatum/cerebellum ratio from the high specific activity scan) was highly significantly lower in alcoholics than that of controls. In conclusion, the low D₂ dopamine receptor B_max/K_d ratio (striatum/cerebellum ratio) indicates that specific aspects of striatal [¹¹C]raclopride binding in vivo are deviant in alcoholics compared to controls. The result is compatible with a reduced avidity of striatal dopamine D₂ receptors in alcoholics, which is in line with the idea that D₂ dopaminergic mechanisms are involved in the biology of alcohol dependence in man.     

Differential effects of olanzapine at dopamine D1 and D2 receptors in dopamine depleted animals

We investigated the degree of striatal dopamine-2 (D₂) receptor occupancy in six schizophrenic patients receiving clinically effective antipsychotic treatment with olanzapine 10–25 mg/day in comparison to patients treated with clozapine 300–600 mg/day (n = 6) or haloperidol 5–20 mg/day (n = 10). ¹²³I Iodobenzamide (IBZM) and single photon emission computerized tomography (SPECT) were used for the visualization of striatal D₂ receptors. For the quantification of striatal D₂ receptor occupancy, striatal IBZM binding in patients treated with antipsychotics was compared to that in untreated healthy controls (n = 8) reported earlier. Olanzapine led to a mean striatal D₂ receptor occupancy rate of 75% (range 63–85). Haloperidol-treated patients showed dose-dependently (Pearson r = 0.64; P < 0.05) a significantly higher (P < 0.05) mean occupancy rate of 84% (range 67–94). During clozapine treatment, the mean D₂ receptor occupancy of 33% (range < 20–49) was significantly lower than with olanzapine (P < 0.005). The higher striatal D₂ receptor occupancy of haloperidol was correlated with the incidence and severity of extrapyramidal motor side-effects (EPS). No clinical relevant EPS occurred during treatment with olanzapine or clozapine. There was no correlation between the degree of striatal D₂ receptor occupancy and clinical improvement. Received: 18 March 1998/Final version: 10 June 1998     

Prolactinemia is uncoupled from central D<Subscript>2</Subscript>/D<Subscript>3</Subscript> dopamine receptor occupancy in amisulpride treated patients

Rationale Atypical antipsychotic drugs are classically associated with lower propensity to extrapyramidal symptoms (EPS) and hyperprolactinemia than typical antipsychotic drugs. It has not been clarified why some atypical antipsychotic drugs, such as amisulpride, induce prolactin plasma concentration (PRL) elevation, but little EPS. Previous studies have found an association between striatal D₂/D₃ receptor occupancy and PRL in typical antipsychotic treated patients suggesting that PRL is a marker of central D₂/D₃ receptors blockade.Objective We have evaluated the relationship between PRL and central (striatum, temporal cortex and thalamus) D₂/D₃ receptor occupancy in amisulpride treated schizophrenic patients.Methods Single photon emission tomography (SPET) and [¹²³I]-epidepride were used to determine D₂/D₃ receptor occupancy in eight amisulpride treated patients. PRL was measured concurrently with the scans.Results The mean PRL was 1166 (range 499–1892 mIU/l) for a mean amisulpride dose of 406 mg/day (range 150–600 mg/day). Amisulpride plasma concentration and central D₂/D₃ receptor occupancy were positively correlated (r=0.83–0.89, df=4, P<0.05). No significant correlations were observed between PRL and amisulpride (daily dose or plasma concentration, P>0.05), or between PRL and central D₂/D₃ receptor occupancy (P>0.05).Conclusions Our findings show that amisulpride-induced hyperprolactinemia is uncoupled from central D₂/D₃ receptor occupancy. Amisulpride has poor blood–brain barrier penetration and reaches much higher concentration at the pituitary, which is outside the blood–brain barrier. Higher D₂/D₃ receptor occupancy at the pituitary gland than at central regions is a possible explanation for amisulpride PRL elevation with low EPS. Further studies evaluating pituitary D₂/D₃ receptor occupancy in vivo are necessary to confirm this hypothesis.This study was partially presented (poster) at the International Congress on Schizophrenia Research, Colorado Springs, USA, 2003 and received the Young Investigator Award.     

Occupancy of dopamine D2 receptors by the atypical antipsychotic drugs risperidone and olanzapine: theoretical implications

Rationale To examine the D₂ occupancy of two commonly used antipsychotic medications and relate this to the D₂ occupancy by endogenous dopamine in schizophrenia.Objectives The aim of this study is to compare the occupancy of striatal D₂ receptors by the atypical antipsychotic medications risperidone and olanzapine at fixed dosages and to estimate the effect on D₂ occupancy by dopamine as a result of these treatments.Methods Seven patients with schizophrenia taking risperidone 6 mg/day and nine patients with schizophrenia taking olanzapine 10 mg/day underwent an [¹²³I]IBZM SPECT scan after 3 weeks of treatment. The specific to non-specific equilibrium partition coefficient (V₃) after bolus plus constant infusion of the tracer was calculated as [(striatal activity)/(cerebellar activity)]–1. D₂ receptor occupancy was calculated by comparing V₃ measured in treated patients to an age-corrected V₃ value derived from a group of untreated patients with schizophrenia, previously published, according to the following formula: OCC=1–(V₃ treated/V₃ drug free).Results V₃ was significantly lower in risperidone treated patients compared with olanzapine treated patients (0.23±0.06 versus 0.34±0.08, P=0.01), which translated to a significantly larger occupancy in schizophrenic patients treated with risperidone compared to olanzapine (69±8% versus 55±11%, P=0.01). Data from our previous study were used to calculate the occupancy of striatal D₂ receptors by antipsychotic medications required to reduce the occupancy of these receptors by endogenous dopamine to control values. In medication-free patients with schizophrenia, the occupancy of striatal D₂ receptors by endogenous dopamine is estimated at 15.8%. In healthy controls, the occupancy of striatal D₂ receptors by dopamine is estimated at 8.8%. In order to reduce the dopamine occupancy of striatal D₂ receptors in patients with schizophrenia to control values, 48% receptor occupancy by antipsychotic medications is required.Conclusions These data indicate that the dosage of these medications, found to be effective in the treatment of schizophrenia, reduces DA stimulation of D₂ receptors to levels slightly lower than those found in unmedicated healthy subjects.     

Dopamine D2 receptor blockade in vivo with the novel antipsychotics risperidone and remoxipride — an123I-IBZM single photon emission tomography (SPET) study

Risperidone and remoxipride are recently introduced atypical antipsychotics, with clinical efficacy comparable to that of classical antipsychotics but lower propensity to induce extrapyramidal side effects (EPS). It is unclear whether these properties relate to weak dopamine D₂ receptor blockade in vivo, as has been suggested for the archetypal atypical antipsychotic clozapine. We have used¹²³I-IBZM single photon emission tomography (SPET) to characterize the patterns of striatal D₂ receptor binding in vivo in DSMIII-R-diagnosed schizophrenic and schizo-affective patients treated with either risperidone (n=6) or remoxipride (n=4) but predominantly EPS free. These groups were compared to age- and BPRS- matched subjects from a previously reported D₂ receptor binding database of patients treated with clozapine (n=10) and classical antipsychotics (n=10). Patients on risperidone and remoxipride had high levels of D₂ receptor blockade, comparable to those of patients on classical antipsychotics, and significantly greater than those obtained with clozapine-treated patients (risperidone versus clozapine,P<0.005; remoxipride versus clozapine,P<0.025). These results suggest high levels of striatal D₂ receptor occupancy in association with remoxipride and risperidone treatment and argue against modest D₂ antagonism as the explanation for the low incidence of EPS associated with these drugs.     

Sertindole and dopamine D2 receptor occupancy in comparison to risperidone, clozapine and haloperidol – a 123I-IBZM SPECT study

The striatal D₂ dopamine binding was studied in schizophrenic patients treated with the novel atypical antipsychotic drug sertindole (n = 10). Comparisons were obtained with haloperidol (n = 8), clozapine (n = 6), risperidone (n = 11) and untreated healthy controls (n = 8) of a dataset which has partly been reported previously. ¹²³I-Iodobenzamide (IBZM) single photon emission computerized tomography (SPECT) was used for estimation of striatal dopamine D₂ receptor binding. Sertindole-treated patients exhibited significantly (P < 0.001) lower levels of striatal D₂ binding (BG/FC ratio:1.28) compared with those treated with haloperidol (BG/FC ratio:1.09) and risperidone (8 mg:1.18) but significantly (P < 0.005) higher levels compared with clozapine (BG/FC ratio:1.49). However, if patients were pretreated with a depot neuroleptic, significantly (P < 0.05) higher striatal D₂ binding (BG/FC ratio:1.12) has been obtained. Since sertindole has been shown to exert distinct clinical efficacy for treatment of positive and negative symptoms, our data are indicative that antipsychotic efficacy is not associated with a high degree of striatal D₂ receptor occupancy in schizophrenic patients. Received: 21 July 1997/Final version: 27 October 1997     

Dopamine and depression — Striatal dopamine D2 receptor SPECT before and after antidepressant therapy

Ten unmedicated and ten medicated patients with major depression and ten controls were investigated with IBZM-SPECT. The ten unmedicated patients were reinvestigated after treatment with tricyclic antidepressants. Dopamine D₂ receptor occupancy was not different between patients and controls, or medicated and unmedicated patients. IBZM binding was increased in four patients with psychomotor retardation. Antidepressant therapy led to a decrease in IBZM binding in the five improved patients. Dopamine D₂ receptor binding remained unchanged in nonresponders. It is concluded that striatal dopamine D₂ receptor binding is not changed in depression or by tricyclic antidepressants; however, it is affected by psychomotor activity. The changes observed might be the result of increased tonic dopamine release in the basal ganglia, but several other explanations exist.     

In vivo (123)I IBZM SPECT imaging of striatal dopamine 2 receptor occupancy in schizophrenic patients

RATIONALE: Single photon emission computed tomography (SPECT) using (123)I iodobenzamide (IBZM) as tracer substance has been shown to be a useful tool to visualize dopamine 2 (D2) receptor occupancy. OBJECTIVES: We investigated the striatal D2 receptor occupancy of zotepine which is referred to the class of atypical antipsychotic drugs. METHODS: (123)I IBZM and SPECT were used to visualize striatal dopamine 2 (D2) receptor occupancy in zotepine-treated schizophrenic patients. Two groups of schizophrenic patients receiving either 150 mg/day zotepine (n=6) or 300 mg/day (n=6) underwent examination. For the quantification of striatal D2 receptor occupancy, striatal IBZM binding in patients treated with antipsychotics was compared to untreated healthy controls (n=8) reported earlier. RESULTS: Zotepine led to a mean overall striatal D2 receptor occupancy of 73%. Patients with 150 mg daily showed a significantly lower occupancy (65.8%, SD=6.2) than patients with 300 mg/day (77.8%, SD=10.7; P<0.05). No clinically relevant extrapyramidal side effects occurred during treatment with zotepine. CONCLUSIONS: There was no correlation between the degree of striatal D2 receptor occupancy and clinical improvement.     

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.     

Dopamine D2 receptors selectively labeled by a benzamide neuroleptic: [3H]-YM-09151-2

Summary In order to label dopamine D₂ receptors selectively we tritiated the potent benzamide neuroleptic, YM-09151-2 (26.7 Ci/mmol). The binding of [³H]-YM-09151-2 to canine striatal membranes was saturable and specific with a K _D of 57 pmol/l and B _max of 36 pmol/g tissue as determined by Scatchard analysis. The K _D, but not the B _max, of [³H]-YM-09151-2 increased 6-fold in the absence of sodium chloride. [³H]-YM-09151-2 labeled 40% more sites than [³H]-spiperone in the same tissue homogenate. [³H]-YM-09151-2 binding was inhibited by dopaminergic drugs in a concentration and stereoselective manner with the appropriate dopamine D₂ receptor profile. Thus, dopamine agonists inhibited [³H]-YM-09151-2 binding to canine striatal membranes with the following rank order of potency: (–)-N-n-propylnorapomorphine > apomorphine > (±)-6,7-dihydroxy-2-aminotetralin > (+)-N-n-propylnorapomorphine > dopamine > (–)-noradrenaline > serotonin > (–)-isoprenaline. Dopaminergic antagonists competed for [³H]-YM-09151-2 binding with the following order of potency: spiperone > (+)-butaclamol > haloperidol > clebopride > (–)-sulpiride > SCH-23390 > (–)-butaclamol. Furthermore, dopamine agonists recognized 2 states of the receptor labeled by [³H]-YM-09151-2, D ₂ ^high and D ₂ ^low . The D ₂ ^high state of the receptor could be converted to D ₂ ^low by guanine nucleotides and sodium ions as is the case for [³H]-spiperone binding to D₂ receptors. [³H]-YM-09151-2 appears to be a more selective ligand for dopamine D₂ receptors than [³H]-spiperone, since YM-09151-2 displays approximately 9-fold lower affinity than spiperone for cortical serotonergic (S₂) receptors. [³H]-YM-09151-2 may become a useful tool for the selective characterization of dopamine D₂ receptors.Abbreviations used (±)ADTN (±)-2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene - NPA N-n-propylnorapomorphine - Gpp(NH)p 5-guanylylimidodiphosphate     

NCQ 298, a new selective iodinated salicylamide ligand for the labelling of dopamine D2 receptors

NCQ 298 ((S)-3-iodo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5,6-dimethoxysalicylamide) has an iodine substituent. We have labelled NCQ 298 with¹²³I and¹²⁵I, and used the radioligands as tracers in receptor studies in vitro, in vivo in autoradiography and in SPECT studies on Cynomolgus monkeys.[¹²⁵I]NCQ 298 bound in vitro to a single binding site with a K^D=19 pM. NCQ 298 has thus a 10-fold higher affinity for the dopamine D₂ receptors than the corresponding des-5-methoxy compound FLA 961 (IBZM), previously used in SPECT studies. The binding of [¹²⁵I]NCQ 298 was entirely reversible (T1/2=17.5 min at 37° C). Autoradiographical studies in vitro on rat and monkey brain tissue sections showed a distinct binding in caudate-putamen, nucleus accumbens, substantia nigra, and in layer 5 of the cerebral cortex. In vivo binding studies in mice showed a ratio of 10 between [¹²⁵I]NCQ 298 binding in striatum and cerebellum. Binding was displaced by the selective dopamine D₂ receptor antagonist raclopride. In SPECT studies with [¹²³I]NCQ 298 in two Cynomolgus monkeys, radioactivity accumulated in the basal ganglia. The measured striatum to cerebellum ratio was about 15 after 3 h. A monkey brain phantom was constructed for the determination of conversion factors from pixel events to actual radioactivity. The resulting, corrected striatum to cerebellum ratio obtained was 30. After administration of 12 mg raclopride to one of the monkeys there was a substantial decrease in striatal radioactivity. [¹²⁵I]NCQ 298 is a suitable ligand for the labelling of dopamine D₂ receptors in vitro and in vivo. The specific properties of [¹²³I]NCQ 298 suggest that this compound is a useful ligand for quantitative SPECT studies of dopamine D₂ receptors in man.     

Savoxepine: striatal dopamine-D2 receptor occupancy in human volunteers measured using positron emission tomography (PET)

Summary The extent and duration of striatal dopamine-D₂ receptor occupancy by savoxepine in humans has been studied using positron emission tomography with [¹¹C]-raclopride, in order to investigate why the anticipated favourable ratio between its extrapyramidal and antipsychotic effects was not achieved in practice.After 0.25 mg savoxepine, striatal D₂ receptor occupancy peaked at 50–60% after 24–36 h and disappeared within 6 days. After doses of 0.1 mg to 0.5 mg, D₂ receptor occupancy in the putamen and caudate nucleus increased from 20 to 70% 3–7 h after administration and amounted to 40 to 75% at the peak time (20–29 h).This suggests that cumulative D₂ receptor blockade would occur if equal or increasing doses of savoxepine were given repeatedly. Extrapyramidal adverse-effects would be likely to occur under such circumstances. An adequate test of the theory that preference for hippocampal dopamine D₂ receptors with afford a good therapeutic ratio requires an alternative dosing regimen.     

Heightened D3 Dopamine Receptor Levels in Cocaine Dependence and Contributions to the Addiction Behavioral Phenotype: A Positron Emission Tomography Study with [11C]-(+)-PHNO

The dopamine system is a primary treatment target for cocaine dependence (CD), but research on dopaminergic abnormalities (eg, D₂ receptor system deficiencies) has so far failed to translate into effective treatment strategies. The D₃ receptor system has recently attracted considerable clinical interest, and D₃ antagonism is now under investigation as a novel avenue for addiction treatment. The objective here was to evaluate the status and behavioral relevance of the D₃ receptor system in CD, using the positron emission tomography (PET) radiotracer [¹¹C]-(+)-PHNO. Fifteen CD subjects (many actively using, but all abstinent 7–240 days on scan day) and fifteen matched healthy control (HC) subjects completed two PET scans: one with [¹¹C]-(+)-PHNO to assess D₃ receptor binding (BP_ND; calculated regionally using the simplified reference tissue model), and for comparison, a second scan with [¹¹C]raclopride to assess D_2/3 binding. CD subjects also completed a behavioral battery to characterize the addiction behavioral phenotype. CD subjects showed higher [¹¹C]-(+)-PHNO BP_ND than HC in the substantia nigra, which correlated with behavioral impulsiveness and risky decision making. In contrast, [¹¹C]raclopride BP_ND was lower across the striatum in CD, consistent with previous literature in ⩾2 week abstinence. The data suggest that in contrast to a D₂ deficiency, CD individuals may have heightened D₃ receptor levels, which could contribute to addiction-relevant traits. D₃ upregulation is emerging as a biomarker in preclinical models of addiction, and human PET studies of this receptor system can help guide novel pharmacological strategies for treatment.