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Background The in vivo binding of clinical dose of venlafaxine on norepinephrine transporter has been questioned because venlafaxine has higher in vitro affinity to serotonin transporter than that to norepinephrine transporter. Although serotonin transporter occupancy of clinically relevant doses of venlafaxine has been reported, there has been no report of norepinephrine transporter occupancy in the human brain. Methods This was an open-label, single center, exploratory positron emission tomography study. Twelve major depressive disorder patients who had responded to venlafaxine extended-release and 9 control subjects were recruited. Each subject participated in one positron emission tomography measurement with [18F]FMeNER-D2. Binding potential in brain was quantified by the area under the curve ratio method with thalamus as target and white matter as reference regions. The difference of binding potential values between control and patient groups divided to 2 dose ranges were evaluated. Norepinephrine transporter occupancy (%) for all the major depressive disorder patients was calculated using mean binding potential of control subjects as baseline. The relationships between dose or plasma concentration of total active moiety and occupancies of norepinephrine transporter were also estimated. Results The binding potential of the patient group with 150 to 300 mg/d was significantly lower than that in the control subjects group (P =.0004 <.05/2). The norepinephrine transporter occupancy (8–61%) increased in a dose-dependent manner although a clear difference beyond 150 mg/d was not observed. Conclusions This study demonstrates that clinically relevant doses of venlafaxine extended-release block the norepinephrine transporter of the major depressive disorder patient's brain. The data support the notion that the antidepressant effect of venlafaxine involves a combination of serotonin transporter and norepinephrine transporter blockades. [ABSTRACT FROM AUTHOR]

Background Tramadol, a centrally acting analgesic drug, has relatively high affinity to serotonin transporter and norepinephrine transporter in addition to μ-opioid receptor. Based on this characteristic, tramadol is expected to have an antidepressant effect. Methods Positron emission tomography measurements with [11C]MADAM and [18F]FMeNER-D2 were performed at baseline and after i.v. administration of 3 different doses (1, 2, and 4 mg/kg) of tramadol using 6 cynomolgus monkeys. The relationship between dose and occupancy for serotonin transporter and norepinephrine transporter was estimated. Results Tramadol occupied similarly both serotonin transporter (40%–72%) and norepinephrine transporter (7%–73%) in a dose-dependent manner. The Kd was 2.2 mg/kg and 2.0 mg/kg for serotonin transporter and norepinephrine transporter, respectively. Conclusions Both serotonin transporter and norepinephrine transporter of in vivo brain were blocked at >70% at a clinically relevant high dose of tramadol. This study suggests tramadol has potential antidepressant effects through the inhibition of serotonin transporter and norepinephrine transporter in the brain. [ABSTRACT FROM AUTHOR]

Tramadol is used for the treatment of pain, and it is generally believed to activate the μ-opioid receptor and inhibit serotonin (5-HT) and norepinephrine (NE) transporters. Recent findings from animal experiments suggest that 5-HT reuptake inhibition in brain is related to pain reduction. However, there has been no report of 5-HT transporter (5-HTT) occupancy by tramadol at clinical doses in humans. In the present study, we investigated 5-HTT occupancy by tramadol in five subjects receiving various doses of tramadol by using positron emission tomography (PET) scanning with the radioligand [11C]DASB. Our data showed that mean 5-HTT occupancies in the thalamus by single doses of tramadol were 34.7% at 50 mg and 50.2% at 100 mg. The estimated median effective dose (ED50) of tramadol was 98.1 mg, and the plasma concentration was 0.33 μg/ml 2 h after its administration; 5-HTT occupancy by tramadol was dose-dependent. We estimated 5-HTT occupancy at 78.7% upon taking an upper limit dose (400 mg) of tramadol. The results of the present study support the finding that 5-HTT inhibition is involved in the mechanism underlying the analgesic effect of tramadol in humans, and a clinical dose of tramadol sufficiently inhibits 5-HTT reuptake; this inhibition is similar to that shown by selective serotonin reuptake inhibitors (SSRIs). [ABSTRACT FROM PUBLISHER]

Modafinil, a wake-promoting drug used to treat narcolepsy, is a dopamine transporter inhibitor and is said to have very low abuse liability; this, however, is still up for debate. We conducted a dopamine transporter (DAT) occupancy study with modafinil (200 or 300 mg) in ten healthy volunteers using positron emission tomography (PET) with [18F]FE-PE2I, a new PET radioligand with high affinity and selectivity for the dopamine transporter, to characterize its relation to abuse liability. Mean striatal DAT occupancies were 51.4% at 200 mg and 56.9% at 300 mg. There was a significant correlation between occupancy and plasma concentration, indicating dose dependency of DAT inhibition by modafinil in the striatum, and especially in the nucleus accumbens. This study showed that DAT occupancy by modafinil was close to that of methylphenidate, indicating that modafinil may be near the same level as methylphenidate in relation to abuse liability in terms of dopaminergic transmission. [ABSTRACT FROM PUBLISHER]

Inflammatory/immunological process and glial contribution are suggested in the pathophysiology of schizophrenia. We investigated peripheral benzodiazepine receptors in brains of patients with chronic schizophrenia, which were reported to be located on mitochondria of glial cells, using [11C]DAA1106 with positron emission tomography. Fourteen patients and 14 age- and sex-matched normal controls participated in this study. PET data were analysed by two-tissue compartment model with metabolite-corrected plasma input. Clinical symptoms were assessed using the Positive and Negative Syndrome Scale. There was no significant difference between [11C]DAA1106 binding of the cortical regions of normal controls and patients with schizophrenia, whereas the patients showed a positive correlation between cortical [11C]DAA1106 binding and positive symptom scores. There was also a positive correlation between [11C]DAA1106 binding and duration of illness. Although the correlations need to be interpreted very cautiously, involvement of glial reaction process in the pathophysiology of positive symptoms or progressive change of schizophrenia might be suggested. [ABSTRACT FROM AUTHOR]

In our previous positron emission tomography (PET) study, we demonstrated that ECT decreased dopamine D2 receptor in major depressive disorder (MDD). Although many animal studies have focused on the effect of ECT on serotonergic neurotransmission, no human study has directly examined the effect of ECT on brain serotonin [5-hydroxytryptamine (5-HT)] 1A receptors (5-HT1ARs). Using PET with [11C]WAY 100635, we aimed to evaluate the effect of ECT on 5-HT1ARs in patients with MDD. Nine patients underwent PET scans before and after a series of 6-7 bilateral ECTs. Region-of-interest analysis was performed based on the simplified reference tissue model. There were no significant changes in 5-HT1AR binding in patients between before and after ECT. ECT did not alter [11C]WAY 100635 binding even after recovery from depressive episode. Although the present finding does not exclude the involvement of brain 5-HT1A systems in the antidepressant action of ECT, it may indicate the involvement of other neurotransmission mechanisms. [ABSTRACT FROM AUTHOR]

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 nonnegligible 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. [ABSTRACT FROM AUTHOR]

Modafinil, a wake-promoting drug used to treat narcolepsy, is a dopamine transporter inhibitor and is said to have very low abuse liability; this, however, is still up for debate. We conducted a dopamine transporter (DAT) occupancy study with modafinil (200 or 300 mg) in ten healthy volunteers using positron emission tomography (PET) with [¹⁸F]FE-PE2I, a new PET radioligand with high affinity and selectivity for the dopamine transporter, to characterize its relation to abuse liability. Mean striatal DAT occupancies were 51.4% at 200 mg and 56.9% at 300 mg. There was a significant correlation between occupancy and plasma concentration, indicating dose dependency of DAT inhibition by modafinil in the striatum, and especially in the nucleus accumbens. This study showed that DAT occupancy by modafinil was close to that of methylphenidate, indicating that modafinil may be near the same level as methylphenidate in relation to abuse liability in terms of dopaminergic transmission.

Norepinephrine transporter (NET) plays important roles in the treatment of various neuropsychiatric disorders, such as depression and attention deficit hyperactivity disorder (ADHD). Nortriptyline is a NET-selective tricyclic antidepressant (TCAs) that has been widely used for the treatment of depression. Previous positron emission tomography (PET) studies have reported over 80% serotonin transporter occupancy with clinical doses of selective serotonin reuptake inhibitors (SSRIs), but there has been no report of NET occupancy in patients treated with relatively NET-selective antidepressants. In the present study, we used PET and (S,S)-[18¹⁸F]FMeNER-D₂ to investigate NET occupancies in the thalamus in 10 patients with major depressive disorder taking various doses of nortriptyline, who were considered to be responders to the treatment. Reference data for the calculation of occupancy were derived from age-matched healthy controls. The result showed approximately 50-70% NET occupancies in the brain as a result of the administration of 75-200 mg/d of nortriptyline. The estimated effective dose (ED₅₀) and concentration (EC₅₀) required to induce 50% occupancy was 65.9 mg/d and 79.8 ng/ml, respectively. Furthermore, as the minimum therapeutic level of plasma nortriptyline for the treatment of depression has been reported to be 70 ng/ml, our data indicate that this plasma nortriptyline concentration corresponds to approximately 50% NET occupancy measured with PET, suggesting that more than 50% of central NET occupancy would be appropriate for the nortriptyline treatment of patients with depression.

The increased proportion of the high-affinity state of dopamine D2/3 receptors (D2,high) is assumed to correlate with dopamine hypersensitivity, implying a relationship with psychotic symptoms observed in psychiatric disorders such as schizophrenia. [11C](R)-2-CH3O-N-n-propylnorapomorphine ([11C]MNPA), which has an agonistic property to dopamine D2 receptors (D2Rs), is expected to bind preferentially to D2,high. The occupancy of dopamine D2Rs by antagonists to receptors has not been investigated using [11C]MNPA. We compared dopamine D2R occupancies by risperidone, an antagonist to receptors, between [11C]MNPA and [11C]raclopride to confirm whether risperidone occupies D2,high and D2,low at almost identical proportions. PET studies were performed on 11 healthy men under resting condition and following oral administration of a single dose of risperidone (0.5-2.0 mg). Striatal receptor occupancy for each radioligand was calculated. The relationship between dose or plasma concentration of risperidone and dopamine D2R occupancy was calculated. Striatal dopamine D2R occupancies measured with [11C]MNPA and [11C]raclopride were 22-65% and 24-69%, respectively. In the striatum, ED50 values measured with [11C]MNPA and [11C]raclopride were 0.98 and 1.03 mg, respectively. The striatal ED50 values as calculated from plasma concentration were 9.15 ng/ml and 8.01 ng/ml, respectively. Almost identical occupancies and ED50 values were observed between the two radioligands, indicating that risperidone bound to D2,high and D2,low at almost identical proportions in a dose-dependent manner.

Inflammatory/immunological process and glial contribution are suggested in the pathophysiology of schizophrenia. We investigated peripheral benzodiazepine receptors in brains of patients with chronic schizophrenia, which were reported to be located on mitochondria of glial cells, using [11C]DAA1106 with positron emission tomography. Fourteen patients and 14 age- and sex-matched normal controls participated in this study. PET data were analysed by two-tissue compartment model with metabolite-corrected plasma input. Clinical symptoms were assessed using the Positive and Negative Syndrome Scale. There was no significant difference between [11C]DAA1106 binding of the cortical regions of normal controls and patients with schizophrenia, whereas the patients showed a positive correlation between cortical [11C]DAA1106 binding and positive symptom scores. There was also a positive correlation between [11C]DAA1106 binding and duration of illness. Although the correlations need to be interpreted very cautiously, involvement of glial reaction process in the pathophysiology of positive symptoms or progressive change of schizophrenia might be suggested.

In our previous positron emission tomography (PET) study, we demonstrated that ECT decreased dopamine D2 receptor in major depressive disorder (MDD). Although many animal studies have focused on the effect of ECT on serotonergic neurotransmission, no human study has directly examined the effect of ECT on brain serotonin [5-hydroxytryptamine (5-HT)] 1A receptors (5-HT1ARs). Using PET with [11C]WAY 100635, we aimed to evaluate the effect of ECT on 5-HT1ARs in patients with MDD. Nine patients underwent PET scans before and after a series of 6-7 bilateral ECTs. Region-of-interest analysis was performed based on the simplified reference tissue model. There were no significant changes in 5-HT1AR binding in patients between before and after ECT. ECT did not alter [11C]WAY 100635 binding even after recovery from depressive episode. Although the present finding does not exclude the involvement of brain 5-HT1A systems in the antidepressant action of ECT, it may indicate the involvement of other neurotransmission mechanisms.

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.