Biomedical subjects

Jun Maeda

Publications and source records attributed to Jun Maeda.

47 records · Page 3Linked to original sources

PubMed2003

Inhibitory effect of hippocampal 5-HT1A receptors on human explicit memory.

OBJECTIVE: Recent studies have indicated that the serotonergic (5-HT) system plays important roles in memory function. However, the specific relationship between 5-HT(1A) receptors and memory function is not clear in the human brain. To clarify this relationship, the authors determined the availability of 5-HT(1A) receptors in the human brain and the relationship between regional receptor binding and memory function. METHOD: Using positron emission tomography (PET) with [(11)C]WAY-100635, the authors examined 5-HT(1A) receptors and assessed their relationship with memory function. The 5-HT(1A )agonist tandospirone was then administered to investigate the effect of 5-HT(1A) receptor stimulation on cognitive function and neuroendocrinological response. RESULTS: There was a significant negative correlation between explicit memory function and 5-HT(1A) receptor binding localized in the bilateral hippocampus where the postsynaptic 5-HT(1A) receptors are enriched. Furthermore, the administration of tandospirone dose-dependently impaired explicit verbal memory, while other cognitive functions showed no significant changes. The change in memory function paralleled those of body temperature and secretion of growth hormone, which were reported to be induced by the stimulation of postsynaptic 5-HT(1A) receptors. CONCLUSIONS: Postsynaptic 5-HT(1A )receptors localized in the hippocampal formation have a negative influence on explicit memory function, which raises the possibility that the antagonistic effect of postsynaptic 5-HT(1A) receptors in the hippocampus leads to improvement of human memory function. Drugs that work as antagonists on postsynaptic 5-HT(1A) receptors may be favorable for improved control of memory impairment.

Adult↗

PubMed2003

Synthesis and brain regional distribution of [11C]NPS 1506 in mice and rat: an N-methyl-D-aspartate (NMDA) receptor antagonist.

NPS 1506 [3-fluoro-gamma-(3-fluorophenyl)-N-methylbenzenepropamine] is representative of a non-psychotomimetic class of N-methyl-D-aspartate (NMDA) receptor antagonists. [11C]NPS 1506 was prepared at high radiochemical purity (>98%) with a specific activity of around 50 GBq/micromol at the end of synthesis by methylation of the desmethyl precursor with [11C]methyl iodide in the presence of NaH. Biodistribution of [11C]NPS 1506 in mice and rat demonstrated that uptake into the brain was rapid and occurred at high levels. [11C]NPS 1506 showed no appreciable specific binding in rodent brains under in vivo conditions, possibly because of both a large non-specific bound fraction and low in vitro binding affinity for NMDA receptors.

Animals↗

PubMed2002

Macaque prefrontal activity associated with extensive tool use.

Macaques can utilize tools sequentially on a single object or they can modify functions effectively in a relevant context. Two Japanese macaques were scanned by positron emission tomography with H(2)15O during a tool combination task and two control tasks (single tool task and simple stick-waving task). In the tool combination task, monkeys were required to use two identical tools properly in different functions. We found increased activity in the bilateral prefrontal cortex (area 9/46), bilateral intraparietal sulcus regions, right cerebellum, and bilateral early visual cortices during the tool combination task with the right hand, compared with the single tool task. These results suggest that interactions between the fronto-cerebellar and the fronto-parietal circuit are responsible for appropriate and effective modifications of tools in their functions.

Animals↗

PubMed2002

In vivo drug action of tandospirone at 5-HT1A receptor examined using positron emission tomography and neuroendocrine response.

RATIONALE: Tandospirone is a selective 5-hydroxytryptamine (HT)(1A) receptor agonist and is clinically used as an anxiolytic in Japan. However, there are no data concerning the occupancy of these receptors by tandospirone in the living human brain. OBJECTIVES: The aim of this study was to assess the effect of tandospirone on in vivo 5-HT(1A) receptor binding of [(11)C]WAY 100635 using positron emission tomography (PET) and the neuroendocrine effect. METHODS: In the PET study, seven healthy volunteers were scanned three times following an oral dose of placebo or tandospirone (30 mg or 60 mg). The binding potential of [(11)C]WAY 100635 was estimated for six regions: prefrontal cortex, temporal cortex, anterior cingulate cortex, parietal cortex, hippocampus and dorsal raphe nucleus. In the neuroendocrine study, six volunteers received a single oral dose of tandospirone (60 mg) or placebo in a randomized double-blind, cross-over design, and then the plasma levels of growth hormone and cortisol and the body temperature were measured. RESULTS: Tandospirone (60 mg) induced a significant decrease in body temperature and an increase in the plasma concentration of growth hormone. However, there was no significant reduction of [(11)C]WAY 100635 binding following the administration of 30 mg or 60 mg tandospirone. CONCLUSION: Despite the significant effect on growth hormone and body temperature, a clinical dose of tandospirone had a negligible effect on [(11)C]WAY 100635 binding. This indicates that the agonist produces a pharmacological effect without measurable occupancy, and a new index other than occupancy will be required for the in vivo evaluation of agonists.

Adult↗

PubMed2002

Serotonin transporter binding in patients with mood disorders: a PET study with [11C](+)McN5652.

BACKGROUND: Several lines of studies have suggested the involvement of serotonin transporter (5-HTT) in the pathophysiology of mood disorders. The aim of this study was to examine whether 5-HTT binding was altered in patients with mood disorders using positron emission tomography (PET). METHODS: Thirteen antidepressant-naive or -free patients with mood disorders and 21 age-matched healthy control subjects participated in this study. The patients consisted of 7 with major depressive disorder (MDD) and 6 with bipolar disorder (BD). Positron emission tomography scans were performed using a selective ligand for 5-HTT, [11C](+)McN5652. The uptake was quantified in the thalamus and midbrain by graphical method with reference tissue, and binding potential (BP) was used for the index of 5-HTT binding. RESULTS: Binding potential in the thalamus was significantly increased in patients with mood disorders as compared to control subjects, whereas BP in the midbrain did not differ between the groups. Subgroup comparison showed that MDD patients had significantly higher BP in the thalamus compared to control subjects. Binding potential of the thalamus was higher by approximately 22% in the combined patients and 23% in MDD patients relative to control subjects. CONCLUSIONS: These findings may suggest the possibility of altered 5-HTT in patients with mood disorders. Functional abnormality in the thalamus may be involved in the pathophysiology of mood disorders.

Adult↗

PubMed2002

A positron-emitter labeled glycine(B) site antagonist, [(11)C]L-703,717, preferentially binds to a cerebellar NMDA receptor subtype consisting of GluR epsilon3 subunit in vivo, but not in vitro.

In previous studies, we have found that [(11)C]L-703,717, a positron-emitter labeled antagonist for the glycine-binding site of NMDA receptors, only localizes in rodent cerebellum under in vivo conditions. In order to understand the unusual cerebellar localization, we have examined the binding of [(11)C]L-703,717 to a cerebellar-specific NMDA receptor subtype consisting of GLuRepsilon3 subunit, by comparing its autoradiographic distributions between GluRepsilon3-deficient and wild-type mice. Ex vivo [(11)C]L-703,717 binding to wild-type mice showed a highly specific localization of radioactivity in the cerebellum, whereas that to the GluRepsilon3-deficient mice showed no specific localization of radioactivity in any of the brain regions. In contrast to the ex vivo binding, in vitro [(11)C]L-703,717 binding displayed a similar binding characteristic between GluRepsilon3-deficient and wild-type mice with highly specific localizations in the hippocampus and cerebral cortex. Therefore, the present study clearly demonstrated that [(11)C]L-703,717 preferentially binds to a cerebellar NMDA receptor subtype consisting of GluRepsilon3 subunit in vivo, but not in vitro.

Animals↗

PubMed2002

Syntheses and pharmacological evaluation of two potent antagonists for dopamine D4 receptors: [11C]YM-50001 and N-[2-[4-(4-Chlorophenyl)-piperizin-1-yl]ethyl]-3-[11C]methoxybenzamide.

Two benzamide derivatives as dopamine D4 receptor antagonists, YM-50001(4) and N- [2-[4-(4-chlorophenyl]piperizin-1-yl]ethyl]-3-methoxybenzamide (9), were labeled by positron-emitter (11C), and their pharmacological specificities to dopamine D4 receptors were examined by quantitative autoradiography and positron emission tomography (PET). Radiosyntheses were accomplished by O-methylation of corresponding phenol precursors (5 and 10) with [11C]CH3I followed by HPLC purifications. In vitro binding on rat brain slices showed different distribution patterns and pharmacological properties between the two radioligands. The [11C]4 showed the highest binding in the striatum, which was inhibited not only by 10 microM 4 but also by 10 microM raclopride, a selective dopamine D2 receptor antagonist. In contrast, [11C]9 showed the highest binding in the cerebral cortex, which was inhibited by several D4 receptor antagonists (9, RBI-254, L-745,870), but not by any other receptor ligands (D1/D5, D2/D3, 5-HT1A, 5-HT2A, sigma1 and alpha1) tested. In vivo brain distribution of [11C]9 in rat showed the highest uptake in the frontal cortex, a region that has a high density of D4 receptors. These results indicate that the pharmacological property of [11C]9 matches the rat brain D4 receptors, but that of [11C]4 rather appears to match the rat brain D2 receptors. The results for the benzamide [11C]9 prompted us to further evaluate its potential as a PET radioligand for D4 receptors by employing PET on monkey brain. Unfortunately, in contrast to rats, neither specific binding nor differences in regional uptake of radioactivity were observed in monkey brain after intravenous 11C]9 injection. Based on that specific activities of radioligands might be critical in mapping the neurotransmitter receptors if they are only faintly expressed in the brain, 11C]9 with an extremely high specific activity (1810 GBq/micromol) was used for PET study. However, the effort to determine the specific binding for D4 failed. These results indicate that both of the benzamide derivatives would not be suitable radioligands for D4 receptors with PET.

Animals↗

PubMed2002

Synthesis and evaluation of 3-(4-chlorobenzyl)-8-[11C]methoxy-1,2,3,4-tetrahydrochromeno[3,4-c]pyridin-5-one: a PET tracer for imaging sigma(1) receptors.

3-(4-Chlorobenzyl)-8-methoxy-1,2,3,4-tetrahydrochromeno[3,4-c]pyridin-5-one (1), a putative dopamine D(4) receptor antagonist (k(i) = 8.7 nM), was labeled by positron-emitter (11C) and its pharmacological evaluation was carried out with in vitro quantitative autoradiography and positron emission tomography (PET). 11C-Methylation of a corresponding desmethyl precursor (2) with [11C]CH(3)I gave [11C]1 with >or=98% of radiochemical purity after HPLC purification and 67-90 GBq/micromol of specific activity at the end of synthesis. The in vitro autoradiography using rat brain sections demonstrated that [11C]1 shows no specific binding to the D(4) receptors, but a high specific binding to sigma(1) receptors (IC(50) = 105 nM). In the PET study with monkey brain, [11C]1 was highly taken up by the brain and trapped in the brain for at least 90 min. The distribution pattern of radioactivity in the brain was striatum > thalamus > frontal cortex > cerebellum, which was same as the result of in vitro autoradiography. Pre-treatment with non-radioactive 1 (1 mg/kg) produced a significant reduction of radioactivity in all the regions including the cerebellum. Pre-treatment with (+)pentazocine (1 mg/kg), a selective sigma(1) receptor agonist, also reduced the radioactivity in the same regions to a similar extent. These results indicate that [11C]1 may have some specific binding to the sigma(1) receptors, which is consistent with the result of in vitro autoradiography.

Animals↗

PubMed2002

Synthesis, in vitro and in vivo pharmacology of a C-11 labeled analog of CP-101,606, (+/-)threo-1-(4-hydroxyphenyl)-2-[4-hydroxy-4-(p-[11C]methoxyphenyl)piperidino]-1-propanol, as a PET tracer for NR2B subunit-containing NMDA receptors.

A carbon-11 labeled methoxyl analog of CP-101,606, (+/-)threo-1-(4-hydroxyphenyl)-2-[4-hydroxy-4-(p-[11C]methoxyphenyl)piperidino]-1-propanol [(+/-)[11C]1], was synthesized as a new subtype-selective PET radioligand for NMDA receptors. The in vitro binding studies using rat brain slices demonstrated that (+/-)[11C]1 shows an extremely high-specific binding to the NR2B subunit of NMDA receptors. In contrast to the in vitro binding, the in vivo binding to mouse and monkey brains showed no apparent specific localization of the radioactivity in any of the brain regions. Metabolism and physicochemical properties such as the lipophilicity of (+/-)[11C]1 seemed unlikely to affect the in vivo (+/-)[11C]1 binding. Among the various endogenous ligands acting at the NMDA receptors, polyamines (spermine and spermidine) and divalent cations (Mg(2+,) Zn(2+,) and Ca(2+)) strongly inhibited the in vitro (+/-)[11C]1 binding. Thus, the present studies point to the possibility that the polyamines and cations behave as endogenous inhibitors for (+/-)[11C]1 binding, leading to the loss of the specific binding in vivo.

Animals↗

PubMed2001

Clozapine can induce high dopamine D(2) receptor occupancy in vivo.

RATIONALE: Clozapine is a unique antipsychotic with very low propensity to cause motor side effects. In contrast to most other antipsychotics that block more than 70% of dopamine D(2) receptors at therapeutic doses, clozapine occupies less than 70%. Furthermore, even at maximum occupancy, 70% is not exceeded. Several mechanisms have been proposed as explanations for this low D(2) receptor occupancy, but clear evidence is limited. OBJECTIVES: In patient studies the data are limited by the dose-range that can be safely used; therefore, the aims of this study were to examine the maximum occupancy of dopamine D(2) receptors with up to 5.0 mg/kg of bolus injection of clozapine to non-human primates and to measure the time course of occupancy. METHODS: PET examination with [(11)C]raclopride was performed to measure the dopamine D(2) receptor occupancy in the striatum of two monkeys after the bolus injection of 0.2-5.0 mg/kg clozapine. [(11)C]raclopride was injected sequentially to follow the time course of occupancy up to 7 h after the clozapine injection. RESULTS: Dopamine D(2) receptor occupancy reached up to 83% after 5.0 mg/kg clozapine injection. Occupancy decreased with a half-life of 7.22 h after 5.0 mg/kg clozapine and 5.25 h after 1.0 and 2.0 mg/kg clozapine. CONCLUSIONS: Clozapine could occupy a high proportion of dopamine D(2) receptors. The time course of occupancy was relatively fast, with a half-life of several hours.

Algorithms↗

PubMed1999

Extrastriatal dopamine D2 receptor density and affinity in the human brain measured by 3D PET.

The aim of the present study was to quantify the density and affinity of human extrastriatal dopamine D2 receptors using positron emission tomography (PET). [(11)C]FLB-457, a high-affinity dopamine D2 receptor antagonist with various specific radioactivities (SA) was used. Eight healthy male subjects, age 20-35 yr, participated twice or three times at different SAs (1-279 GBq/ µmol), and serial dynamic scans were performed in the 3D data acquisition mode. The peak of the specific binding was not well defined with high SA due to the flatness of the curves after 60 min but was observed within the PET measurement. In the experiment with low SA, the peak came earlier than that with high SA. Scatchard analysis was performed using the maximal specific binding value (transient equilibrium) and the radioactivity in the cerebellum as free ligand concentration. The highest density was observed in the thalamus (2.3+/-0.6 pmol/ml), followed by the temporal cortex (1.5+/-0.5 pmol/ml), hippocampus (1.4+/-0.5 pmol/ml), parietal cortex (0.9+/-0.4 pmol/ml), frontal cortex (0.8+/-0.2 pmol/ml) and occipital cortex (0.7+/-0.3 pmol/ml). There was no significant difference in K(d) values in these six regions. The present results demonstrate that dopamine D2 receptor densities in the extrastriatal regions were only 2-8% of that in the striatum. Although the density of extrastriatal dopamine D2 receptor was low, significant regional differences were observed in the present study, as reported in postmortem studies.

Journal Article↗