Biomedical subjects

Shigeru Obayashi

Publications and source records attributed to Shigeru Obayashi.

13 recordsLinked to original sources

PubMed2005

Correlation between quantitative imaging and behavior in unilaterally 6-OHDA-lesioned rats.

We evaluated correlation between neurochemical and functional alterations of the nigrostriatal dopaminergic system in rat brains lesioned with 6-hydroxydopamine (6-OHDA), that model hemi-Parkinson's disease (PD), by using three different quantitative in vivo and in vitro methods. Rats unilaterally lesioned with different doses of 6-OHDA underwent two types of in vivo experiments: (1) a rotational behavioral study with methamphetamine (MAP) or apomorphine (APO); and (2) a positron emission tomography (PET) study with [11C]PE2I (radioligand for dopamine transporters) or [11C]raclopride (radioligand for dopamine D2 receptors). An in vitro autoradiographic study with the same radioligands was also conducted. The number of rotations after the MAP or APO injection increased with increased doses of 6-OHDA. The in vitro and in vivo binding of [11C]PE2I dose-dependently decreased in response to the 6-OHDA injections, while that of [11C]raclopride dose-dependently increased. There was a significant negative hyperbolic correlation between the number of rotations after MAP injection and the binding of [11C]PE2I. In contrast, there was a significant positive linear correlation between the number of rotations after APO injections and the binding of [11C]raclopride. These results robustly reveal a molecular pharmacological basis of parkinsonian symptoms in animal models of PD, and indicate the utility and validity of in vivo PET measurements in assessing pre- and post-synaptic dopaminergic functions.

Animals↗

PubMed2005

In vivo evaluation of P-glycoprotein function at the blood-brain barrier in nonhuman primates using [11C]verapamil.

P-glycoprotein (P-gp) is a major efflux transporter contributing to the efflux of a range of xenobiotic compounds at the blood-brain barrier (BBB). In the present study, we evaluated the P-gp function at the BBB using positron emission tomography (PET) in nonhuman primates. Serial brain PET scans were obtained in three rhesus monkeys after intravenous administration of [(11)C]verapamil under control and P-gp inhibition conditions ([PSC833 ([3'-keto-Me-Bmt(1)]-[Val(2)]-cyclosporin) 20 mg/kg/2 h]). The parent [(11)C]verapamil and its metabolites in plasma were determined by HPLC with a positron detector. The initial brain uptake clearance calculated from the integration plot was used for the quantitative analysis. After intravenous administration, [(11)C]verapamil was taken up rapidly into the brain (time to reach the peak, 0.58 min). The blood level of [(11)C]verapamil decreased rapidly, and it underwent metabolism with time. The inhibition of P-gp by PSC833 increased the brain uptake of [(11)C]verapamil 4.61-fold (0.141 versus 0.651 ml/g brain/min, p < 0.05). These results suggest that PET measurement with [(11)C]verapamil can be used for the evaluation of P-gp function at the BBB in the living brain.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2004

Novel peripheral benzodiazepine receptor ligand [11C]DAA1106 for PET: an imaging tool for glial cells in the brain.

Peripheral benzodiazepine receptor (PBR) is expressed in most organs and its expression is reported to be increased in activated microglia in the brain. [(11)C]PK11195 has been widely used for the in vivo imaging of PBRs, but its signal in the brain was not high enough for stable quantitative analysis. We synthesized a novel positron emission tomography (PET) ligand, [(11)C]DAA1106, for PBR and investigated its in vivo properties in rat and monkey brain. High uptake of [(11)C]DAA1106 was observed in the olfactory bulb and choroid plexus area, followed by the pons/medulla and cerebellum by in vivo autoradiography of rat brain, correlating with the binding in vitro. [(11)C]DAA1106 binding was increased in the dorsal hippocampus with neural destruction, suggesting glial reaction. [(11)C]DAA1106 binding was both inhibited and displaced by 1.0 mg/kg of DAA1106 and 5 mg/kg of PK11195 by 80% and 70%, respectively. Specific binding was estimated as 80% of total binding. [(11)C]DAA1106 binding was four times higher compared to the binding of [(11)C]PK11195 in the monkey occipital cortex. These results indicated that [(11)C]DAA1106 might be a good ligand for in vivo imaging of PBR.

Acetamides↗

PubMed2004

Development of a new radioligand, N-(5-fluoro-2-phenoxyphenyl)-N-(2-[18F]fluoroethyl-5-methoxybenzyl)acetamide, for pet imaging of peripheral benzodiazepine receptor in primate brain.

To develop a positron emission tomography (PET) ligand for imaging the 'peripheral benzodiazepine receptor' (PBR) in brain and elucidating the relationship between PBR and brain diseases, four analogues (4-7) of N-(2,5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamide (2) were synthesized and evaluated as ligands for PBR. Of these compounds, fluoromethyl (4) and fluoroethyl (5) analogues had similar or higher affinities for PBR than the parent compound 2 (K(i) = 0.16 nM for PBR in rat brain sections). Iodomethyl analogue 6 displayed a moderate affinity, whereas tosyloxyethyl analogue 7 had weak affinity. Radiolabeling was performed for the fluoroalkyl analogues 4 and 5 using fluorine-18 ((18)F, beta(+); 96.7%, T(1/2) = 109.8 min). Ligands [(18)F]4 and [(18)F]5 were respectively synthesized by the alkylation of desmethyl precursor 3 with [(18)F]fluoromethyl iodide ([(18)F]8) and 2-[(18)F]fluoroethyl bromide ([(18)F]9). The distribution patterns of [(18)F]4 and [(18)F]5 in mice were consistent with the known distribution of PBR. However, compared with [(18)F]5, [(18)F]4 displayed a high uptake in the bone of mice. The PET image of [(18)F]4 for monkey brain also showed significant radioactivity in the bone, suggesting that this ligand was unstable for in vivo defluorination and was not a useful PET ligand. Ligand [(18)F]5 displayed a high uptake in monkey brain especially in the occipital cortex, a region with richer PBR than the other regions in the brain. The radioactivity level of [(18)F]5 in monkey brain was 1.5 times higher than that of [(11)C]2, and 6 times higher than that of (R)-(1-(2-chlorophenyl)-N-[(11)C]methyl,N-(1-methylpropyl)isoquinoline ([(11)C]1). Moreover, the in vivo binding of [(18)F]5 was significantly inhibited by PBR-selective 2 or 1, indicating that the binding of [(18)F]5 in the monkey brain was mainly due to PBR. Metabolite analysis revealed that [(18)F]4 was rapidly metabolized by defluorination to [(18)F]F(-) in the plasma and brain of mice, whereas [(18)F]5 was metabolized by debenzylation to a polar product [(18)F]13 only in the plasma. No radioactive metabolite of [(18)F]5 was detected in the mouse brain. The biological data indicate that [(18)F]5 is a useful PET ligand for PBR and is currently used for imaging PBR in human brain.

Acetamides↗

PubMed2004

Possible mechanism for transfer of motor skill learning: implication of the cerebellum.

Transfer of learning takes place whenever our previous knowledge and skills affect the way in which new knowledge and skills are learned. The magnitude of transfer may depend on how prior memory is retrieved so that it may be relevant and usable in the present in terms of internal representation. This review highlights the power of neuroimaging techniques such as positron emission tomography (PET) to identify the underlying neuronal system of intermanual transfer by showing the asymmetry in the system for the same motor skill between hands. The review focuses on cerebellar cross-activation, cerebellar activation contralateral to the active hand, which would contribute to intermanual transfer of monkey tool-use learning, together with the fronto-parietal cortical circuit. Finally, this article proposes the relationship between the cerebellum and the possible mechanism underlying non-specific transfer that allows thinking in a flexible and productive manner.

Animals↗

PubMed2004

Relation between cortical dopamine D(2) receptor occupancy and suppression of conditioned avoidance response in non-human primate.

Suppression of the conditioned avoidance response (CAR), a useful test for screening for antipsychotic effects, has been discussed in relation to the blockade of dopaminergic transmission. The purpose of the present paper was to investigate the relationship between cortical dopamine D(2) receptor occupancy and the suppression of CAR by haloperidol in non-human primate. The avoidance rate was measured for four different doses of haloperidol treatment in a rhesus monkey, and the cortical D(2) receptor occupancy was measured in a parallel session using positron emission tomography with [(11)C]FLB 457. The successful avoidance response rate was decreased for doses of 10 and 30 microg/kg of haloperidol, and this decrement was associated with 65-77% of D(2) receptor occupancy. It is suggested that the threshold level of cortical dopamine D(2) receptor occupancy for the suppression of CAR is demonstrated in the present study.

Animals↗

PubMed2004

Monkey brain areas underlying remote-controlled operation.

We can control distant tools effectively by manipulating other objects as controllers in various remote-operated ways, even when the two mechanics are altered. To master the remote operation, we may rely on internal representation to organize individual moves of the controller and tool into a set of sequences by mapping the motor space among hand, controller and tool as a continuum. The present study confirmed that monkeys could also organize a sequence by mapping such a motor space or reorganize by remapping even after alteration. In addition, to investigate the neural substrates underlying such mapping/remapping, we measured the regional cerebral blood flow of two monkeys during joystick-controlled operation with alterable function of mechanics using positron emission tomography with. The monkeys were scanned during three different tasks produced by altering the directional gains of the x or y axis of the joystick - the two mechanics are congruent (standard task) and not congruent (reversed in the X or Y axis, X reverse or Y reverse task, respectively). Compared with random movement of the joystick as the control task, increased activities were detected in the prefrontal cortex, higher-ordered motor cortex, posterior parietal cortex and cerebellum during the standard task. Common brain areas during performance of the X reverse and Y reverse task were identified as showing almost the same pattern as during the standard task. These shared areas may not simply be associated with organization of individual motor imagery, but also with context-dependent processing of reorganization based on current functions by means of internal representation.

Animals↗

PubMed2003

Fronto-parieto-cerebellar interaction associated with intermanual transfer of monkey tool-use learning.

Prior motor skill learning (original learning; OL) with one hand (original hand; OH) can affect relearning of the same skill (transfer learning; TL) with the opposite hand (transferred hand; TH). This phenomenon is known as intermanual transfer of learning. We explored specialization of brain activation underlying tool-use between hands by measuring regional cerebral blood flow in two monkeys using positron emission tomography. We found brain activation specified for TL in the bilateral prefrontal cortex, bilateral intraparietal sulcus region, and cerebellum contralateral to TH. The results suggest that those regions may be related to intermanual transfer of tool-use learning, presumably in terms of modifying a motor engram specific for OH.

Animals↗

PubMed2003

Visualization of alpha5 subunit of GABAA/benzodiazepine receptor by 11C Ro15-4513 using positron emission tomography.

Although [(11)C]Ro15-4513 and [(11)C]flumazenil both bind to the central benzodiazepine (BZ) receptors, the distributions of the two ligands are not identical in vivo. Moreover, the in vivo pharmacological properties of [(11)C]Ro15-4513 have not been thoroughly examined. In the present study, we examined the pharmacological profile of [(11)C]Ro15-4513 binding in the monkey brain using positron emission tomography (PET). [(11)C]Ro15-4513 showed relatively high accumulation in the anterior cingulate cortex, hippocampus, and insular cortex, with the lowest uptake being observed in the pons. Accumulation in the cerebral cortex was significantly diminished by the BZ antagonist flumazenil (0.1 mg/kg, i.v.), but not that in the pons. Using the pons as a reference region, the specific binding of [(11)C]Ro15-4513 in most of the cerebral cortex including the limbic regions clearly revealed two different affinity sites. On the other hand, specific binding in the occipital cortex and cerebellum showed only a low affinity site. Zolpidem with affinity for alpha1, alpha2, and alpha3 subunits of GABA(A)/BZ receptor fully inhibited [(11)C]Ro15-4513 binding in the occipital cortex and cerebellum, while only about 23% of the binding was blocked in the anterior cingulate cortex. Diazepam with affinity for alpha1, alpha2, alpha3, and alpha5 subunits inhibited the binding in all brain regions. Since Ro15-4513 has relatively high affinity for the alpha5 subunit in vitro, these in vivo bindings of [(11)C]Ro15-4513 can be interpreted as the relatively high accumulation in the fronto-temporal limbic regions representing binding to the GABA(A)/BZ receptor alpha5 subunit.

Animals↗

PubMed2003

Rapid learning of sequential tool use by macaque monkeys.

Earlier reports have described monkeys in their natural habitat as being capable of purposefully using tools for activities such as obtaining food. However, little is known regarding the extent of macaque monkeys' ability to understand the functional meaning of objects as tools. We have trained Japanese macaques in tool-use behavior to demonstrate their abilities to solve stick problems involving the use of a novel tool and a sequential combination of different tools. Results suggest that macaque monkeys have cognitive abilities, such as (1). flexibility in applying previous experience in accordance with the requirements of the learning situation, (2). the foresight needed to conduct a series of acts in a continuous sequential manner and the ability to internally plan the necessary strategy.

Adaptation, Psychological↗

PubMed2003

Exploratory eye movements during the Benton Visual Retention Test: characteristics of visual behavior in schizophrenia.

In order to investigate the relationship between the behavioral patterns and clinical symptomatology in schizophrenia, exploratory eye movements of schizophrenic subjects and healthy controls during the Benton Visual Retention Test were examined using an eye-mark recorder. The results were as follows: (i) with card 1, the number of eye fixations of schizophrenic subjects was fewer, and the total and mean eye scanning lengths of schizophrenic subjects were shorter than those of healthy controls; (ii) with card 3, almost none of the schizophrenic subjects looked at the blank area opposite the peripheral figure on the right; (iii) with cards 3, 5, 6 and 9 there were some schizophrenic subjects who did not look at the peripheral figures; (iv) with card 6, many of the schizophrenic subjects made stereotypical movements; (v) with card 9, schizophrenic subjects used a narrow vertical gaze to look at the large figure on the right. Based on these characteristics among the schizophrenic subjects themselves, factors such as longer eye scanning length, looking at peripheral figures without fail, and not making stereotypical movements were reflected directly in the results of the Benton test, while there was no relationship between the width of the vertical gaze and the Benton results. Correlations between visual behavior and some psychiatric symptoms were observed. The visual behavioral patterns of schizophrenic subjects were various according to the characteristics of the Benton figures, while those of normal subjects were always almost the same. It was suggested that these results were caused by disturbances of the mental attitude of schizophrenic subjects toward objects or environments.

Adult↗

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

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↗