Publications by authors named "Yuji Nagai"

52 Publications

Quantification of monoacylglycerol lipase and its occupancy by an exogenous ligand in rhesus monkey brains using [F]T-401 and PET.

J Cereb Blood Flow Metab 2021 Nov 2:271678X211058285. Epub 2021 Nov 2.

National Institutes for Quantum Science and Technology, Chiba, Japan.

Monoacylglycerol lipase (MAGL) is a cytosolic serine hydrolase that cleaves monoacylglycerols into fatty acids and is a potential target for the novel treatment of CNS disorders related to the endocannabinoid system and neuroinflammation. We have developed [F]T-401 as a selective Positron emission tomography (PET) imaging agent for MAGL. In this study, we determined an analytical method to quantify MAGL availability and its occupancy by an exogenous inhibitor in rhesus monkey brains using [F]T-401-PET. In rhesus monkeys, regional time-activity curves were described well when using an extended 2-tissue compartment model that accommodated the formation of a radiometabolite in the brain. This model yielded reliable estimates of the total distribution volume (), and the rank order of was consistent with known regional activity of MAGL enzyme in primates. The pretreatment of monkeys with JW642 resulted in a dose-dependent reduction of [F]T-401 retentions in the brain, and . Lassen's graphical analysis indicated a of 0.69 mL/cm and a plasma JW642 concentration of 126 ng/mL for inhibiting the specific binding by 50%. [F]T-401 and the method established can be used for quantification of MAGL in healthy brain and in disease conditions, and is suitable for evaluations of target engagement at cerebral MAGL.
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http://dx.doi.org/10.1177/0271678X211058285DOI Listing
November 2021

Chemogenetic sensory fMRI reveals behaviorally relevant bidirectional changes in primate somatosensory network.

Neuron 2021 10;109(20):3312-3322.e5

Department of Functional Brain Imaging, National Institutes for Quantum and Radiological Sciences and Technology, Anagawa 4-9-1, Inage-ku, Chiba, Japan.

Concurrent genetic neuromodulation and functional magnetic resonance imaging (fMRI) in primates has provided a valuable opportunity to assess the modified brain-wide operation in the resting state. However, its application to link the network operation with behavior still remains challenging. Here, we combined chemogenetic silencing of the primary somatosensory cortex (SI) with tactile fMRI and related behaviors in macaques. Focal chemogenetic silencing of functionally identified SI hand region impaired grasping behavior. The same silencing also attenuated hand stimulation-evoked fMRI signal at both the local silencing site and the anatomically and/or functionally connected downstream grasping network, suggesting altered network operation underlying the induced behavioral impairment. Furthermore, the hand region silencing unexpectedly disinhibited foot representation with accompanying behavioral hypersensitization. These results demonstrate that focal chemogenetic silencing with sensory fMRI in macaques unveils bidirectional network changes to generate multifaceted behavioral impairments, thereby opening a pivotal window toward elucidating the causal network operation underpinning higher brain functions in primates.
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http://dx.doi.org/10.1016/j.neuron.2021.08.032DOI Listing
October 2021

A genetically targeted reporter for PET imaging of deep neuronal circuits in mammalian brains.

EMBO J 2021 Nov 12;40(22):e107757. Epub 2021 Oct 12.

Department of Functional Brain Imaging, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

Positron emission tomography (PET) allows biomolecular tracking but PET monitoring of brain networks has been hampered by a lack of suitable reporters. Here, we take advantage of bacterial dihydrofolate reductase, ecDHFR, and its unique antagonist, TMP, to facilitate in vivo imaging in the brain. Peripheral administration of radiofluorinated and fluorescent TMP analogs enabled PET and intravital microscopy, respectively, of neuronal ecDHFR expression in mice. This technique can be used to the visualize neuronal circuit activity elicited by chemogenetic manipulation in the mouse hippocampus. Notably, ecDHFR-PET allows mapping of neuronal projections in non-human primate brains, demonstrating the applicability of ecDHFR-based tracking technologies for network monitoring. Finally, we demonstrate the utility of TMP analogs for PET studies of turnover and self-assembly of proteins tagged with ecDHFR mutants. These results establish opportunities for a broad spectrum of previously unattainable PET analyses of mammalian brain circuits at the molecular level.
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http://dx.doi.org/10.15252/embj.2021107757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8591537PMC
November 2021

Chemogenetic activation of nigrostriatal dopamine neurons in freely moving common marmosets.

iScience 2021 Sep 30;24(9):103066. Epub 2021 Aug 30.

Department of Functional Brain Imaging, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555 Japan.

To interrogate particular neuronal pathways in nonhuman primates under natural and stress-free conditions, we applied designer receptors exclusively activated by designer drugs (DREADDs) technology to common marmosets. We injected adeno-associated virus vectors expressing the excitatory DREADD hM3Dq into the unilateral substantia nigra (SN) in four marmosets. Using multi-tracer positron emission tomography imaging, we detected DREADD expression in vivo, which was confirmed in nigrostriatal dopamine neurons by immunohistochemistry, as well as by assessed activation of the SN following agonist administration. The marmosets rotated in a contralateral direction relative to the activated side 30-90 min after consuming food containing the highly potent DREADD agonist deschloroclozapine (DCZ) but not on the following days without DCZ. These results indicate that non-invasive and reversible DREADD manipulation will extend the utility of marmosets as a primate model for linking neuronal activity and natural behavior in various contexts.
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http://dx.doi.org/10.1016/j.isci.2021.103066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8449082PMC
September 2021

Single caudate neurons encode temporally discounted value for formulating motivation for action.

Elife 2021 07 30;10. Epub 2021 Jul 30.

Department of Functional Brain Imaging, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

The term 'temporal discounting' describes both choice preferences and motivation for delayed rewards. Here we show that neuronal activity in the dorsal part of the primate caudate head (dCDh) signals the temporally discounted value needed to compute the motivation for delayed rewards. Macaque monkeys performed an instrumental task, in which visual cues indicated the forthcoming size and delay duration before reward. Single dCDh neurons represented the temporally discounted value without reflecting changes in the animal's physiological state. Bilateral pharmacological or chemogenetic inactivation of dCDh markedly distorted the normal task performance based on the integration of reward size and delay, but did not affect the task performance for different reward sizes without delay. These results suggest that dCDh is involved in encoding the integrated multi-dimensional information critical for motivation.
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http://dx.doi.org/10.7554/eLife.61248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8352586PMC
July 2021

D1- and D2-like receptors differentially mediate the effects of dopaminergic transmission on cost-benefit evaluation and motivation in monkeys.

PLoS Biol 2021 07 1;19(7):e3001055. Epub 2021 Jul 1.

Department of Functional Brain Imaging, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

It has been widely accepted that dopamine (DA) plays a major role in motivation, yet the specific contribution of DA signaling at D1-like receptor (D1R) and D2-like receptor (D2R) to cost-benefit trade-off remains unclear. Here, by combining pharmacological manipulation of DA receptors (DARs) and positron emission tomography (PET) imaging, we assessed the relationship between the degree of D1R/D2R blockade and changes in benefit- and cost-based motivation for goal-directed behavior of macaque monkeys. We found that the degree of blockade of either D1R or D2R was associated with a reduction of the positive impact of reward amount and increasing delay discounting. Workload discounting was selectively increased by D2R antagonism. In addition, blocking both D1R and D2R had a synergistic effect on delay discounting but an antagonist effect on workload discounting. These results provide fundamental insight into the distinct mechanisms of DA action in the regulation of the benefit- and cost-based motivation, which have important implications for motivational alterations in both neurological and psychiatric disorders.
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http://dx.doi.org/10.1371/journal.pbio.3001055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248602PMC
July 2021

Chemogenetic dissection of the primate prefronto-subcortical pathways for working memory and decision-making.

Sci Adv 2021 Jun 23;7(26). Epub 2021 Jun 23.

Department of Functional Brain Imaging, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555 Japan.

The primate prefrontal cortex (PFC) is situated at the core of higher brain functions via neural circuits such as those linking the caudate nucleus and mediodorsal thalamus. However, the distinctive roles of these prefronto-subcortical pathways remain elusive. Combining in vivo neuronal projection mapping with chemogenetic synaptic silencing, we reversibly dissected key pathways from dorsolateral part of the PFC (dlPFC) to the dorsal caudate (dCD) and lateral mediodorsal thalamus (MDl) individually in single monkeys. We found that silencing the bilateral dlPFC-MDl projections, but not the dlPFC-dCD projections, impaired performance in a spatial working memory task. Conversely, silencing the unilateral dlPFC-dCD projection, but not the unilateral dlPFC-MDl projection, altered preference in a decision-making task. These results revealed dissociable roles of the prefronto-subcortical pathways in working memory and decision-making, representing the technical advantage of imaging-guided pathway-selective chemogenetic manipulation for dissecting neural circuits underlying cognitive functions in primates.
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http://dx.doi.org/10.1126/sciadv.abg4246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221616PMC
June 2021

[C]deschloroclozapine is an improved PET radioligand for quantifying a human muscarinic DREADD expressed in monkey brain.

J Cereb Blood Flow Metab 2021 10 14;41(10):2571-2582. Epub 2021 Apr 14.

Laboratory of Neuropsychology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.

Previous work found that [C]deschloroclozapine ([C]DCZ) is superior to [C]clozapine ([C]CLZ) for imaging Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). This study used PET to quantitatively and separately measure the signal from transfected receptors, endogenous receptors/targets, and non-displaceable binding in other brain regions to better understand this superiority. A genetically-modified muscarinic type-4 human receptor (hMDi) was injected into the right amygdala of a male rhesus macaque. [C]DCZ and [C]CLZ PET scans were conducted 2-24 months later. Uptake was quantified relative to the concentration of parent radioligand in arterial plasma at baseline (n = 3 scans/radioligand) and after receptor blockade (n = 3 scans/radioligand). Both radioligands had greater uptake in the transfected region and displaceable uptake in other brain regions. Displaceable uptake was not uniformly distributed, perhaps representing off-target binding to endogenous receptor(s). After correction, [C]DCZ signal was 19% of that for [C]CLZ, and background uptake was 10% of that for [C]CLZ. Despite stronger [C]CLZ binding, the signal-to-background ratio for [C]DCZ was almost two-fold greater than for [C]CLZ. Both radioligands had comparable DREADD selectivity. All reference tissue models underestimated signal-to-background ratio in the transfected region by 40%-50% for both radioligands. Thus, the greater signal-to-background ratio of [C]DCZ was due to its lower background uptake.
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http://dx.doi.org/10.1177/0271678X211007949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8504956PMC
October 2021

PET imaging of colony-stimulating factor 1 receptor: A head-to-head comparison of a novel radioligand, C-GW2580, and C-CPPC, in mouse models of acute and chronic neuroinflammation and a rhesus monkey.

J Cereb Blood Flow Metab 2021 09 24;41(9):2410-2422. Epub 2021 Mar 24.

National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

Colony-stimulating factor 1 receptor (CSF1R) is a specific biomarker for microglia. In this study, we developed a novel PET radioligand for CSF1R, C-GW2580, and compared it to a reported CSF1R tracer, C-CPPC, in mouse models of acute and chronic neuroinflammation and a rhesus monkey. Dynamic C-GW2580- and C-CPPC-PET images were quantified by reference tissue-based models and standardized uptake value ratio. Both tracers exhibited increased uptake in the lesioned striata of lipopolysaccharide-injected mice and in the forebrains of -knock-in mice, spatially in agreement with an increased 18-kDa translocator protein radioligand retention. Moreover, C-GW2580 captured changes in CSF1R availability more sensitively than C-CPPC, with a larger dynamic range and a smaller inter-individual variability, in these model animals. PET imaging of CSF1R in a rhesus monkey displayed moderate-to-high tracer retention in the brain at baseline. Homologous blocker (i. e. unlabeled tracer) treatment reduced the uptake of C-GW2580 by ∼30% in all examined brain regions except for centrum semi-ovale white matter, but did not affect the retention of C-CPPC. In summary, our results demonstrated that C-GW2580-PET captured inflammatory microgliosis in the mouse brain with higher sensitivity than a reported radioligand, and displayed saturable binding in the monkey brain, potentially providing an imaging-based quantitative biomarker for reactive microgliosis.
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http://dx.doi.org/10.1177/0271678X211004146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8393303PMC
September 2021

Synthesis and preclinical evaluation of [C]MTP38 as a novel PET ligand for phosphodiesterase 7 in the brain.

Eur J Nucl Med Mol Imaging 2021 09 5;48(10):3101-3112. Epub 2021 Mar 5.

Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba, 263-8555, Japan.

Purpose: Phosphodiesterase (PDE) 7 is a potential therapeutic target for neurological and inflammatory diseases, although in vivo visualization of PDE7 has not been successful. In this study, we aimed to develop [C]MTP38 as a novel positron emission tomography (PET) ligand for PDE7.

Methods: [C]MTP38 was radiosynthesized by C-cyanation of a bromo precursor with [C]HCN. PET scans of rat and rhesus monkey brains and in vitro autoradiography of brain sections derived from these species were conducted with [C]MTP38. In monkeys, dynamic PET data were analyzed with an arterial input function to calculate the total distribution volume (V). The non-displaceable binding potential (BP) in the striatum was also determined by a reference tissue model with cerebellar reference. Finally, striatal occupancy of PDE7 by an inhibitor was calculated in monkeys according to changes in BP.

Results: [C]MTP38 was synthesized with radiochemical purity ≥99.4% and molar activity of 38.6 ± 12.6 GBq/μmol. Autoradiography revealed high radioactivity in the striatum and its reduction by non-radiolabeled ligands, in contrast with unaltered autoradiographic signals in other regions. In vivo PET after radioligand injection to rats and monkeys demonstrated that radioactivity was rapidly distributed to the brain and intensely accumulated in the striatum relative to the cerebellum. Correspondingly, estimated V values in the monkey striatum and cerebellum were 3.59 and 2.69 mL/cm, respectively. The cerebellar V value was unchanged by pretreatment with unlabeled MTP38. Striatal BP was reduced in a dose-dependent manner after pretreatment with MTP-X, a PDE7 inhibitor. Relationships between PDE7 occupancy by MTP-X and plasma MTP-X concentration could be described by Hill's sigmoidal function.

Conclusion: We have provided the first successful preclinical demonstration of in vivo PDE7 imaging with a specific PET radioligand. [C]MTP38 is a feasible radioligand for evaluating PDE7 in the brain and is currently being applied to a first-in-human PET study.
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http://dx.doi.org/10.1007/s00259-021-05269-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426238PMC
September 2021

Deschloroclozapine, a potent and selective chemogenetic actuator enables rapid neuronal and behavioral modulations in mice and monkeys.

Nat Neurosci 2020 09 6;23(9):1157-1167. Epub 2020 Jul 6.

Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.

The chemogenetic technology designer receptors exclusively activated by designer drugs (DREADDs) afford remotely reversible control of cellular signaling, neuronal activity and behavior. Although the combination of muscarinic-based DREADDs with clozapine-N-oxide (CNO) has been widely used, sluggish kinetics, metabolic liabilities and potential off-target effects of CNO represent areas for improvement. Here, we provide a new high-affinity and selective agonist deschloroclozapine (DCZ) for muscarinic-based DREADDs. Positron emission tomography revealed that DCZ selectively bound to and occupied DREADDs in both mice and monkeys. Systemic delivery of low doses of DCZ (1 or 3 μg per kg) enhanced neuronal activity via hM3Dq within minutes in mice and monkeys. Intramuscular injections of DCZ (100 μg per kg) reversibly induced spatial working memory deficits in monkeys expressing hM4Di in the prefrontal cortex. DCZ represents a potent, selective, metabolically stable and fast-acting DREADD agonist with utility in both mice and nonhuman primates for a variety of applications.
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http://dx.doi.org/10.1038/s41593-020-0661-3DOI Listing
September 2020

Macaques Exhibit Implicit Gaze Bias Anticipating Others' False-Belief-Driven Actions via Medial Prefrontal Cortex.

Cell Rep 2020 03;30(13):4433-4444.e5

Department of Physiology, Niigata University School of Medicine, Niigata, Japan. Electronic address:

The ability to infer others' mental states is essential to social interactions. This ability, critically evaluated by testing whether one attributes false beliefs (FBs) to others, has been considered to be uniquely hominid and to accompany the activation of a distributed brain network. We challenge the taxon specificity of this ability and identify the causal brain locus by introducing an anticipatory-looking FB paradigm combined with chemogenetic neuronal manipulation in macaque monkeys. We find spontaneous gaze bias of macaques implicitly anticipating others' FB-driven actions. Silencing of the medial prefrontal neuronal activity with inhibitory designer receptor exclusively activated by designer drugs (DREADDs) specifically eliminates the implicit gaze bias while leaving the animals' visually guided and memory-guided tracking abilities intact. Thus, neuronal activity in the medial prefrontal cortex could have a causal role in FB-attribution-like behaviors in the primate lineage, emphasizing the importance of probing the neuronal mechanisms underlying theory of mind with relevant macaque animal models.
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http://dx.doi.org/10.1016/j.celrep.2020.03.013DOI Listing
March 2020

Visualization of AMPA receptors in living human brain with positron emission tomography.

Nat Med 2020 02 20;26(2):281-288. Epub 2020 Jan 20.

Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan.

Although aberrations in the number and function of glutamate AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors are thought to underlie neuropsychiatric disorders, no methods are currently available for visualizing AMPA receptors in the living human brain. Here we developed a positron emission tomography (PET) tracer for AMPA receptors. A derivative of 4-[2-(phenylsulfonylamino)ethylthio]-2,6-difluoro-phenoxyacetamide radiolabeled with C ([C]K-2) showed specific binding to AMPA receptors. Our clinical trial with healthy human participants confirmed reversible binding of [C]K-2 in the brain according to Logan graphical analysis (UMIN000020975; study design: non-randomized, single arm; primary outcome: dynamics and distribution volumes of [C]K-2 in the brain; secondary outcome: adverse events of [C]K-2 during the 4-10 d following dosing; this trial met prespecified endpoints). In an exploratory clinical study including patients with epilepsy, we detected increased [C]K-2 uptake in the epileptogenic focus of patients with mesial temporal lobe epilepsy, which was closely correlated with the local AMPA receptor protein distribution in surgical specimens from the same individuals (UMIN000025090; study design: non-randomized, single arm; primary outcome: correlation between [C]K-2 uptake measured with PET before surgery and AMPA receptor protein density examined by biochemical study after surgery; secondary outcome: adverse events during the 7 d following PET scan; this trial met prespecified endpoints). Thus, [C]K-2 is a potent PET tracer for AMPA receptors, potentially providing a tool to examine the involvement of AMPA receptors in neuropsychiatric disorders.
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http://dx.doi.org/10.1038/s41591-019-0723-9DOI Listing
February 2020

Design, Synthesis, and Evaluation of (4 R)-1-{3-[2-(F)Fluoro-4-methylpyridin-3-yl]phenyl}-4-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]pyrrolidin-2-one ([F]T-401) as a Novel Positron-Emission Tomography Imaging Agent for Monoacylglycerol Lipase.

J Med Chem 2019 03 26;62(5):2362-2375. Epub 2019 Feb 26.

Research, Takeda Pharmaceutical Company Limited , 26-1 Muraoka-Higashi , 2-Chome, Fujisawa , Kanagawa 251-8555 , Japan.

Monoacylglycerol lipase (MAGL) is a cytosolic serine hydrolase involved in endocannabinoid and inflammatory signaling. Positron-emission tomography (PET) imaging of MAGL serves to validate target engagement of therapeutic MAGL inhibitors as well as to investigate MAGL levels under normal and disease conditions. However, PET radioligands with reversible binding kinetics for MAGL, which allow quantitative assessment of MAGL, are hitherto unavailable. In this study, we designed and synthesized fluoro-containing PET probes starting from a recently identified piperazinyl pyrrolidine-2-one derivative with reversible binding to MAGL. By tailoring the lipophilicity of the molecule to optimize nonspecific binding and blood-brain barrier permeability, we successfully identified two compounds that show high uptake to regions enriched with MAGL. PET imaging of wild-type and MAGL-deficient mice as well as a macaque monkey indicated that [F]5 ((4 R)-1-{3-[2-(F)fluoro-4-methylpyridin-3-yl]phenyl}-4-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]pyrrolidin-2-one, [F]T-401) specifically binds to MAGL with adequate reversibility, yielding a high contrast for MAGL within an appropriate imaging time.
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http://dx.doi.org/10.1021/acs.jmedchem.8b01576DOI Listing
March 2019

A Series of Dibenzofuran-Based n-Type Exciplex Host Partners Realizing High-Efficiency and Stable Deep-Red Phosphorescent OLEDs.

Chemistry 2019 May 12;25(30):7308-7314. Epub 2019 Mar 12.

Research Center for Organic Electronics (ROEL), Yamagata University, 4-3-16 Jonan, Yonezawa, Yamagata, 992-8510, Japan.

Deep-red to near-infrared (NIR) OLEDs, which yield emission peak wavelengths beyond λ=660 nm, are applicable as unique light sources in plant growth or health monitoring systems. Compared with other visible-spectrum OLEDs, however, research in the field of deep-red OLEDs is not as advanced. In this work, three new types of dibenzofuran-based host materials are developed as n-type exciplex host partners. Combining these with the deep-red iridium complex bis(2,3-diphenylquinoxaline)iridium(dipivaloylmethane) ([(DPQ) Ir(dpm)]) and N,N'-di(naphalene-1-yl)-N,N'-diphenylbenzidine (α-NPD) as a p-type exciplex host partner, a highly efficient deep-red OLED can be realized with a maximum external quantum efficiency (η ) of over 16 % with Comission Internationale de l'Éclairge (CIE) coordinates of (0.71, 0.28). In addition, the effect of the doping concentration and the p/n ratio of the exciplex host on the efficiency and the lifetime of the OLEDs are investigated. Consequently, the optimized device exhibits a η of over 15 % and a six-time longer lifetime operating at high brightness of 100 cd m compared with other state-of-the-art deep-red OLEDs.
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http://dx.doi.org/10.1002/chem.201805907DOI Listing
May 2019

Signaling Incentive and Drive in the Primate Ventral Pallidum for Motivational Control of Goal-Directed Action.

J Neurosci 2019 03 9;39(10):1793-1804. Epub 2019 Jan 9.

Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan 263-8555

Processing incentive and drive is essential for control of goal-directed behavior. The limbic part of the basal ganglia has been emphasized in these processes, yet the exact neuronal mechanism has remained elusive. In this study, we examined the neuronal activity of the ventral pallidum (VP) and its upstream area, the rostromedial caudate (rmCD), while two male macaque monkeys performed an instrumental lever release task in which a visual cue indicated the forthcoming reward size. We found that the activity of some neurons in VP and rmCD reflected the expected reward size transiently following the cue. Reward size coding appeared earlier and stronger in VP than in rmCD. We also found that the activity in these areas was modulated by the satiation level of monkeys, which also occurred more frequently in VP than in rmCD. The information regarding reward size and satiation level was independently signaled in the neuronal populations of these areas. The data thus highlighted the neuronal coding of key variables for goal-directed behavior in VP. Furthermore, pharmacological inactivation of VP induced more severe deficit of goal-directed behavior than inactivation of rmCD, which was indicated by abnormal error repetition and diminished satiation effect on the performance. These results suggest that VP encodes incentive value and internal drive and plays a pivotal role in the control of motivation to promote goal-directed behavior. The limbic part of the basal ganglia has been implicated in the motivational control of goal-directed action. Here, we investigated how the ventral pallidum (VP) and the rostromedial caudate (rmCD) encode incentive value and internal drive and control goal-directed behavior. Neuronal recording and subsequent pharmacological inactivation revealed that VP had stronger coding of reward size and satiation level than rmCD. Reward size and satiation level were independently encoded in the neuronal population of these areas. Furthermore, VP inactivation impaired goal-directed behavior more severely than rmCD inactivation. These results highlight the central role of VP in the motivational control of goal-directed action.
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http://dx.doi.org/10.1523/JNEUROSCI.2399-18.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407294PMC
March 2019

Recruitment of calbindin into nigral dopamine neurons protects against MPTP-Induced parkinsonism.

Mov Disord 2019 02 30;34(2):200-209. Epub 2018 Aug 30.

Systems Neuroscience Section, Department of Neuroscience, Primate Research Institute, Kyoto University, Inuyama, Aichi, Japan.

Background: Parkinson's disease is caused by dopamine deficiency in the striatum, which is a result of loss of dopamine neurons from the substantia nigra pars compacta. There is a consensus that a subpopulation of nigral dopamine neurons that expresses the calcium-binding protein calbindin is selectively invulnerable to parkinsonian insults. The objective of the present study was to test the hypothesis that dopamine neuron degeneration might be prevented by viral vector-mediated gene delivery of calbindin into the dopamine neurons that do not normally contain it.

Methods: A calbindin-expressing adenoviral vector was injected into the striatum of macaque monkeys to be conveyed to cell bodies of nigral dopamine neurons through retrograde axonal transport, or the calbindin-expressing lentiviral vector was injected into the nigra directly because of its predominant uptake from cell bodies and dendrites. The animals in which calbindin was successfully recruited into nigral dopamine neurons were administered systemically with MPTP.

Results: In the monkeys that had received unilateral vector injections, parkinsonian motor deficits, such as muscular rigidity and akinesia/bradykinesia, appeared predominantly in the limbs corresponding to the non-calbindin-recruited hemisphere after MPTP administration. Data obtained from tyrosine hydroxylase immunostaining and PET imaging for the dopamine transporter revealed that the nigrostriatal dopamine system was preserved better on the calbindin-recruited side. Conversely, on the non-calbindin-recruited control side, many more dopamine neurons expressed α-synuclein.

Conclusions: The present results indicate that calbindin recruitment into nigral dopamine neurons protects against the onset of parkinsonian insults, thus providing a novel approach to PD prevention. © 2018 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.107DOI Listing
February 2019

In Vitro and in Vivo Evaluation of C-Labeled Azetidinecarboxylates for Imaging Monoacylglycerol Lipase by PET Imaging Studies.

J Med Chem 2018 03 9;61(6):2278-2291. Epub 2018 Mar 9.

Division of Nuclear Medicine and Molecular Imaging, Department of Radiology , Massachusetts General Hospital and Harvard Medical School , Boston , Massachusetts 02114 , United States.

Monoacylglycerol lipase (MAGL) is the principle enzyme for metabolizing endogenous cannabinoid ligand 2-arachidonoyglycerol (2-AG). Blockade of MAGL increases 2-AG levels, resulting in subsequent activation of the endocannabinoid system, and has emerged as a novel therapeutic strategy to treat drug addiction, inflammation, and neurodegenerative diseases. Herein we report a new series of MAGL inhibitors, which were radiolabeled by site-specific labeling technologies, including C-carbonylation and spirocyclic iodonium ylide (SCIDY) radiofluorination. The lead compound [C]10 (MAGL-0519) demonstrated high specific binding and selectivity in vitro and in vivo. We also observed unexpected washout kinetics with these irreversible radiotracers, in which in vivo evidence for turnover of the covalent residue was unveiled between MAGL and azetidine carboxylates. This work may lead to new directions for drug discovery and PET tracer development based on azetidine carboxylate inhibitor scaffold.
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http://dx.doi.org/10.1021/acs.jmedchem.7b01400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966020PMC
March 2018

High-Contrast PET Imaging of Vasopressin V Receptors with a Novel Radioligand, C-TASP699.

J Nucl Med 2017 10 27;58(10):1652-1658. Epub 2017 Apr 27.

National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan; and

Vasopressin 1B receptors (VRs) are abundantly expressed in the pituitary, and in vivo PET of VRs was recently enabled by our development of a specific radioligand, C-TASP0434299, derivatized from pyridopyrimidin-4-one. Here, we identified a novel pyridopyrimidin-4-one analog, --butyl-2-[2-(6-C-methoxypyridine-2-yl)-6-[3-(morpholin-4-yl)propoxy]-4-oxopyrido[2,3-]pyrimidin-3(4)-yl]acetamide (C-TASP0410699, hereafter referred to as C-TASP699), as a potent VR radioligand producing a higher image contrast for the target than C-TASP0434299. In vitro properties of TASP699 were assessed by assaying its affinity for human VR and its selectivity for off-target molecules. Radioactive uptake in the pituitary was analyzed using PET in rhesus monkeys after intravenous administration of C-TASP699. Serial doses of a selective VR antagonist, 2-[2-(3-chloro-4-fluorophenyl)-6-[3-(morpholin-4-yl)propoxy]-4-oxopyrido[2,3-]pyrimidin-3(4)-yl]--isopropylacetamide hydrochloride (TASP0390325), were administered before the radioligand injection. Autoradiographic labeling of monkey pituitary slices with C-TASP699 was conducted with or without nonradioactive VR antagonists. The half maximal inhibitory concentration (IC) of TASP699 for human VRs (0.165 nM) was lower than that of TASP0434299 (0.526 nM), whereas its IC values for off-target molecules exceeded 1 μM. PET imaging in monkeys demonstrated that the peak pituitary uptake of C-TASP699 was almost equivalent to that of C-TASP0434299 and that pretreatment with TASP0390325 inhibited the retention of C-TASP699 in a dose-dependent manner, inducing nearly full occupancy at 0.3 mg/kg. Specific radioligand binding was determined as a specific-to-nondisplaceable uptake ratio at equilibrium using radioactivity retentions at 60 min in baseline and blocking studies. This ratio for C-TASP699 was approximately 2.5-fold greater than that of C-TASP0434299. A reversed-phase high-performance liquid chromatography study identified the parent and polar radiometabolites. Affinities of 2 predicted metabolite candidates for VRs were more than 10 times weaker than that of the parent. Intense autoradiographic labeling of the anterior pituitary with C-TASP699 was inhibited with TASP0390325 in a concentration-dependent manner. C-TASP699 yielded PET images of pituitary VRs with a higher contrast than C-TASP0434299, supporting the applicability of C-TASP699 in the assessment of neuropsychiatric diseases and dose findings for test drugs in clinical trials.
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http://dx.doi.org/10.2967/jnumed.116.188698DOI Listing
October 2017

High Power Efficiency Blue-to-Green Organic Light-Emitting Diodes Using Isonicotinonitrile-Based Fluorescent Emitters.

Chem Asian J 2017 Mar 27;12(6):648-654. Epub 2017 Jan 27.

Research Center for Organic Electronics (ROEL), Yamagata University, 4-3-16 Jonan, Yonezawa, Yamagata, 992-8510, Japan.

Herein, 9,10-dihydro-9,9-dimethylacridine (Ac) or phenoxazine (PXZ)-substituted isonicotinonitrile (INN) derivatives, denoted as 2AcINN, 26AcINN, and 26PXZINN, were developed as a series of thermally activated delayed fluorescence (TADF) emitters. These emitters showed reasonably high photoluminescence quantum yields of 71-79 % in the host films and high power efficiency organic light-emitting diodes (OLEDs). Sky-blue emitter 26AcINN exhibited a low turn-on voltage of 2.9 V, a high external quantum efficiency (η ) of 22 %, and a high power efficiency (η ) of 66 lm W with Commission Internationale de l'Eclairage (CIE) chromaticity coordinates of (0.22, 0.45), whereas green emitter 26PXZINN exhibited a low turn-on voltage of 2.2 V, a high η of 22 %, and a high η of 99 lm W with CIE chromaticity coordinates of (0.37, 0.58). These performances are among the best for TADF OLEDs to date.
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http://dx.doi.org/10.1002/asia.201601641DOI Listing
March 2017

PET imaging-guided chemogenetic silencing reveals a critical role of primate rostromedial caudate in reward evaluation.

Nat Commun 2016 12 6;7:13605. Epub 2016 Dec 6.

Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.

The rostromedial caudate (rmCD) of primates is thought to contribute to reward value processing, but a causal relationship has not been established. Here we use an inhibitory DREADD (Designer Receptor Exclusively Activated by Designer Drug) to repeatedly and non-invasively inactivate rmCD of macaque monkeys. We inject an adeno-associated viral vector expressing the inhibitory DREADD, hM4Di, into the rmCD bilaterally. To visualize DREADD expression in vivo, we develop a non-invasive imaging method using positron emission tomography (PET). PET imaging provides information critical for successful chemogenetic silencing during experiments, in this case the location and level of hM4Di expression, and the relationship between agonist dose and hM4Di receptor occupancy. Here we demonstrate that inactivating bilateral rmCD through activation of hM4Di produces a significant and reproducible loss of sensitivity to reward value in monkeys. Thus, the rmCD is involved in making normal judgments about the value of reward.
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http://dx.doi.org/10.1038/ncomms13605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5150653PMC
December 2016

Synthesis and Preclinical Evaluation of Sulfonamido-based [(11)C-Carbonyl]-Carbamates and Ureas for Imaging Monoacylglycerol Lipase.

Theranostics 2016 21;6(8):1145-59. Epub 2016 May 21.

1. Gordon Center of Medical Imaging, Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA, 02114, USA.

Monoacylglycerol lipase (MAGL) is a 33 kDa member of the serine hydrolase superfamily that preferentially degrades 2-arachidonoylglycerol (2-AG) to arachidonic acid in the endocannabinoid system. Inhibition of MAGL is not only of interest for probing the cannabinoid pathway but also as a therapeutic and diagnostic target for neuroinflammation. Limited attempts have been made to image MAGL in vivo and a suitable PET ligand for this target has yet to be identified and is urgently sought to guide small molecule drug development in this pathway. Herein we synthesized and evaluated the physiochemical properties of an array of eleven sulfonamido-based carbamates and ureas with a series of terminal aryl moieties, linkers and leaving groups. The most potent compounds were a novel MAGL inhibitor, N-((1-(1H-1,2,4-triazole-1-carbonyl)piperidin-4-yl) methyl)-4-chlorobenzenesulfonamide (TZPU; IC50 = 35.9 nM), and the known inhibitor 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(((4-chlorophenyl)sulfonamido) methyl)piperidine-1-carboxylate (SAR127303; IC50 = 39.3 nM), which were also shown to be selective for MAGL over fatty acid amide hydrolase (FAAH), and cannabinoid receptors (CB1 & CB2). Both of these compounds were radiolabeled with carbon-11 via [(11)C]COCl2, followed by comprehensive ex vivo biodistribution and in vivo PET imaging studies in normal rats to determine their brain permeability, specificity, clearance and metabolism. Whereas TZPU did not show adequate specificity to warrant further evaluation, [(11)C]SAR127303 was advanced for preliminary PET neuroimaging studies in nonhuman primate. The tracer showed good brain permeability (ca. 1 SUV) and heterogeneous regional brain distribution which is consistent with the distribution of MAGL.
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http://dx.doi.org/10.7150/thno.15257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4893642PMC
October 2017

TASP0434299: A Novel Pyridopyrimidin-4-One Derivative as a Radioligand for Vasopressin V1B Receptor.

J Pharmacol Exp Ther 2016 06 30;357(3):495-508. Epub 2016 Mar 30.

Pharmacology Laboratories (K.K., Y.U., S.C.) and Chemistry Laboratories (M.Y., N.M., N.O.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan; and Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan (Y.N., Y.S., M.F., T.M., M.-R.Z., M.H., T.S.)

A novel pyridopyrimidin-4-one derivative, N-tert-butyl-2-[2-(3-methoxyphenyl)-6-[3-(morpholin-4-yl)propoxy]-4-oxopyrido[2,3-d]pyrimidin-3(4H)-yl]acetamide (TASP0434299), was characterized as a radioligand candidate for arginine vasopressin 1B (V1B) receptor. TASP0434299 exhibited high binding affinities for human and rat V1B receptors with IC50 values of 0.526 and 0.641 nM, respectively, and potent antagonistic activity at the human V1B receptor with an IC50 value of 0.639 nM without apparent binding affinities for other molecules at 1 μM. [(3)H]TASP0434299 bound to membranes expressing the human V1B receptor as well as those prepared from the rat anterior pituitary in a saturable manner. The binding of [(3)H]TASP0434299 to the membranes was dose-dependently displaced by several ligands for the V1B receptor. In addition, the intravenous administration of [(3)H]TASP0434299 to rats produced a saturable radioactive accumulation in the anterior pituitary where the V1B receptor is enriched, and it was dose-dependently blocked by the oral administration of 2-[2-(3-chloro-4-fluorophenyl)-6-[3-(morpholin-4-yl)propoxy]-4-oxopyrido[2,3-d]pyrimidin-3(4H)-yl]-N-isopropylacetamide hydrochloride, a V1B receptor antagonist, indicating that [(3)H]TASP0434299 can be used as an in vivo radiotracer to measure the occupancy of the V1B receptor. Finally, the intravenous administration of [(11)C]TASP0434299 provided positron emission tomographic images of the V1B receptor in the pituitary in an anesthetized monkey, and the signal was blocked by pretreatment with an excess of unlabeled TASP0434299. These results indicate that radiolabeled TASP0434299 is the first radioligand to be capable of quantifying the V1B receptor selectively in both in vitro and in vivo studies and will provide a clinical biomarker for determining the occupancy of the V1B receptor during drug development or for monitoring the levels of the V1B receptor in diseased conditions.
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http://dx.doi.org/10.1124/jpet.116.232942DOI Listing
June 2016

Development of TASP0410457 (TASP457), a novel dihydroquinolinone derivative as a PET radioligand for central histamine H3 receptors.

EJNMMI Res 2016 Dec 9;6(1):11. Epub 2016 Feb 9.

Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba, 263-8555, Japan.

Background: Histamine H3 receptor (H3R) is a potential therapeutic target of sleep- and cognition-related disorders. The purpose of the present study is to develop a novel positron emission tomography (PET) ligand for H3Rs from dihydroquinolinone derivatives, which we previously found to have high affinity with these receptors.

Methods: Six compounds were selected from a dihydroquinolinone compound library based on structural capability for (11)C labeling and binding affinity for H3Rs. Their in vivo kinetics in the rat brain were examined in a comparative manner by liquid chromatography and tandem mass spectrometry (LC-MS/MS). Chemicals with appropriate kinetic properties were then labeled with (11)C and evaluated in rats and monkeys using PET.

Results: Of the six compounds, TASP0410457 (also diminutively called TASP457) and TASP0434988 exhibited fast kinetics and relatively high brain uptakes in ex vivo LC-MS/MS and were selected as candidate PET imaging agents. PET data in rat brains were mostly consistent with LC-MS/MS findings, and rat and monkey PET scans demonstrated that [(11)C]TASP0410457 was superior to [(11)C]TASP0434988 for high-contrast H3R PET imaging. In the monkey brain PET, distribution volume for [(11)C]TASP0410457 could be quantified, and receptor occupancy by a nonradioactive compound was measurable using this radioligand. The specific binding of [(11)C]TASP0410457 to H3Rs was confirmed by autoradiography using rat and monkey brain sections.

Conclusions: We developed [(11)C]TASP0410457 as a radioligand enabling a robust quantification of H3Rs in all brain regions and demonstrated the utility of ex vivo LC-MS/MS and in vivo PET assays for selecting appropriate imaging tracers. [(11)C]TASP0410457 will help to examine the implication of H3Rs in neuropsychiatric disorders and to characterize emerging therapeutic agents targeting H3Rs.
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http://dx.doi.org/10.1186/s13550-016-0170-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747952PMC
December 2016

A Primary Role for Nucleus Accumbens and Related Limbic Network in Vocal Tics.

Neuron 2016 Jan;89(2):300-7

Systems Neuroscience Section, Primate Research Institute, Kyoto University, Inuyama, Aichi 484-8506, Japan; Laboratory of Cognitive and Behavioral Neuroscience, Division of Biomedical Science, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan.

Inappropriate vocal expressions, e.g., vocal tics in Tourette syndrome, severely impact quality of life. Neural mechanisms underlying vocal tics remain unexplored because no established animal model representing the condition exists. We report that unilateral disinhibition of the nucleus accumbens (NAc) generates vocal tics in monkeys. Whole-brain PET imaging identified prominent, bilateral limbic cortico-subcortical activation. Local field potentials (LFPs) developed abnormal spikes in the NAc and the anterior cingulate cortex (ACC). Vocalization could occur without obvious LFP spikes, however, when phase-phase coupling of alpha oscillations were accentuated between the NAc, ACC, and the primary motor cortex. These findings contrasted with myoclonic motor tics induced by disinhibition of the dorsolateral putamen, where PET activity was confined to the ipsilateral sensorimotor system and LFP spikes always preceded motor tics. We propose that vocal tics emerge as a consequence of dysrhythmic alpha coupling between critical nodes in the limbic and motor networks. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.neuron.2015.12.025DOI Listing
January 2016

Development of Novel PET Probes for Central 2-Amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic Acid Receptors.

J Med Chem 2015 Nov 2;58(21):8444-62. Epub 2015 Nov 2.

Molecular Imaging Center, National Institute of Radiological Sciences , 4-9-1 Anagawa, Inage-ku, Chiba, Chiba 263-8555, Japan.

We document the development of PET probes for central AMPA receptors and their application to in vivo animal imaging. An initial screening of perampanel derivatives was performed to identify probe candidates. Despite the high autoradiographic contrast yielded by several radioligands, rat PET scans did not support their in vivo suitability. Further focused derivatization and a second screening by ex vivo LC-MS measurements led to the selection of 2-[1-(3-methylaminophenyl)-2-oxo-5-(pyrimidin-2-yl)-1,2-dihydropyridin-3-yl]benzonitrile, 21a, and its analogues as candidates. [(11)C]21a was shown by autoradiography to specifically bind to the neocortex and hippocampus, consistent with AMPA receptor localization. PET imaging with [(11)C]21a demonstrated moderate uptake of radioactivity in rat and monkey brains, with the retention of radiosignals being consistent with that from the autoradiogram data, and the uptake was blocked by pretreatment with unlabeled 21a in a dose-dependent manner. The current approach has facilitated the discovery of a PET probe potentially suitable for translational research and development focused on AMPA receptors.
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http://dx.doi.org/10.1021/acs.jmedchem.5b00712DOI Listing
November 2015

Development of [(11)C]MFTC for PET imaging of fatty acid amide hydrolase in rat and monkey brains.

ACS Chem Neurosci 2015 Feb 26;6(2):339-46. Epub 2014 Nov 26.

Molecular Imaging Center, National Institute of Radiological Sciences , Chiba 263-8555, Japan.

We developed 2-methylpyridin-3-yl-4-(5-(2-fluorophenyl)-4H-1,2,4-triazol-3-yl)piperidine-1-[(11)C]carboxylate ([(11)C]MFTC) as a promising PET tracer for in vivo imaging of fatty acid amide hydrolase (FAAH) in rat and monkey brains. [(11)C]MFTC was synthesized by reacting 3-hydroxy-2-methylpyridine (2) with [(11)C]phosgene ([(11)C]COCl2), followed by reacting with 4-(5-(2-fluorophenyl)-4H-1,2,4-triazol-3-yl)piperidine (3), with a 20 ± 4.6% radiochemical yield (decay-corrected, n = 30) based on [(11)C]CO2 and 40 min synthesis time from the end of bombardment. A biodistribution study in mice showed high uptake of radioactivity in FAAH-rich organs, including the lung, liver, and kidneys. Positron emission tomography (PET) summation images of rat brains showed high radioactivity in the frontal cortex, cerebellum, and hippocampus, which was consistent with the regional distribution pattern of FAAH in rodent brain. Pretreatment with MFTC or FAAH-selective URB597 significantly reduced the uptake in the brain. PET imaging of monkey brain showed relatively high uptake in the whole brain, particularly in the occipital cortex, which was also inhibited by treatment with MFTC or URB597. More than 96% of the total radioactivity was irreversible in the brain homogenate of rats 5 min after the radiotracer injection. The specific in vivo FAAH binding indicates that [(11)C]MFTC is a promising PET tracer for visualizing FAAH in the brain.
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http://dx.doi.org/10.1021/cn500269gDOI Listing
February 2015

Evaluation of [(11)C]oseltamivir uptake into the brain during immune activation by systemic polyinosine-polycytidylic acid injection: a quantitative PET study using juvenile monkey models of viral infection.

EJNMMI Res 2014 2;4:24. Epub 2014 Jul 2.

Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku 265-8555, Chiba, Japan.

Background: Abnormal behaviors of young patients after taking the anti-influenza agent oseltamivir (Tamiflu®, F. Hoffmann-La Roche, Ltd., Basel, Switzerland) have been suspected as neuropsychiatric adverse events (NPAEs). Immune response to viral infection is suspected to cause elevation of drug concentration in the brain of adolescents. In the present study, the effect of innate immune activation on the brain uptake of [(11)C]oseltamivir was quantitatively evaluated in juvenile monkeys.

Methods: Three 2-year-old monkeys underwent positron emission tomography (PET) scans at baseline and immune-activated conditions. Both scans were conducted under pre-dosing of clinically relevant oseltamivir. The immune activation condition was induced by the intravenous administration of polyinosine-polycytidylic acid (poly I:C). Dynamic [(11)C]oseltamivir PET scan and serial arterial blood sampling were performed to obtain [(11)C]oseltamivir kinetics. Brain uptake of [(11)C]oseltamivr was evaluated by its normalized brain concentration, brain-to-plasma concentration ratio, and plasma-to-brain transfer rate. Plasma pro-inflammatory cytokine levels were also measured.

Results: Plasma interleukin-6 was elevated after intravenous administration of poly I:C in all monkeys. Brain radioactivity was uniform both at baseline and under poly I:C treatment. The mean brain concentrations of [(11)C]oseltamivir were 0.0033 and 0.0035% ID/cm(3) × kg, the mean brain-to-plasma concentration ratios were 0.58 and 0.65, and the plasma-to-brain transfer rates were 0.0047 and 0.0051 mL/min/cm(3) for baseline and poly I:C treatment, respectively. Although these parameters were slightly changed by immune activation, the change was not notable.

Conclusions: The brain uptake of [(11)C]oseltamivir was unchanged by poly I:C treatment in juvenile monkeys. This study demonstrated that the innate immune response similar to the immune activation of influenza would not notably change the brain concentration of oseltamivir in juvenile monkeys.
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http://dx.doi.org/10.1186/s13550-014-0024-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4100568PMC
July 2014

PET brain kinetics studies of (11)C-ITMM and (11)C-ITDM,radioprobes for metabotropic glutamate receptor type 1, in a nonhuman primate.

Am J Nucl Med Mol Imaging 2014 25;4(3):260-9. Epub 2014 Apr 25.

Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences Inage-ku, Chiba, Japan.

The metabotropic glutamate receptor type 1 (mGluR1) is a novel target protein for the development of new drugs against central nervous system disorders. Recently, we have developed (11)C-labeled PET probes (11)C-ITMM and (11)C-ITDM, which demonstrate similar profiles, for imaging of mGluR1. In the present study, we compared (11)C-ITMM and (11)C-ITDM PET imaging and quantitative analysis in the monkey brain. Respective PET images showed similar distribution of uptake in the cerebellum, thalamus, and cingulate cortex. Slightly higher uptake was detected with (11)C-ITDM than with (11)C-ITMM. For the kinetic analysis using the two-tissue compartment model (2-TCM), the distribution volume (VT) in the cerebellum, an mGluR1-rich region in the brain, was 2.5 mL∙cm(-3) for (11)C-ITMM and 3.6 mL∙cm(-3) for (11)C-ITDM. By contrast, the VT in the pons, a region with negligible mGluR1 expression, was similarly low for both radiopharmaceuticals. Based on these results, we performed noninvasive PET quantitative analysis with general reference tissue models using the time-activity curve of the pons as a reference region. We confirmed the relationship and differences between the reference tissue models and 2-TCM using correlational scatter plots and Bland-Altman plots analyses. Although the scattergrams of both radiopharmaceuticals showed over- or underestimations of reference tissue model-based the binding potentials against 2-TCM, there were no significant differences between the two kinetic analysis models. In conclusion, we first demonstrated the potentials of (11)C-ITMM and (11)C-ITDM for noninvasive PET quantitative analysis using reference tissue models. In addition, our findings suggest that (11)C-ITDM may be superior to (11)C-ITMM as a PET probe for imaging of mGluR1, because regional VT values in PET with (11)C-ITDM were higher than those of (11)C-ITMM. Clinical studies of (11)C-ITDM in humans will be necessary in the future.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3999406PMC
May 2014

Titanium and manganese complexes supported by a xanthene-bridged bis(tripodal N2O2) ligand: isomerization, intramolecular hydrogen bonding and metal-binding ability.

Dalton Trans 2013 Sep 10;42(34):12220-7. Epub 2013 Jul 10.

Department of Chemistry, Graduate School of Science, Osaka City University, Osaka 558-8585, Japan.

A new bis(N2O2) ligand, L(4-), in which two tripodal diamine-bis(phenolate) moieties are bridged by a xanthene backbone, was prepared. The reaction of H4L with 2 equiv. of [Ti(O(i)Pr)4] produced C2 and Cs symmetrical isomers of the dititanium(IV,IV) complex [Ti2(L)(O(i)Pr)4]. The isolated C2 isomer was slowly converted to the Cs isomer via Ti-N bond cleavage to form a 3 : 2 mixture in equilibrium. A similar dimanganese(III,III) complex [Mn2(L)(OMe)2(MeOH)2] was synthesized from a 1 : 2 mixture of H4L and manganese(II) perchlorate in the presence of triethylamine. An X-ray analysis of [Mn2(L)(OMe)2(MeOH)2] revealed that two Mn-N2O4 octahedrons are connected by intramolecular hydrogen bonds as well as a xanthene bridge to form a C2 symmetrical structure. The dimanganese(III,III) complex further reacted with manganese(II) acetate to form the mixed-valence trimanganese(III,II,III) complex [Mn3(L)(μ-OMe)2(μ-OAc)2]. Electrochemical data of the trimanganese(III,II,III) complex indicated that the xanthene-bridged dimanganese(III,III) unit effectively binds a Mn(II) ion in solution.
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http://dx.doi.org/10.1039/c3dt51389kDOI Listing
September 2013
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