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Biomedical subjects

Jun Maeda

Publications and source records attributed to Jun Maeda.

At least 19 recordsLinked to original sources
PubMed2005

Synthesis and evaluation of N-(5-fluoro-2-phenoxyphenyl)-N-(2-[(18)F]fluoromethoxy-d(2)-5-methoxybenzyl)acetamide: a deuterium-substituted radioligand for peripheral benzodiazepine receptor.

N-(5-Fluoro-2-phenoxyphenyl)-N-(2-[(18)F]fluoromethoxy-d(2)-5-methoxybenzyl)acetamide ([(18)F]2) is a potent ligand (IC(50): 1.71 nM) for peripheral benzodiazepine receptor (PBR). However, in vivo evaluation on rodents and primates showed that this ligand was unstable and rapidly metabolized to [(18)F]F(-) by defluorination of the [(18)F]fluoromethyl moiety. In this study, we designed a deuterium-substituted analogue, N-(5-fluoro-2-phenoxyphenyl)-N-(2-[(18)F]fluoromethoxy-d(2)-5-methoxybenzyl)acetamide ([(18)F]5) as a radioligand for PBR to reduce the in vivo metabolic rate of the non-deuterated [(18)F]2. The design principle was based on the hypothesis that the deuterium substitution may reduce the rate of defluorination initiated by cleavage of the C-H bond without altering the binding affinity for PBR. The non-radioactive 5 was prepared by reacting diiodomethane-d(2) (CD(2)I(2), 6) with a phenol precursor 7, followed by treatment with tetrabutylammonium fluoride. The ligand [(18)F]5 was synthesized by the alkylation of 7 with [(18)F]fluoromethyl iodide-d(2) ([(18)F]FCD(2)I, [(18)F]9). Compound 5 displayed a similar in vitro affinity to PBR (IC(50): 1.90 nM) with 2. In vivo evaluation demonstrated that [(18)F]5 was metabolized by defluorination to [(18)F]F(-) as a main radioactive component, but its metabolic rate was slower than that of [(18)F]2 in the brain of mice. The deuterium substitution decreased the radioactivity level of [(18)F]5 in the bone of mouse, augmented by the percentage of specific binding to PBR in the rat brain determined by ex vivo autoradiography. However, the PET image of [(18)F]5 for monkey brain showed high radioactivity in the brain and skull, suggesting a possible species difference between rodents and primates.

Acetamides↗
PubMed2005

False positive accumulation in 18F fluorodeoxyglucose positron emission tomography scan due to sarcoid reaction following induction chemotherapy for lung cancer.

We present a case of lung cancer that showed false positive accumulation in an 18F fluorodeoxyglucose positron emission tomography (FDG-PET) scan following induction chemotherapy for suspected metastasis and progression of malignancy. A 66-year-old man was diagnosed with squamous cell carcinoma in the lung, classified as clinical stage IIIA (T2N2M0), and underwent induction chemotherapy. An FDG-PET scan prior to chemotherapy demonstrated accumulation only in the tumor, whereas following treatment it revealed a strong accumulation not only in the tumor, but also in the supraclavicular lymph nodes, which indicated lymph node metastasis. The patient underwent a biopsy of the right supraclavicular lymph node and mediastinoscopy, after which all dissected lymph nodes showed sarcoid reactions and no tumor cells were found pathologically. We concluded that when evaluating the effect of induction chemotherapy for malignancy, a sarcoid reaction might lead to the false positive accumulation of FDG.

Aged↗
PubMed2004

Tbx1 regulates fibroblast growth factors in the anterior heart field through a reinforcing autoregulatory loop involving forkhead transcription factors.

Birth defects, which occur in one out of 20 live births, often affect multiple organs that have common developmental origins. Human and mouse studies indicate that haploinsufficiency of the transcription factor TBX1 disrupts pharyngeal arch development, resulting in the cardiac and craniofacial features associated with microdeletion of 22q11 (del22q11), the most frequent human deletion syndrome. Here, we have generated an allelic series of Tbx1 deficiency that reveals a lower critical threshold for Tbx1 activity in the cardiac outflow tract compared with other pharyngeal arch derivatives, including the palatal bones. Mice hypomorphic for Tbx1 failed to activate expression of the forkhead transcription factor Foxa2 in the pharyngeal mesoderm, which contains cardiac outflow precursors derived from the anterior heart field. We identified a Fox-binding site upstream of Tbx1 that interacted with Foxa2 and was necessary for pharyngeal mesoderm expression of Tbx1, revealing an autoregulatory loop that may explain the increased cardiac sensitivity to Tbx1 dose. Downstream of Tbx1, we found a fibroblast growth factor 8 (Fgf8) enhancer that was dependent on Tbx1 in vivo for regulating expression in the cardiac outflow tract, but not in pharyngeal arches. Consistent with its role in regulating cardiac outflow tract cells Tbx1 gain of function resulted in expansion of the cardiac outflow tract segment derived from the anterior heart field as marked by Fgf10. These findings reveal a Tbx1-dependent transcriptional and signaling network in the cardiac outflow tract that renders mouse cardiovascular development more susceptible than craniofacial development to a reduction in Tbx1 dose, similar to humans with del22q11.

Alleles↗
PubMed2004

Marfanoid habitus with abnormal situs.

Marfanoid habitus suggests abnormal microfibril formation, whereas a situs ambiguus or situs inversus phenotype points to defective left-right axis determination. The concurrence of these two abnormalities has been reported only once in the literature. We report a similar phenotype in two unrelated patients. Documentation of this specific combination of Marfanoid habitus and abnormal situs gives further credence to the notion that the combination may represent a distinct syndrome.

Female↗
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

Genitourinary anomaly in congenital varicella syndrome: case report and review.

We describe a 1-year-old boy with congenital varicella syndrome who had vesicoureteral reflux (VUR) and neurogenic bladder. His mother had varicella during the 3rd month of pregnancy. At birth the patient presented with right microphthalmia, right microcornea, and persistent hyperplastic primary vitreous of the right eye. He had chronic constipation from 3 months of age. He had urinary tract infection at 1 year of age. Urological investigation revealed left grade V VUR and neurogenic bladder. His varicella zoster virus IgG titer measured by ELISA was 39.4 antibody index (normal <0.1). He had repeated episodes of urinary tract infection despite antibiotic prophylaxis and clean intermittent catheterization, and underwent a uretero-vesiconeostomy at 2 years of age. Maternal infection during early pregnancy and the serological evidence of varicella zoster IgG antibodies without a history of varicella after birth led to the diagnosis of congenital varicella syndrome. Urogenital anomalies have previously been described in 14 cases of congenital varicella syndrome. Most of these patients had neurogenic bladder, the pathophysiology of which could be explained by the known neurotropic nature of the virus.

Abnormalities, Multiple↗
PubMed2004

Estimation of the time-course of dopamine D2 receptor occupancy in living human brain from plasma pharmacokinetics of antipsychotics.

Although the kinetic profile of antipsychotics at dopamine D2 receptor sites has been suggested to be important for antipsychotic action and dosing schedule, the kinetic profiles of the respective antipsychotic drugs in the brain have not yet been clearly defined. We aimed to estimate the time-course of dopamine D2 receptor occupancy from plasma pharmacokinetics and the apparent in-vivo affinity parameter (ED50; concentration required to induce 50% occupancy). Dopamine D2 receptor occupancies and plasma concentrations of risperidone were measured in five patients with schizophrenia using positron emission tomography with [11C]FLB 457. Measured dopamine D2 occupancies were compared with those estimated from plasma kinetics and in-vivo ED50. The time-course of dopamine D2 receptor occupancy was simulated with altered plasma kinetics or apparent in-vivo affinity parameters of the drug. Mean half-life of dopamine D2 receptor occupancy of risperidone was 80.2 h while that of the plasma concentration was 17.8 h. Dopamine D2 receptor occupancy estimated from plasma pharmacokinetics and in-vivo ED50 was within 1 S.D. of the mean measured occupancy. When the ED50 value was changed to one-tenth and 10-fold, the simulated half-life of receptor occupancy changed to 117.6 h and 27.3 h respectively. Using plasma pharmacokinetics and in-vivo ED50, the time-course of receptor occupancy could be calculated. Simulation of drug kinetics at receptors would provide useful information for the evaluation of antipsychotics.

Adult↗
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↗
PubMed2004

Synthesis of 11C-labelled bis(phenylalkyl)amines and their in vitro and in vivo binding properties in rodent and monkey brains.

Two new (11)C-labelled ligands, N-(3-(4-hydroxyphenyl)propyl)-3-(4-methoxyphenyl)propylamine ([(11)C]2) and N-(3-(4-hydroxyphenyl)butyl)-3-(4-methoxyphenyl)butylamine ([(11)C]3) were designed based on bis(phenylalkyl)amines (1) which have been reported as polyamine site antagonists with high-selectivity for NR1A/2B NMDA receptors, and radiolabelling of the corresponding phenol precursors with [(11)C]methyl iodide was readily accomplished. The in vitro inhibition experiments using rat brain slices showed that [(11)C]2 and [(11)C]3 share the binding sites with spermine and/or ifenprodil but not with CP-101,606, a highly potent NR2B-selective NMDA antagonist, and that divalent cations such as Zn(2+) produced significant inhibition of both [(11)C]2 and [(11)C]3 bindings. Intravenous injection of [(11)C]3 in mice showed almost homogeneous distribution throughout the brain. Attempts to block the tracer uptake of [(11)C]3 by pre-injection with the unlabelled 3 or spermine in rats were unsuccessful, but a small decrease in the cerebral uptake of [(11)C]3 by co-treatment with the unlabelled 3 was observed in a monkey PET study. The present findings indicate that none of these (11)C-labelled analogues have potential for PET study of binding sites on the N-methyl-D-aspartate (NMDA) receptors.

Amines↗
PubMed2003

Pd-catalyzed sulfinylzincation of activated alkynes with 1-alkynyl sulfoxides as a sulfinyl source.

Unprecedented Pd-catalyzed sulfinylzincation with 1-alkynyl sulfoxide as a sulfinyl source was developed. Bis-sulfinyl alkenes were formed in good yields on treatment of 1-alkynyl sulfoxides with Et(2)Zn in the presence of a Pd-catalyst, wherein zinc sulfenate (or sulfinylzinc) species would be generated in situ to undergo highly syn-selective conjugate addition to the 1-alkynyl sulfoxides. By using 3,3-dimethyl-1-butynyl sulfoxides, formation of the bis-sulfinyl alkenes was completely suppressed and the sulfinylzincation of activated alkynes was accomplished. The reaction tolerates various functionalities, and was promoted considerably by the neighboring group participation of the heteroatom at the delta-position in the alkynoates. Stereodivergent synthesis of two diastereomeric vinylic sulfoxides and reaction of the resulting vinylzinc species with electrophiles were also described.

Journal Article↗
PubMed2003

N-[18F]fluoroethyl-4-piperidyl acetate ([18F]FEtP4A): A PET tracer for imaging brain acetylcholinesterase in vivo.

N-[(18)F]Fluoroethyl-4-piperidyl acetate ([(18)F]FEtP4A) was synthesized and evaluated as a PET tracer for imaging brain acetylcholinesterase (AchE) in vivo. [(18)F]FEtP4A was previously prepared by reacting 4-piperidyl acetate (P4A) with 2-[(18)F]fluoroethyl bromide ([(18)F]FEtBr) at 130 degrees C for 30 min in 37% radiochemical yield using an automated synthetic system. In this work, [(18)F]FEtP4A was synthesized by reacting P4A with 2-[(18)F]fluoroethyl iodide ([(18)F]FEtI) or 2-[(18)F]fluoroethyl triflate ([(18)F]FEtOTf in improved radiochemical yields, compared with [(18)F]FEtBr under the corresponding condition. Ex vivo autoradiogram of rat brain and PET summation image of monkey brain after iv injection of [(18)F]FEtP4A displayed a high radioactivity in the striatum, a region with the highest AchE activity in the brain. Moreover, the distribution pattern of (18)F radioactivity was consistent with that of AchE in the brain: striatum>frontal cortex>cerebellum. In the rat and monkey plasma, two radioactive metabolites were detected. However, their presence might not preclude the imaging studies for AchE in the brain, because they were too hydrophilic to pass the blood-brain barrier and to enter the brain. In the rat brain, only [(18)F]fluoroethyl-4-piperidinol ([(18)F]FEtP4OH) was detected at 30 min postinjection. The hydrolytic [(18)F]FEtP4OH displayed a slow washout and a long retention in the monkey brain until the PET experiment (120 min). Although [(18)F]FEtP4A is a potential PET tracer for imaging AchE in vivo, its lower hydrolytic rate and lower specificity for AchE than those of [(11)C]MP4A may limit its usefulness for the quantitative measurement for AchE in the primate brain.

Acetates↗
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

Different roles of group I and group II metabotropic glutamate receptors on phencyclidine-induced dopamine release in the rat prefrontal cortex.

The dopamine system in the limbic-prefrontal cortex has been assumed to play an important role in the cognitive dysfunction of schizophrenia and phencyclidine (PCP)-induced psychosis. In the present study, the role of metabotropic glutamate (mGlu) receptor subtypes on PCP-induced cortical dopamine release was investigated using the microdialysis technique. Infusion of 50 and 100 microM of non-selective mGlu receptor agonist trans-(1S,3R)-1-amino-1,3-cyclopentanedicarboxylic acid inhibited PCP-induced dopamine release, while the basal dopamine level was not significantly affected. A similar inhibition of PCP-induced dopamine release was observed with 100 and 500 microM of selective group I mGlu receptor agonist, (+)-3-hydroxy-phenylglycine. On the other hand, infusion of 10 microM of selective group II mGlu receptor agonist, 2-(2, 3-dicarboxycyclopropyl)-glycine, enhanced the PCP-induced dopamine increase. These results suggest that group I and II mGlu receptors exert opposite modulations on the PCP-induced dopamine release.

Animals↗
PubMed2003

[18F]FMDAA1106 and [18F]FEDAA1106: two positron-emitter labeled ligands for peripheral benzodiazepine receptor (PBR).

We synthesized and evaluated N-(5-fluoro-2-phenoxyphenyl)-N-(2-[(18)F]fluoromethyl-5-methoxybenzyl)acetamide ([(18)F]-FMDAA1106) and N-(5-fluoro-2-phenoxyphenyl)-N-(2-[(18)F]fluoroethyl-5-methoxybenzyl)acetamide ([(18)F]FEDAA1106) as two potent radioligands for peripheral benzodiazepine receptors (PBR). [(18)F]FMDAA1106 and [(18)F]FEDAA1106 were respectively synthesized by fluoroalkylation of the desmethyl precursor DAA1123 with [(18)F]FCH(2)I and [(18)F]FCH(2)CH(2)Br. Ex vivo autoradiograms of [(18)F]FMDAA1106 and [(18)F]FEDAA1106 binding sites in the rat brains revealed that a high radioactivity was present in the olfactory bulb, the highest PBR density region in the brain.

Acetamides↗
PubMed2003

Tbx1 is regulated by tissue-specific forkhead proteins through a common Sonic hedgehog-responsive enhancer.

Haploinsufficiency of Tbx1 is likely a major determinant of cardiac and craniofacial birth defects associated with DiGeorge syndrome. Although mice deficient in Tbx1 exhibit pharyngeal and aortic arch defects, the developmental program and mechanisms through which Tbx1 functions are relatively unknown. We identified a single cis-element upstream of Tbx1 that recognized winged helix/forkhead box (Fox)-containing transcription factors and was essential for regulation of Tbx1 transcription in the pharyngeal endoderm and head mesenchyme. The Tbx1 regulatory region was responsive to signaling by Sonic hedgehog (Shh) in vivo. We show that Shh is necessary for aortic arch development, similar to Tbx1, and is also required for expression of Foxa2 and Foxc2 in the pharyngeal endoderm and head mesenchyme, respectively. Foxa2, Foxc1, or Foxc2 could bind and activate transcription through the critical cis-element upstream of Tbx1, and Foxc proteins were required, within their expression domains, for Tbx1 transcription in vivo. We propose that Tbx1 is a direct transcriptional target of Fox proteins and that Fox proteins may serve an intermediary role in Shh regulation of Tbx1.

Animals↗