Publications by authors named "Takehito Ito"

28 Publications

  • Page 1 of 1

Suggestive Diagnostic Process in a Case of Multiple Myeloma with Gastrointestinal Immunoglobulin Light-Chain Amyloidosis Accompanied by Protein-Losing Enteropathy.

Case Rep Gastrointest Med 2021 27;2021:5533993. Epub 2021 May 27.

Division of Gastroenterology, Tohoku Medical and Pharmaceutical University School of Medicine, Sendai, Miyagi, Japan.

Multiple myeloma is a type of plasma cell neoplasm that produces monoclonal immunoglobulin. Multiple myeloma is known to cause immunoglobulin light-chain (AL) amyloidosis, which frequently involves the kidney and heart. Bone pain or fractures caused by osteolytic lesions and physical disorders related to renal or cardiac AL amyloidosis are major initial symptoms in multiple myeloma. Multiple myeloma diagnosed from the gastrointestinal symptoms is rare. We report a case of an 80-year-old man with multiple myeloma accompanied by gastrointestinal AL amyloidosis and secondary protein-losing enteropathy. The diagnostic process was suggestive, in that diarrhea and refractory leg edema related to protein-losing enteropathy were the primary symptoms and the trigger for making a sequential diagnosis of gastrointestinal AL amyloidosis and underlying multiple myeloma. This case is highly suggestive, in that multiple myeloma with gastrointestinal AL amyloidosis should be considered one of the background diseases of protein-losing enteropathy.
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http://dx.doi.org/10.1155/2021/5533993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177977PMC
May 2021

Histamine H receptor density is negatively correlated with neural activity related to working memory in humans.

EJNMMI Res 2018 Jun 14;8(1):48. Epub 2018 Jun 14.

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

Background: The histamine H receptor is regarded as a drug target for cognitive impairments in psychiatric disorders. H receptors are expressed in neocortical areas, including the prefrontal cortex, the key region of cognitive functions such as working memory. However, the role of prefrontal H receptors in working memory has not yet been clarified. Therefore, using functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) techniques, we aimed to investigate the association between the neural activity of working memory and the density of H receptors in the prefrontal cortex.

Findings: Ten healthy volunteers underwent both fMRI and PET scans. The N-back task was used to assess the neural activities related to working memory. H receptor density was measured with the selective PET radioligand [C] TASP457. The neural activity of the right dorsolateral prefrontal cortex during the performance of the N-back task was negatively correlated with the density of H receptors in this region.

Conclusions: Higher neural activity of working memory was associated with lower H receptor density in the right dorsolateral prefrontal cortex. This finding elucidates the role of H receptors in working memory and indicates the potential of H receptors as a therapeutic target for the cognitive impairments associated with neuropsychiatric disorders.
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http://dx.doi.org/10.1186/s13550-018-0406-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999593PMC
June 2018

Neuromolecular basis of faded perception associated with unreality experience.

Sci Rep 2018 05 23;8(1):8062. Epub 2018 May 23.

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.

Perceptual changes in shape, size, or color are observed in patients with derealization symptoms; however, the underlying neural and molecular mechanisms are not well understood. The current study explored the relationship between neural activity associated with altered colorfulness perception assessed by fMRI and striatal dopamine D receptor availability measured by [C]raclopride PET in healthy participants. Inside an fMRI scanner, participants performed the saturation adaptation task, where they rated how much vivid/faded visual objects looked like real/unreal ones using a visual analog scale. We found that participants experienced greater unreality when they perceived fadedness than vividness despite physically identical saturation. The combined fMRI and PET analyses revealed that the faded perception-related activities of the dorsolateral prefrontal and parietal cortex were positively correlated with striatal D receptor availability. This finding may help to understand the neuromolecular mechanisms of faded perception associated with feeling unreal in derealization symptoms.
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http://dx.doi.org/10.1038/s41598-018-26382-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966381PMC
May 2018

Neural basis of negativity bias in the perception of ambiguous facial expression.

Sci Rep 2017 03 24;7(1):420. Epub 2017 Mar 24.

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

Negativity bias, which describes the tendency to interpret ambiguous stimuli or events as negative, is often observed in patients with depression and may prevent psychological well-being. Here, we used ambiguous facial stimuli, with negative (sad) and positive (happy) emotions simultaneously accessible, to examine neural activation during perceptual decision-making in healthy participants. The negativity bias was positively correlated with the activity of the bilateral pregenual anterior cingulate cortex (pgACC) when ambiguous faces were perceived as sad versus happy. Additionally, the strength of the functional connectivity between the bilateral pgACC and the right dorsal ACC (dACC)/right thalamus was positively correlated with hopelessness, one of the core characteristics of depression. Given the role of the pgACC as a major site of depressive affect and the roles of the dACC and thalamus in conflict monitoring and vigilance, respectively, our results reveal valid and important neuroanatomical correlates of the association between negativity bias and hopelessness in the healthy individuals.
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http://dx.doi.org/10.1038/s41598-017-00502-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5428736PMC
March 2017

Norepinephrine Transporter in Major Depressive Disorder: A PET Study.

Am J Psychiatry 2017 Jan 15;174(1):36-41. Epub 2016 Sep 15.

From the Department of Functional Brain Imaging Research, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan; the Department of Neuropsychiatry, Keio University School of Medicine, Tokyo; Decoding and Controlling Brain Information, Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Saitama, Japan; and the Department of Psychiatry, National Center of Neurology and Psychiatry, Tokyo.

Objective: The norepinephrine transporter has been suggested to play a crucial role in major depressive disorder. However, norepinephrine transporter availability in major depressive disorder and its role with clinical symptoms are not known. The authors tested norepinephrine transporter availability in patients with major depressive disorder with the aim to identify any associations between test results and clinical symptoms.

Method: The present research was a cross-sectional study in which 19 patients with major depressive disorder and 19 age- and sex-matched healthy comparison subjects underwent positron emission tomography scanning to evaluate the norepinephrine transporter availability measured by the radioligand (S,S)-[F]FMeNER-D. Norepinephrine transporter availability in the thalamus and its subregions was quantified in terms of nondisplaceable binding potential (BP). The authors also analyzed the association between norepinephrine transporter availability and clinical symptoms.

Results: Compared with healthy subjects, patients with major depressive disorder showed 29.0% higher BP values in the thalamus and, in particular, 28.2% higher values in the thalamic subregion anatomically connected to the prefrontal cortex. Elevated norepinephrine transporter availability in the thalamus in patients was positively correlated with attention, as measured by the Trail Making Test, part A.

Conclusions: These findings revealed altered norepinephrine transmission in patients with major depressive disorder, suggesting that this alteration could be related to attention in this patient population.
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http://dx.doi.org/10.1176/appi.ajp.2016.15101334DOI Listing
January 2017

Efficient radiosynthesis and non-clinical safety tests of the TSPO radioprobe [(18)F]FEDAC: Prerequisites for clinical application.

Nucl Med Biol 2016 07 26;43(7):445-53. Epub 2016 Apr 26.

Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.

Introduction: [(18)F]FEDAC ([(18)F]1) has potent binding affinity and selectivity for translocator protein (18kDa, TSPO), and has been used to noninvasively visualize neuroinflammation, lung inflammation, acute liver damage, nonalcoholic fatty liver disease, and liver fibrosis. We had previously synthesized [(18)F]1 in two steps: (i) preparation of [(18)F]fluoroethyl bromide and (ii) coupling of [(18)F]fluoroethyl bromide with the appropriate precursor (2) for labeling. In this study, to clinically utilize [(18)F]1 as a PET radiopharmaceutical and to transfer the production technique of [(18)F]1 to other PET centers, we simplified its preparation by using a direct, one-step, tosyloxy-for-fluorine substitution. We also performed an acute toxicity study as a major non-clinical safety test, and determined radiometabolites using human liver microsomes.

Methods: [(18)F]1 was prepared via direct (18)F-fluorination by heating the corresponding tosylated derivative (3) with [(18)F]fluoride as its Kryptofix 222 complex in dimethyl sulfoxide at 110°C for 15min, following by HPLC purification. Non-clinical safety tests were performed for the extended single-dose toxicity study in rats, and for the in vitro metabolite analysis with human liver microsomal incubation.

Results: High quality batches of [(18)F]1, compatible with clinical applications, were obtained. At the end of irradiation, the decay-corrected radiochemical yield of [(18)F]1 using 1 and 5mg of precursor based on [(18)F]fluoride was 18.5±7.9% (n=10) and 52.0±5.8% (n=3), respectively. A single-dose of [(18)F]1 did not show toxicological effects for 14 days after the injection in male and female rats. In human liver microsomal incubations, [(18)F]1 was easily metabolized to [(18)F]desbenzyl-FEDAC ([(18)F]10) by CYPs (4.2% of parent compound left 60min after incubation).

Conclusion: We successfully synthesized clinical grade batches of [(18)F]1 and verified the absence of innocuity of this radiotracer. [(18)F]1 will be used to first-in-human studies in our facility.
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http://dx.doi.org/10.1016/j.nucmedbio.2016.04.004DOI Listing
July 2016

Identification of a major radiometabolite of [11C]PBB3.

Nucl Med Biol 2015 Dec 2;42(12):905-10. Epub 2015 Sep 2.

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

Introduction: [(11)C]PBB3 is a clinically used positron emission tomography (PET) probe for in vivo imaging of tau pathology in the brain. Our previous study showed that [(11)C]PBB3 was rapidly decomposed to a polar radiometabolite in the plasma of mice. For the pharmacokinetic evaluation of [(11)C]PBB3 it is important to elucidate the characteristics of radiometabolites. In this study, we identified the chemical structure of a major radiometabolite of [(11)C]PBB3 and proposed the metabolic pathway of [(11)C]PBB3.

Methods: Carrier-added [(11)C]PBB3 was injected into a mouse for in vivo metabolite analysis. The chemical structure of a major radiometabolite was identified using LC-MS. Mouse and human liver microsomes and liver S9 samples were incubated with [(11)C]PBB3 in vitro. In silico prediction software was used to assist in the determination of the metabolite and metabolic pathway of [(11)C]PBB3.

Results: In vivo analysis showed that the molecular weight of a major radiometabolite of [(11)C]PBB3, which was called as [(11)C]M2, was m/z 390 [M+H(+)]. In vitro analysis assisted by in silico prediction showed that [(11)C]M2, which was not generated by cytochrome P450 enzymes (CYPs), was generated by sulfated conjugation mediated by a sulfotransferase.

Conclusion: The major radiometabolite, [(11)C]M2, was identified as a sulfated conjugate of [(11)C]PBB3. [(11)C]PBB3 was metabolized mainly by a sulfotransferase and subsidiarily by CYPs.
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http://dx.doi.org/10.1016/j.nucmedbio.2015.08.006DOI Listing
December 2015

Functional connectivity of the striatum in experts of stenography.

Brain Behav 2015 May 25;5(5):e00333. Epub 2015 Mar 25.

Division of Biology and Biological Engineering/Computation and Neural Systems, California Institute of Technology 139-74, Pasadena, California, 91125.

Introduction: Stenography, or shorthand, is a unique set of skills that involves intensive training which is nearly life-long and orchestrating various brain functional modules, including auditory, linguistic, cognitive, mnemonic, and motor. Stenography provides cognitive neuroscientists with a unique opportunity to investigate the neural mechanisms underlying the neural plasticity that enables such a high degree of expertise. However, shorthand is quickly being replaced with voice recognition technology. We took this nearly final opportunity to scan the brains of the last alive shorthand experts of the Japanese language.

Methods: Thirteen right-handed stenographers and fourteen right-handed controls participated in the functional magnetic resonance imaging (fMRI) study.

Results: The fMRI data revealed plastic reorganization of the neural circuits around the putamen. The acquisition of expert skills was accompanied by structural and functional changes in the area. The posterior putamen is known as the execution center of acquired sensorimotor skills. Compared to nonexperts, the posterior putamen in stenographers had high covariation with the cerebellum and midbrain.The stenographers' brain developed different neural circuits from those of the nonexpert brain.

Conclusions: The current data illustrate the vigorous plasticity in the putamen and in its connectivity to other relevant areas in the expert brain. This is a case of vigorous neural plastic reorganization in response to massive overtraining, which is rare especially considering that it occurred in adulthood.
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http://dx.doi.org/10.1002/brb3.333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4396401PMC
May 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

Radiosynthesis, photoisomerization, biodistribution, and metabolite analysis of 11C-PBB3 as a clinically useful PET probe for imaging of tau pathology.

J Nucl Med 2014 Sep 24;55(9):1532-8. Epub 2014 Jun 24.

Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan

Unlabelled: 2-((1E,3E)-4-(6-((11)C-methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-ol ((11)C-PBB3) is a clinically useful PET probe that we developed for in vivo imaging of tau pathology in the human brain. To ensure the availability of this probe among multiple PET facilities, in the present study we established protocols for the radiosynthesis and quality control of (11)C-PBB3 and for the characterization of its photoisomerization, biodistribution, and metabolism.

Methods: (11)C-PBB3 was synthesized by reaction of the tert-butyldimethylsilyl desmethyl precursor ( 1: ) with (11)C-methyl iodide using potassium hydroxide as a base, followed by deprotection. Photoisomerization of (11)C-PBB3 under fluorescent light was determined. The biodistribution and metabolite analysis of (11)C-PBB3 was determined in mice using the dissection method.

Results: (11)C-PBB3 was synthesized with 15.4% ± 2.8% radiochemical yield (decay-corrected, n = 50) based on the cyclotron-produced (11)C-CO2 and showed an averaged synthesis time of 35 min from the end of bombardment. The radiochemical purity and specific activity of (11)C-PBB3 were 98.0% ± 2.3% and 180.2 ± 44.3 GBq/μmol, respectively, at the end of synthesis (n = 50). (11)C-PBB3 showed rapid photoisomerization, and its radiochemical purity decreased to approximately 50% at 10 min after exposure to fluorescent light. After the fluorescent light was switched off, (11)C-PBB3 retained more than 95% radiochemical purity over 60 min. A suitable brain uptake (1.92% injected dose/g tissue) of radioactivity was observed at 1 min after the probe injection, which was followed by rapid washout from the brain tissue. More than 70% of total radioactivity in the mouse brain homogenate at 5 min after injection represented the unchanged (11)C-PBB3, despite its rapid metabolism in the plasma.

Conclusion: (11)C-PBB3 was produced with sufficient radioactivity and high quality, demonstrating its clinical utility. The present results of radiosynthesis, photoisomerization, biodistribution, and metabolite analysis could be helpful for the reliable production and application of (11)C-PBB3 in diverse PET facilities.
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http://dx.doi.org/10.2967/jnumed.114.139550DOI Listing
September 2014

Changing the mind? Not really-activity and connectivity in the caudate correlates with changes of choice.

Soc Cogn Affect Neurosci 2014 Oct 13;9(10):1546-51. Epub 2013 Sep 13.

Brain Science Institute, Tamagawa University, 6-1-1, Tamagawa Gakuen, Machida, Tokyo 194-8610, Japan, Division of Biology/Option Representative, Computation and Neural Systems, California Institute of Technology, 139-74, Pasadena, CA 91125, USA, and Department of Pharmacology, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan

Changes in preference are inherently subjective and internal psychological events. We have identified brain events that presage ultimate (rather than intervening) choices, and signal the finality of a choice. At the first exposure to a pair of faces, caudate activity reflected the face of final choice, even if an initial choice was different. Furthermore, the orbitofrontal cortex and hippocampus exhibited correlations only when the subject had made a choice that would not change.
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http://dx.doi.org/10.1093/scan/nst147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4187272PMC
October 2014

Functional magnetic resonance imaging study on the effects of acute single administration of paroxetine on motivation-related brain activity.

Psychiatry Clin Neurosci 2011 Mar;65(2):191-8

Tamagawa University Brain Science Institute, Tokyo, Japan.

Aim: The aim of the present study was to investigate the effects of acute paroxetine administration on brain activity related to motivation.

Methods: Sixteen healthy subjects participated in a randomized, single-blind, no-drug/placebo-controlled, cross-over study. After administration of no drug, placebo or paroxetine (selective serotonin reuptake inhibitor; 20 mg), subjects underwent functional magnetic resonance imaging while performing a monetary incentive delay task. We analyzed the differences in brain activities of the reward anticipation/motor preparation period that are subject to motivational modulation. For this purpose, we subdivided the incentive trials on the basis of whether the reaction times (RT) were slower or faster than the subject's mean RT (slow RT and fast RT trials).

Results: No drug and placebo showed robust activation differences in the globus pallidus and putamen for the fast RT trials compared to the slow RT trials, whereas paroxetine showed none. Paroxetine showed significantly lower activations in the globus pallidus, insula, putamen and dorsolateral prefrontal cortex compared to no drug in the fast RT trials.

Conclusions: Paroxetine single acute administration diminished brain activity induced by motivation in healthy subjects. This may partially explain the increased lack of motivation seen in patients with relatively mild symptoms after taking a dose of paroxetine for the first time.
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http://dx.doi.org/10.1111/j.1440-1819.2011.02189.xDOI Listing
March 2011

Ultrafast LC method for purification and metabolite analysis of PET probes.

Nucl Med Biol 2010 Jan 3;37(1):67-72. Epub 2009 Oct 3.

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

An ultrafast and efficient high-performance liquid chromatographic (LC) method was developed to purify positron emission tomography (PET) radiopharmaceuticals as well as for metabolite analysis of the plasma sample. Chromatographic separation was achieved on a short (60 mm length) semipreparative (10 mm I.D.) column packed with 2.5-mum particles using a mixture of acetonitrile and sodium phosphate buffer as the mobile phase at a flow rate of 8-10 ml/min. Under the optimum conditions, excellent separation of the target PET probe was obtained from chemical/radiochemical impurities or radioactive metabolites with a very short run time of 2 min. This characteristic enabled significant shortening of the purification and evaporation processes in the production of short-lived radiopharmaceuticals and highly sensitive radiometric analysis with good temporal resolution during the metabolism study.
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http://dx.doi.org/10.1016/j.nucmedbio.2009.08.002DOI Listing
January 2010

Nurr1 is required for maintenance of maturing and adult midbrain dopamine neurons.

J Neurosci 2009 Dec;29(50):15923-32

Ludwig Institute for Cancer Research, Stockholm Branch, SE-171 77 Stockholm, Sweden.

Transcription factors involved in the specification and differentiation of neurons often continue to be expressed in the adult brain, but remarkably little is known about their late functions. Nurr1, one such transcription factor, is essential for early differentiation of midbrain dopamine (mDA) neurons but continues to be expressed into adulthood. In Parkinson's disease, Nurr1 expression is diminished and mutations in the Nurr1 gene have been identified in rare cases of disease; however, the significance of these observations remains unclear. Here, a mouse strain for conditional targeting of the Nurr1 gene was generated, and Nurr1 was ablated either at late stages of mDA neuron development by crossing with mice carrying Cre under control of the dopamine transporter locus or in the adult brain by transduction of adeno-associated virus Cre-encoding vectors. Nurr1 deficiency in maturing mDA neurons resulted in rapid loss of striatal DA, loss of mDA neuron markers, and neuron degeneration. In contrast, a more slowly progressing loss of striatal DA and mDA neuron markers was observed after ablation in the adult brain. As in Parkinson's disease, neurons of the substantia nigra compacta were more vulnerable than cells in the ventral tegmental area when Nurr1 was ablated at late embryogenesis. The results show that developmental pathways play key roles for the maintenance of terminally differentiated neurons and suggest that disrupted function of Nurr1 and other developmental transcription factors may contribute to neurodegenerative disease.
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http://dx.doi.org/10.1523/JNEUROSCI.3910-09.2009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6666174PMC
December 2009

1-Minute quality control tests for positron emission tomography radiopharmaceuticals.

J Pharm Biomed Anal 2009 Sep 19;50(2):245-51. Epub 2009 Apr 19.

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

An ultra-fast, sensitive and versatile radio-liquid chromatographic (LC) procedure was developed and validated for quality control (QC) tests of PET radiopharmaceuticals. For a wide variety of radio-probes, the usual LC conditions were used: (1) column: Waters XBridge RP(18) (50 mm x 3.0 mm ID, 2.5 microm), (2) mobile phase: a mixture of three modifiers (90% CH3CN, ammonium phosphate at pH 2.1 and pH 9.3), and (3) detection: UV absorption and NaI(Tl) scintillation. The introduction of a short column packed with small particles of 2.5 microm allowed excellent separation of target analytes within a very short run time of 1 min; only a 3% decline of radioactivity was observed during QC analysis of (11)C-labelled pharmaceuticals. Combining ammonium-phosphate buffer as the mobile-phase component and low-wavelength UV detection led to an improvement in the applicability and sensitivity. All 34 pharmaceuticals investigated could be successfully applied to determine the specific radioactivity, radiochemical and chemical purity with 10-times better sensitivity than traditional LC. We could analyze different pharmaceuticals in a short period since this system utilized a common column and mobile phase. The proposed procedure fulfils the requirements for routine QC tests in terms of rapidity, sensitivity, simplicity and applicability.
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http://dx.doi.org/10.1016/j.jpba.2009.04.016DOI Listing
September 2009

Rapid and efficient purification of positron emission tomography probes by hydrophilic interaction chromatography.

J Chromatogr A 2009 May 13;1216(18):3933-40. Epub 2009 Mar 13.

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

A rapid and efficient preparative high-performance liquid chromatographic procedure was established to purify short-lived positron emission tomography radio-probes. This method is based on hydrophilic interaction chromatography utilizing a semi-preparative silica column (10 mm I.D.) and a high volatile organic mobile phase (>90% acetonitrile). In nine different radiopharmaceuticals studied, six compounds could be separated from the unlabeled precursor with good resolution and faster elution than its precursor. These characteristics enabled significant shortening of the separation and evaporation processes in the manufacture of short-lived radiopharmaceuticals. Several (11)C-radiopharmaceuticals could be prepared within one half-life of carbon-11 (20.4 min), including radiosynthesis, purification and formulation steps with sufficient radiochemical/chemical purity and high levels of radioactivity/specific radioactivity.
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http://dx.doi.org/10.1016/j.chroma.2009.03.012DOI Listing
May 2009

Simultaneous analysis of FDG, ClDG and Kryptofix 2.2.2 in [18F]FDG preparation by high-performance liquid chromatography with UV detection.

Nucl Med Biol 2008 Feb;35(2):239-44

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

A practical, sensitive and rapid analytical method was established and validated for chemical impurity tests of 2-deoxy-2-fluoro-d-glucose (FDG), 2-deoxy-2-chloro-d-glucose (ClDG) and Kryptofix 2.2.2 (K-222) in [18F]FDG. This method was based on precolumn derivatization with ultraviolet (UV) detection. FDG and ClDG were rapidly derivatized with 1-phenyl-3-methyl-5-pyrazolone in the presence of borate buffer at 40 degrees C, and the labeled derivatives and K-222 were separated by reversed-phase high-performance liquid chromatography and monitored by UV absorbance at 210 nm. After optimization of the conditions, FDG, ClDG and K-222 could be determined within 15 min and showed good performance in terms of sensitivity, linearity and reproducibility. This method could be successfully applied to the quality control test of [18F]FDG produced by a commercially available apparatus.
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http://dx.doi.org/10.1016/j.nucmedbio.2007.11.003DOI Listing
February 2008

Development of polyclonal antibodies specific to ATP-binding cassette transporters human ABCG4 and mouse Abcg4: site-specific expression of mouse Abcg4 in brain.

J Exp Ther Oncol 2007 ;6(4):321-33

Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama 226-8501, Japan.

In our recent study on seeking new mouse ATP-binding cassette (ABC) transporters of the G subfamily, we succeeded in cloning mouse Abcg4 from a cDNA library of mouse brain, and we characterized the tissue-specific expression and chromosomal localization of the mouse Abcg4 gene. To further characterize the physiological function of mouse Abcg4 protein and to compare its function with that of ABCG2, in the present study, we developed polyclonal antibodies against mouse Abcg4 and established the Abcg4-expression system. To raise antibodies, we selected three different epitope peptides that correspond to the amino acid residues of 46-60, 465-479, and 600-613 in mouse Abcg4 protein. The antibody raised against the epitope encoding the amino acids 46-60 was found to be specific to mouse Abcg4, exhibiting a band with molecular weight of 63,000 on immunoblotting, whereas this band was dose-dependently diminished by adding the corresponding epitope peptide into the immunoblot medium. Use of the antibody for immunoblot detection in mouse normal tissues revealed that the Abcg4 protein is expressed in brain, spleen, and testis. Immunohistochemical studies showed that mouse Abcg4 is site-specifically expressed in the cerebral cortex and medulla of mouse brain. These results suggest that mouse Abcg4 plays a certain physiological role in the brain. It is of importance to note that the sequence of amino acids 46-60 is completely identical between mouse Abcg4 and human ABCG4. Thus, this antibody is applicable to the detection of human ABCG4 as well as mouse Abcg4.
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January 2008

Blood flow dependence of the intratumoral distribution of peripheral benzodiazepine receptor binding in intact mouse fibrosarcoma.

Nucl Med Biol 2006 Nov 4;33(8):971-5. Epub 2006 Oct 4.

Radiochemistry Section, Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555, Japan.

The intratumoral distribution of [(11)C]AC-5216 binding, a novel peripheral benzodiazepine receptor (PBR) ligand, was examined by autoradiography both in vitro and in vivo using a murine fibrosarcoma model. The regional distribution of [(11)C]AC-5216 in a tumor in vivo was significantly heterogeneous; the uptake of [(11)C]AC-5216 was comparatively higher in the outer rim of the tumor and was lower in the central area. In contrast, the images obtained following the injection of [(11)C]AC-5216 with a large amount of nonlabeled PK11195 showed a relatively homogeneous distribution, suggesting that [(11)C]AC-5216 uptake represented specific binding to PBRs. In vitro autoradiograms of [(11)C]AC-5216 binding were also obtained using the section of the fibrosarcoma that was the same as that used to examine in vivo binding. In vitro autoradiographic binding images showed homogeneous distribution, and significant discrepancies of the intratumoral distribution of [(11)C]AC-5216 were observed between in vivo and in vitro images. The in vivo images of [(11)C]AC-5216 uptake, compared with those of [(14)C]iodoantipyrine uptake, obtained by dual autoradiography to evaluate the influence of blood flow revealed the similar intratumoral distributions of both tracers. These results indicate that the delivery process from the plasma to the tumor might be the rate-limiting step for the intratumoral distribution of PBR binding in vivo in a fibrosarcoma model.
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http://dx.doi.org/10.1016/j.nucmedbio.2006.08.004DOI Listing
November 2006

[2-11C]isopropyl-, [1-11C]ethyl-, and [11C]methyl-labeled phenoxyphenyl acetamide derivatives as positron emission tomography ligands for the peripheral benzodiazepine receptor: radiosynthesis, uptake, and in vivo binding in brain.

J Med Chem 2006 May;49(9):2735-42

Department of Medical Imaging, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555, Japan.

The peripheral benzodiazepine receptor (PBR) is widely expressed in peripheral tissues, blood cells, and in glia cells in the brain. We have previously developed two positron emission tomography (PET) ligands, N-(2-[(11)C],5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamide ([(11)C]2) and its [(18)F]fluoroethyl analogue ([(18)F]6), for the current investigation of PBR in the human brain. The aim of this study was to label the potent PBR agonist N-(4-chloro-2-phenoxyphenyl)-N-(isopropoxybenzyl)acetamide (3) and its ethyl (7) and methyl (8) homologues with (11)C and to evaluate them as PET ligands for PBR with mice, rats, and monkeys. Ligands [(11)C]3, [(11)C]7, and [(11)C]8 were synthesized by alkylation of phenol precursor 9 with 2-[2-(11)C]iodopropane ([(11)C]10), [1-(11)C]iodoethane ([(11)C]11), and [(11)C]iodomethane ([(11)C]12), respectively. The alkylating agent [(11)C]10 or [(11)C]11 was prepared by reacting CH(3)MgBr with [(11)C]CO(2), followed by reduction with LiAlH(4) and iodination with HI. In vitro quantitative autoradiography determined that 3, 7, and 8 had potent binding affinities (K(i) = 0.07-0.19 nM) for PBR in the rat brain. These [(11)C]ligands could pass across the blood-brain barrier and enter the rat brain (0.17-0.32% of injected dose per gram wet tissue). Ex vivo autoradiography showed that the [(11)C]ligands preferably distributed in the olfactory bulb and cerebellum, two regions with richer PBR density in the rat brain. The co-injection of PBR-selective 2 reduced the [(11)C]ligand binding in the two regions, suggesting that binding in the rat brain was specific to PBR. PET study determined that the [(11)C]ligands preferably accumulate in the occipital cortex of the monkey brain, a region with a high density of PBR in the primate brain. Moreover, in vivo binding of the methyl homologue [(11)C]8 in the monkey brain could be inhibited by PBR-selective 2 or 1, indicating that some of the [(11)C]8 binding was due to PBR. Metabolite analysis demonstrated that these [(11)C]ligands were metabolized by debenzylation to polar products mainly in the plasma.
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http://dx.doi.org/10.1021/jm060006kDOI Listing
May 2006

Phosphoinositide 3-kinase in nitric oxide synthesis in macrophage: critical dimerization of inducible nitric-oxide synthase.

J Biol Chem 2006 Jun 24;281(26):17736-42. Epub 2006 Apr 24.

Department of Microbiology and Immunology, Yamaguchi University School of Medicine, 1-1-1 Minami-Kogushi, Ube-shi, Yamaguchi-Ken 755-8505, Japan.

Phosphoinositide 3-kinase (PI3K) has important functions in various biological systems, including immune response. Although the role of PI3K in signaling by antigen-specific receptors of the adaptive immune system has been extensively studied, less is known about the function of PI3K in innate immunity. In the present study, we demonstrate that macrophages deficient for PI3K (p85alpha regulatory subunit) are impaired in nitric oxide (NO) production upon lipopolysaccharide and interferon-gamma stimulation and thus vulnerable for intracellular bacterial infection such as Chlamydophila pneumoniae. Although expression of inducible nitric-oxide synthase (iNOS) is induced normally in PI3K-deficient macrophages, dimer formation of iNOS protein is significantly impaired. The amount of intracellular tetrahydrobiopterin, a critical stabilizing cofactor for iNOS dimerization, is decreased in the absence of PI3K. In addition, induction of GTP cyclohydrolase 1, a rate-limiting enzyme for biosynthesis of tetrahydrobiopterin, is greatly reduced. Our current results demonstrate a critical role of class IA type PI3K in the bactericidal activity of macrophages by regulating their NO production through GTP cyclohydrolase 1 induction.
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http://dx.doi.org/10.1074/jbc.M601896200DOI Listing
June 2006

Improved quality control of [18F]FDG by HPLC with UV detection.

Nucl Med Biol 2005 Nov;32(8):907-12

Department of Medical Imaging, National Institute of Radiological Sciences, Chiba 263-8555, Japan.

A conventional high-performance liquid chromatographic (HPLC) method for the analysis of 2-fluoro-2-deoxy-d-glucose (FDG) and 2-deoxy-2-chloro-d-glucose (ClDG) in [18F]FDG preparations is described. This method was based on a postcolumn derivatization with 2-cyanoacetamide (2-CA) and UV detection. FDG and ClDG were separated on a normal-phase column using acetonitrile/water as the mobile phase. The eluate was mixed with 2-CA in sodium borate buffer solution at the outlet of a PTFE coil (10 m x 0.5 mm id) from the column, and the reaction was carried out at 100 degrees C during the passage through the coil. The UV absorbance of the resultant product was monitored at 276 nm. Under optimum conditions, the detection limits [signal-to-noise (S/N) ratio=3] for FDG and ClDG were 0.31 and 0.17 microg/ml for a 20-microl injection volume, respectively, and the linearity ranges were 0.5-100 microg/ml for both compounds. The intra- and interday reproducibilities were better than 2.2% [relative standard deviation (R.S.D.)]. This HPLC separation procedure is also useful for determining the radiochemical purity of [18F]FDG preparations since it allows the analysis of 2-[18F]fluoro-1,3,4,6-tetra-O-acetyl-d-glucose ([18F]TAG), partially hydrolyzed [18F]TAG and [18F]F-. This method can be used at many positron emission tomography (PET) facilities since it does not require an expensive, sophisticated electrochemical detector.
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http://dx.doi.org/10.1016/j.nucmedbio.2005.07.002DOI Listing
November 2005

Nerve growth factor-induced expression of the GTP cyclohydrolase I gene via Ras/MEK pathway in PC12D cells.

J Neurochem 2005 Oct;95(2):563-9

Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan.

Neurotrophins are essential for the development and survival of the catecholaminergic neurons. GTP cyclohydrolase I (GCH) is the first and rate-limiting enzyme in the biosynthesis of 5,6,7,8-tertahydrobiopterin (BH4), the required cofactor for tyrosine hydroxylase. Previously, we reported that TH requires the Ras/mitogen-activated protein kinase kinase (MEK) pathway for its induction by nerve growth factor (NGF). Here, we examined intracellular signals required for NGF-induced expression of the GCH gene in PC12D cells. The activity of GCH was increased up to 5-fold after the NGF treatment, and the increase was repressed by pretreatment with U0126, an MEK1/2 inhibitor, but not with protein kinase A (PKA), phosphoinositide 3-kinase (PI3K), p38 mitogen-activated protein kinase (MAPK), and c-Jun NH2-terminal kinase (JNK) inhibitors. Induction of GCH mRNA by NGF was also abolished by pretreatment with U0126. The human GCH promoter activity was significantly enhanced by NGF treatment. Deletion analysis showed that the 465-bp 5'-flanking region is responsible for NGF-enhanced promoter activity. These data suggest that the Ras-MEK pathway is required for coordinate expression of the GCH and TH genes induced by neurotrophins.
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http://dx.doi.org/10.1111/j.1471-4159.2005.03414.xDOI Listing
October 2005

Input-output analysis of in vivo photoassimilate translocation using Positron-Emitting Tracer Imaging System (PETIS) data.

J Exp Bot 2005 May 4;56(415):1419-25. Epub 2005 Apr 4.

Takasaki Radiation Chemistry Research Establishment, Japan Atomic Energy Research Institute, Gunma 370-1207, Japan.

The Positron-Emitting Tracer Imaging System (PETIS) is introduced for monitoring the distribution of (11)C-labelled photoassimilates in Sorghum. The obtained two-dimensional image data were quantitatively analysed using a transfer function analysis approach. While one half of a Sorghum root in a split root system was treated with either 0, 100, or 500 mM NaCl dissolved in the nutrient solution, tracer images of the root halves and the lower stem section were recorded using PETIS. From the observed tracer levels, parameters were estimated, from which the mean speed of tracer transport and the proportion of tracer moved between specified image positions were deduced. Transport speed varied between 0.7 and 1.8 cm min(-1) with the difference depending on which part of the stem was involved. When data were collected in the lowest 0.5-1 cm of the stem, which included the point where the roots emerge, transport speed was less. Rapid changes in NaCl concentration, from 0 to 100 mM, resulted in short-term increases of assimilate import into the treated root. This response represented a transient osmotic effect, that was compensated for in the medium-term by osmotic adaptation. Higher concentrations of NaCl (500 mM) resulted in distinctly less photoassimilate transport into the treated root half. The present results agree with earlier observations, showing that transport of (11)C-labelled photoassimilates measured with the PETIS detector system can be quantified using the method of input-output analysis. It is worth noting that with the PETIS detector system, areas of interest do not need to be defined until after data collection. This means that unexpected behaviour of a plant organ will be seen, which is not necessarily the case with conventional detector systems looking at predefined areas of interest.
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http://dx.doi.org/10.1093/jxb/eri143DOI Listing
May 2005

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.

Bioorg Med Chem 2005 Mar;13(5):1811-8

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

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.
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http://dx.doi.org/10.1016/j.bmc.2004.11.058DOI Listing
March 2005

Proposal of blood-collecting needle approach to semi-invasive method.

Diabetes Res Clin Pract 2004 Dec;66 Suppl 1:S179-83

Department of Material Systems Engineering and Life Science, Faculty of Engineering, Toyama University, 3190 Gofuko, Toyama 930-8555, Japan.

Many diabetic patients carry a portable self-monitoring of blood glucose (SMBG)-analyzer in order to collect their own blood and examine their glucose levels; this allows them to determine such factors as insulin dose, diet and exercise to stay healthy. However, the test causes physical and mental stress for the subjects. The authors aim to develop a semi-invasive blood-collecting needle which does not need a power source for the pump mechanism. In this study, we fabricated a capillary action needle that can collect the blood sample automatically. A blood-collecting needle was fabricated from 25 gage sized medical needle (diameter of 0.5 mm, stainless steel) by cutting process, and it had a half-opened crevice in the tip. In order to evaluate the physical characteristics of the blood-collecting needle, the relationship between the size and suction time and/or suction volume were measured using an isotonic sodium chloride solution, whole rabbit blood, and whole human blood with anticoagulant. Next, in order to evaluate the degree of invasion, the diameters of erythema in auricles of rabbits were observed for 2 days using a CCD camera-type microscope. The mean suction time of the isotonic sodium chloride solution and the whole rabbit blood were 1.5 s (n = 10) and 9.0 s (n = 5), respectively. Selection of a suitable size of the blood-collecting needle enabled the collection of 0.1 microL of whole human blood in 10 s. Moreover, it was shown, by comparing the observed diameter of the erythema, that the invasiveness of the blood-collecting needle was smaller than for commercial needles of the equal diameter. It became clear that this fulfils the fundamental functions of a semi-invasive blood-collecting needle.
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http://dx.doi.org/10.1016/j.diabres.2003.08.016DOI Listing
December 2004

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.

J Med Chem 2004 Apr;47(9):2228-35

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

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.
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http://dx.doi.org/10.1021/jm0304919DOI Listing
April 2004

Quick and reversible inhibition of soybean root nodule growth by nitrate involves a decrease in sucrose supply to nodules.

J Exp Bot 2003 May;54(386):1379-88

Faculty of Agriculture, Niigata University, 2-8050 Ikarashi, Niigata, 950-2181, Japan.

The upper part of a nodulated soybean root hydroponically cultured in a glass bottle was monitored using a computer microscope under controlled environmental conditions, and the diameter of individual nodules was measured from 10-24 d after planting. The diameter of a root nodule attached to the primary root increased from 1 mm to 6 mm for 2 weeks under nitrogen-free conditions. The increase in diameter of the nodules was almost completely stopped after 1 d of supplying 5 mM nitrate, and was due to the cessation of nodule cell expansion. However, nodule growth quickly returned to the normal growth rate following withdrawal of nitrate from the solution. The reversible depression of nodule growth by nitrate was similar to the restriction of photoassimilate supply by continuous dark treatment for 2 d followed by normal light/dark conditions. In addition, the inhibitory effect of nitrate was partially alleviated by the addition of 3% (w/v) sucrose to the medium. Plant leaves were exposed to (11)C or (14)C-labelled carbon dioxide to investigate the effects of 5 mM nitrate on the translocation and distribution of photosynthates to nodules and roots. Supplying 5 mM nitrate stimulated the translocation rate and the distribution of labelled C in nitrate-fed parts of the roots. However, the (14)C partitioning to nodules decreased from 9% to 4% of total (14)C under conditions of 5 mM nitrate supply. These results indicate that the decrease in photoassimilate supply to nodules may be involved in the quick and reversible nitrate inhibition of soybean nodule growth.
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http://dx.doi.org/10.1093/jxb/erg147DOI Listing
May 2003
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