Junichi Shimada

KYOWA HAKKO BIO Co., Ltd., Edo, Tōkyō, Japan

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Publications (37)99.12 Total impact

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    Full-text · Dataset · Dec 2012
  • J. SHIMADA · F. SUZUKI
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    ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
    No preview · Article · Nov 2010 · ChemInform
  • J. SHIMADA · T. KURODA · F. SUZUKI
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    ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
    No preview · Article · Sep 2010 · ChemInform
  • [Show abstract] [Hide abstract]
    ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
    No preview · Article · Jan 2010 · ChemInform
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    ABSTRACT: Research and development of the adenosine A2A receptor selective antagonist KW6002 have focused on developing a novel nondopaminergic therapy for Parkinson's disease (PD). Salient pharmacologic features of KW6002 were investigated in several animal models of PD. In rodent and primate models, KW6002 provides symptomatic relief from parkinsonian motor deficits without provoking dyskinesia or exacerbating existing dyskinesias. The major target neurons of the A2A receptor antagonist were identified as GABAergic striatopallidal medium spiny neurons. A possible mechanism of A2A receptor antagonist action in PD has been proposed based on the involvement of striatal and pallidal presynaptic A2A receptors in the "dual" modulation of GABAergic synaptic transmission. Experiments with dopamine D2 receptor knockout mice showed that A2A receptors can function and anti-PD activities of A2A antagonists can occur independent of the dopaminergic system. Clinical studies of KW6002 in patients with advanced PD with L-dopa-related motor complications yielded promising results with regard to motor symptom relief without motor side effects. The development of KW6002 represents the first time that a concept gleaned from A2A biologic research has been applied successfully to "proof of concept" clinical studies. The selective A2A antagonist should provide a novel nondopaminergic approach to PD therapy.
    No preview · Article · Jan 2004 · Neurology
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    ABSTRACT: We examined whether measurement of the adenosine A(1) receptor (A1-R) with PET can predict the severity of ischemic brain damage using an occlusion and reperfusion model of the cat middle cerebral artery (MCA) and [1-methyl-(11)C]8-dicyclopropylmethyl-1-methyl-3-propylxanthine (MPDX), a positron-emitting radioligand developed at our institution. Eighteen adult cats underwent PET measurement of cerebral blood flow (CBF), A1-R, central benzodiazepine receptor (BDZ-R), and glucose metabolism with (15)O-labeled water, MPDX, (11)C-flumazenil (FMZ), and (18)F-FDG, respectively. The right MCAs of 13 cats were transiently occluded via a transorbital approach with microvascular clips. CBF was measured before occlusion of MCA, during occlusion, and immediately after reperfusion. After CBF measurement, A1-R, BDZ-R, and (18)F-FDG uptake were serially measured in the order listed. Two months later, the degree of ischemic damage was evaluated by T2-weighted MR images obtained with an animal MRI system and by analysis of histologic specimens. Five cats that received no operations were used as controls. The cats that underwent occlusion were divided into 3 groups: cats that did not survive the first day because of severe neurologic and systemic conditions (n = 4), cats that survived and had infarcted lesions in both the cortex and the striatum (n = 3), and cats that survived and had infarcted lesions only in the striatum (n = 6). CBF during occlusion of the MCA was significantly lower in all 3 ischemic groups than in the control group, but there was no significant difference among the ischemic groups. Right-to-left ratios of CBF and (18)F-FDG uptake did not significantly differ among the groups. MPDX binding and FMZ binding were significantly lower in the groups with severe ischemic insult than in the groups with little to no insult. The degree of decreased MPDX binding to A1-Rs after reperfusion was a sensitive predictor of severe ischemic insult. MPDX PET has good potential to become a suitable in vivo imaging technique for evaluating the function of adenosine and A1-Rs in relation to cerebral ischemia.
    No preview · Article · Dec 2003 · Journal of Nuclear Medicine
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    ABSTRACT: To determine the changes in the adenosine A(1) and benzodiazepine receptor density and in glucose metabolism in the visual centers of the rat brain following monocular enucleation or eyelid suture on postnatal day 10 (PN10). Following monocular enucleation or eyelid suture on PN10 rats, the alterations in adenosine A(1) and benzodiazepine receptor density, and in glucose metabolism were evaluated in the superior colliculus (SC), the dorsal lateral geniculate body (DLG), and the visual cortex (VC) by ex vivo autoradiography with [11C]MPDX, [11C]flumazenil and [14C]2-deoxyglucose, respectively. Enucleation reduced the [11C]MPDX binding in the SC and DLG, and enhanced the [11C]flumazenil binding in the SC. Eyelid suture reduced the [11C]flumazenil binding in the VC at day 20. [14C]2-deoxyglucose uptake was not decreased by enucleation in any region except in the SC and DLG at day 1, but was decreased by eyelid suture in the SC at days 20 and 55 and in the VC at day 55. The decrease in the presynaptic adenosine A(1) receptors in the SC following enucleation is coupled with an upregulation of postsynaptic benzodiazepine receptors. These neural reactions are completely different from those following eyelid suture. The development of neural architecture for visual functions is not completed at PN10 in rats.
    Full-text · Article · Mar 2003 · Japanese Journal of Ophthalmology
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    ABSTRACT: Measurement of the adenosine A1 receptor (A1-R) with positron emission tomography (PET) using a newly developed positron ligand, [1-methyl-11C]8-dicyclopropylmethyl-1-methyl-3-propylxanthine (MPDX). were performed in a cat middle cerebral artery (MCA) occlusion and reperfusion. Eighteen adult cats underwent PET measurement of; 1) cerebral blood flow (CBF). 2) A1-R, 3) central benzodiazepine receptor (BDZ-R) and 4) glucose metabolism with 15O labeled water, MPDX, 11C-flumazenil (FMZ) and 18F-fluorodeoxyglucose (FDG), respectively. The CBF, A1-R, BDZ-R and FDG uptake were serially measured after 60 min occlusion of MCA in this order. MPDX binding and FMZ binding, but not CBF and FDG uptake, were significantly reduced in the groups with severer ischemic insult than in the groups with no or milder insults. Of the two receptor ligands, the reduction rate of the MPDX binding to A1-Rs was larger in a group that caused fatal ischemic insult. The newly developed PET in vivo imaging technique using MPDX was suitable in evaluating the function of adenosine and A1-Rs in relation to cerebral ischemia.
    No preview · Article · Feb 2003 · Acta neurochirurgica. Supplement
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    ABSTRACT: In previous in vivo studies with mice, rats and cats, we have demonstrated that [11C]MPDX ([1-methyl-11C]8-dicyclopropylmethyl-1-methyl-3-propylxanthine) is a potential radioligand for mapping adenosine A1 receptors of the brain by positron emission tomography (PET). In the present study, we performed a preclinical study. The radiation absorbed-dose by [11C]MPDX in humans estimated from the tissue distribution in mice was low enough for clinical use, and the acute toxicity and mutagenicity of MPDX were not found. The monkey brain was clearly visualized by PET with [11C]MPDX. We have concluded that [11C]MPDX is suitable for mapping adenosine A1 receptors in the human brain by PET.
    Full-text · Article · Oct 2002 · Annals of Nuclear Medicine
  • K. Ishikawa · J. Shimada · K. Ishii · F. Suzuki

    No preview · Article · Jun 2002 · Drugs of the Future
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    ABSTRACT: We investigated the biochemical and pharmacological properties of a new adenosine A(3) receptor antagonist, KF26777 (2-(4-bromophenyl)-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one dihydrochloride). This compound was characterized using N(6)-(4-amino-3-iodobenzyl)adenosine-5'-N-methyluronamide ([125I]AB-MECA) or [35S]guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS) binding to membranes from human embryonic kidney 293 (HEK293) cells expressing human adenosine A(3) receptors. KF26777 showed a K(i) value of 0.20+/-0.038 nM for human adenosine A(3) receptors labeled with [125I]AB-MECA and possessed 9000-, 2350- and 3100-fold selectivity vs. human adenosine A(1), A(2A) and A(2B) receptors, respectively. The inhibitory mode of binding was competitive. KF26777 inhibited the binding of [35S]GTPgammaS stimulated by 1 microM 2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide (Cl-IB-MECA). The IC(50) value was 270+/-85 nM; the compound had no effect on basal activity. Dexamethasone treatment for HL-60 cells, human promyelocytic leukemia, up-regulated functional adenosine A(3) receptors expression, and resulted in the enhanced elevation of intracellular Ca(2+) concentration ([Ca(2+)](i)) via the adenosine A(3) receptor. KF26777 antagonized this [Ca(2+)](i) mobilization induced by Cl-IB-MECA, with a K(B) value of 0.42+/-0.14 nM. These results indicate that KF26777 is a highly potent and selective antagonist of the human adenosine A(3) receptor.
    No preview · Article · Jun 2002 · European Journal of Pharmacology
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    ABSTRACT: We have evaluated the feasibility of using four positron emission tomography (PET) tracers for imaging the globus pallidus by ex vivo autoradiography in rats. The tracers investigated were [11C]KF18446, [11C]SCH 23390 and [11C]raclopride for mapping adenosine A2A, dopamine D1 and dopamine D2 receptors, respectively, and [18F]FDG. The highest uptake by the globus pallidus was found for [11C]SCH 23390, followed by [18F]FDG, [11C]KF18446 and [11C]raclopride. The receptor-specific uptake by the globus pallidus was observed in [11C]KF18446 and [11C]SCH 23390, but not in [11C]raclopride. Uptake ratios of globus pallidus to the striatum for [18F]FDG and [11C]KF18446 were approximately 0.6, which was twice as large as that for [11C]SCH 23390. In a rat model of degeneration of striatopallidal gamma-aminobutyric acid-ergic-enkephalin neurons induced by intrastriatal injection of quinolinic acid, the uptake of [11C]KF18446 by the striatum and globus pallidus was remarkably reduced. To prove the visualization of the globus pallidus by PET with [18F]FDG and [11C]KF18446, PET-MRI registration technique and advances in PET technologies providing high-resolution PET scanner will be required. The metabolic activity of the globus pallidus could then be measured by PET with [18F]FDG, and [11C]KF18446 may be a candidate tracer for imaging the pallidal terminals projecting from the striatum.
    Full-text · Article · Jan 2001 · Annals of Nuclear Medicine
  • Junichi Shimada · Fumio Suzuki
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    ABSTRACT: This chapter discusses the fact that there are different types of receptors which help to regulate the intracellular signaling system in various ways. On the basis of both pharmacological and biochemical studies, these receptors have been usually divided into four subtypes such as adenosine A1, A2A, A2B, and A3 receptors. These receptors generally belong to the family of receptors coupled to G-proteins. The thoroughly investigated subtypes are the high-affinity A1 and A2A receptors, both of which are activated by adenosine in low, nanomolar, or at least submicromolar concentrations, depending on the cell system investigated. This chapter also reviews the two promising areas where A1 antagonists may be therapeutic. These are cognitive deficit and acute renal failure. Selective adenosine A2A antagonists such as KW-6002 provide new possibilities for the treatment of Parkinson's disease. Noteworthy progress has been made with the synthesis of new compounds, such as 8-styrylxanthines and new nonxanthine heterocycles. Theophylline, the nonselective adenosine antagonist, has been shown to improve motor scores and the mental state of parkinsonian patients.
    No preview · Chapter · Dec 2000
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    ABSTRACT: In vivo assessment of the adenosine A2A receptors localized in the striatum by PET or SPECT offers us a new diagnostic tool for neurological disorders. In the present study, we evaluated the potential of iodinated and brominated styrylxanthine derivatives labeled with 11C as an in vivo probe. [7-Methyl-11C]-(E)-3,7-dimethyl-8-(3-iodostyryl)-1-propargylxan thine ([11C]IS-DMPX) and [7-methyl-11C]-(E)-8-(3-bromostyryl)-3,7-dimethyl-1-propargylxa nthine ([11C]BS-DMPX) were prepared by the 11C-methylation of corresponding 7-demethyl derivatives. An in vitro membrane binding study showed a high affinity (Ki values) of the two ligands for A2A receptor: 8.9 nM for IS-DMPX and 7.7 nM for BS-DMPX, and a high A2A/A1 selectivity: > 1100 for IS-DMPX and 300 for BS-DMPX. In mice, [11C]IS-DMPX and [11C]BS-DMPX were taken up slightly more in the striatum than in the reference regions such as the cortex and cerebellum. The uptake ratios of striatum to cortex and striatum to cerebellum gradually increased but were very small: 1.6-1.7 for the striatum-to-cortex ratio and 1.2 for the striatum-to-cerebellum ratio at 60 min postinjection. The uptake by these three regions was reduced by co-injection of an excess amount of carrier or an A2A antagonist KF17837, but not by an A1 antagonist KF15372. The blocking effects in the three regions were greater for [11C]BS-DMPX (32-57%) than for [11C]IS-DMPX (6-29%). Ex vivo autoradiography confirmed that the two ligands were slightly concentrated in the striatum. [11C]BS-DMPX showed more selective affinity for adenosine A2A receptors than [11C]IS-DMPX, but these results have shown that the two tracers were not suitable as in vivo ligands because of low selectivity for the striatal A2A receptors and a high nonspecific binding.
    Full-text · Article · Sep 2000 · Annals of Nuclear Medicine
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    ABSTRACT: PET assessment of the adenosine A2a receptors localized in the striatum offers us a potential new diagnostic tool for neurological disorders. In the present study, we carried out in vitro receptor autoradiography of a newly developed PET ligand [11C]KF18446 ([7-methyl-11C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthin e) with rat brain sections. [11C]KF18446 showed a high striatum/cortex binding ratio (5.0) and low nonspecific binding (<10%), suggesting that [11C]KF18446 has characteristics comparable or slightly superior to [3H]CGS 21680 or [3H]SCH 58261, which are currently available representative A2a receptor ligands. Scatchard analysis indicated a Kd of 9.8 nM and a Bmax of 170 fmol/mm3 tissue in the striatum and a Kd of 16.4 nM and a Bmax of 33 fmol/mm3 tissue in the cortex. Seven xanthine-type and four nonxanthine-type adenosine receptor ligands with an affinity for the adenosine A2a receptors significantly reduced the in vitro binding of [11C]KF18446 to the brain section. The blocking effects were much stronger in the striatum than in the cortex, but did not necessarily parallel their affinity. On the other hand, four xanthine-type ligands and one nonxanthine-type ligand (SCH 58261) of the 11 ligands studied reduced the in vivo uptake of [11C]KF18446 in mice, but other ligands, including A1-selective and nonselective ligands and three nonxanthine-type A2a-selective antagonists did not. We conclude that [11C]KF18446 is a promising adenosine A2a receptor ligand for PET study.
    Full-text · Article · May 2000 · Annals of Nuclear Medicine
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    ABSTRACT: To develop PET ligands for mapping central nervous system (CNS) adenosine A2a receptors that are localized in the striatum and are coupled with dopamine receptors, 3 11C-labeled xanthine-type adenosine A2a antagonists, [11C]KF18446 ([7-methyl-11C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthin e), [11C]KF19631 ([7-methyl-11C]-(E)-1,3-diallyl-7-methyl-8-(3,4,5-trimethoxystyryl)xanth ine), and [11C]CSC ([7-methyl-11C]-8-chlorostyrylcaffeine), were compared with [11C]KF17837 ([7-methyl-11C]-(E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylx anthine). The regional brain uptake of the tracers, the effect of the coinjected adenosine antagonists on the uptake, and the metabolism were studied in mice. In rats, the regional brain uptake of the tracers was visualized by ex vivo autoradiography (ARG). The A2a receptor binding of antagonist 1 was also measured by in vitro ARG. Imaging of the monkey brain was performed with PET with antagonist 1. In mice, the highest striatal uptake was found for antagonist 1 followed by antagonists 2 and 4. The uptake was inhibited by each of 3 KF compounds and by CSC, but not by an A1 antagonist KF15372. Another selective nonxanthine-type A2a antagonist SCH 58261 significantly decreased the striatal uptake of only antagonist 1, the labeled metabolites of which were less than 20% in the plasma 30 min postinjection, but were negligible in the brain tissue. In ex vivo ARG, antagonist 1 showed the highest striatal uptake and the highest uptake ratio of the striatum to the other brain regions. A high and selective binding of antagonist 1 to the striatum was also confirmed by in vitro ARG. PET with antagonist 1 visualized adenosine A2a receptors in the monkey striatum. These results indicate that antagonist 1 ([11C]KF18446) is the most suitable PET ligand for mapping adenosine A2a receptors in the CNS.
    Full-text · Article · Mar 2000 · Journal of Nuclear Medicine
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    ABSTRACT: Adenosine A2a receptors are found in the endothelia, vascular smooth muscle cells and cardiac myocytes. The properties of a carbon-11 labeled A2a antagonist [11C]KF17837 ([7-methyl-11C](E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methy lxa nthine) for myocardial imaging were evaluated by dynamic PET scanning of the myocardium in rabbits. Myocardial uptake of [11C]KF17837 was clearly visualized by PET. The tracer was taken up at a high level by the myocardium immediately after the injection, and the myocardial level of radioactivity gradually decreased. On the other hand, an inactive [11C]Z-isomer of [11C]KF17837 showed a very low myocardial uptake and the myocardium was not visualized with a selective A1 antagonist [11C]KF15372. By co-injection with carrier KF17837 or a xanthine type A2a antagonist 7-chlorostyrylcaffeine (CSC), the myocardial uptake of [11C]KF17837 was completely blocked. The effect of non-xanthine A2a antagonists ZM 241,385 and SCH 58,261, which have a higher affinity than CSC, was smaller than that of the CSC. The effect of weak antagonists caffeine and alloxazine or a xanthine type A1 antagonist KF15372 on the radioactivity level was small. It is concluded that PET with [11C]KF17837 can image myocardial adenosine A2a receptors.
    No preview · Article · Sep 1997 · Annals of Nuclear Medicine
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    ABSTRACT: Structure-activity relationship of 8-styrylxanthines for in vivo adenosine A2A antagonism were explored. Diethyl substitution both at the 1- and 3-position was found to dramatically potentiate the anti-cataleptic activity.
    No preview · Article · Sep 1997 · Bioorganic & Medicinal Chemistry Letters
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    ABSTRACT: 1. We demonstrate that 8-(noradamantan-3-yl)-1,3-dipropylxanthine (KW-3902) is a very potent and selective adenosine A1 receptor antagonist, assessed by radioligand binding and cyclic AMP response in cells. 2. In rat forebrain adenosine A1 receptors labelled with [3H]-cyclohexyladenosine (CHA), KW-3902 had a Ki value of 0.19 nM, whereas it showed a Ki value of 170 nM in rat striatal A2A receptors labelled with [3H]-2-[p-(2-carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamidoad enosine (CGS21680), indicating 890 fold A1 receptor selectivity versus the A2A receptor. KW-3902 at 10 microM showed no effect on recombinant rat A3 receptors expressed on CHO cells. 3. Saturation studies with [3H]-KW-3902 revealed that it bound with high affinity (Kd = 77 pM) and limited capacity (Bmax = 470 fmol mg-1 of protein) to a single class of recognition sites. A high positive correlation was observed between the pharmacological profile of adenosine ligands inhibiting the binding of [3H]-KW-3902 and that of [3H]-CHA. 4. KW-3902 showed potent A1 antagonism against the inhibition of forskolin-induced cyclic AMP accumulation in DDT1 MF-2 cells by the A1-selective agonist, cyclopentyladenosine with a dissociation constant (KB value) of 0.34 nM. KW-3902 antagonized 5'-N-ethylcarboxamidoadenosine-elicited cyclic AMP accumulation via A2B receptors with a KB value of 52 nM. 5. KW-3902 exhibited marked species-dependent differences in the binding affinities. The highest affinity was for the rat A1 receptor (ki = 0.19 nM) and these values for guinea-pig and dog A1 receptors were 1.3 and 10 nM, respectively.
    Full-text · Article · May 1996 · British Journal of Pharmacology
  • F Suzuki · J Shimada

    No preview · Article · Aug 1995 · Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme

Publication Stats

1k Citations
99.12 Total Impact Points

Institutions

  • 1994-2010
    • KYOWA HAKKO BIO Co., Ltd.
      Edo, Tōkyō, Japan
  • 2002
    • Tokyo Metropolitan Institute
      Edo, Tōkyō, Japan
    • Kyowa Hakko Kirin Co., Ltd.
      Edo, Tokyo, Japan
  • 1997-2000
    • Tokyo Metropolitan Institute of Gerontology
      Edo, Tokyo, Japan