Joji Yui

National Institute of Radiological Sciences, Tiba, Chiba, Japan

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Publications (53)167.35 Total impact

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    ABSTRACT: Visualization of activated microglia/TSPO is one of the main aspects of neuroimaging. Here we are describing two new 18F-labelled molecules, 2-[5-(4-[18F]fluoroethoxy- ([18F]2) and 2-[5-(4-[18F]fluoropropyloxy- ([18F]3) -2-oxo-1,3-benzoxazol-3(2H)-yl)-N-methyl-N-phenyl acetamide as novel PET ligands for imaging translocator protein (18 kDa, TSPO) in the brain. Three-D pharmacophore evaluation and docking studies suggested their high affinity for TSPO and in vitro binding assays of TSPO showed binding affinities 6.6 ± 0.7 nM and 16.7 ± 2.5 nM for 2 and 3, respectively. Radiochemical yield for [18F]2 and [18F]3 was found 22 ± 4% (n = 8) and 5 ± 2% (n = 5) respectively at EOB. The radiochemical purity for both was found ≥ 98% and specific activity in the range of 98–364 GBq/µmol at EOS. In vitro autoradiography with ischemic rat brain showed significantly increased binding on the ipsilateral side compared to contralateral side. The specificity of [18F]2 and [18F]3 for binding TSPO was confirmed using the TSPO ligands PK11195 and MBMP. Biodistribution patterns of both PET ligands were evaluated in normal mice by 1-h dynamic PET imaging. In the brain regional radioactivity reached the maximum very rapidly within 0–4 min for both ligands, similar to (R)[11C]PK11195. Metabolite study of [18F]2 also favoured more favourable profile for quantification in comparison to (R)[11C]PK11195. In summary these data indicated that [18F]2 and [18F]3 have good potential to work as PET ligands, therefore it has merit to use these radioligands for in vivo evaluation in animal models to see their efficacy in the living brain.
    Organic & Biomolecular Chemistry 10/2014; · 3.57 Impact Factor
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    ABSTRACT: 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.
    Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 06/2014;
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    ABSTRACT: CEP-32496 is a novel, orally active serine/threonine-protein kinase B-raf (BRAF) (V600E) kinase inhibitor that is being investigated in clinical trials for the treatment of some cancers in patients. In this study, we developed [(11)C-carbonyl]CEP-32496 as a novel positron emission tomography (PET) probe to study its biodistribution in the whole bodies of mice. [(11)C]CEP-32496 was synthesized by the reaction of 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-amine hydrochloride (1·HCl) with [(11)C]phosgene, followed by treatment with 3-(6,7-dimethoxyquinozolin-4-yloxy)aniline (2). Small-animal PET studies with [(11)C]CEP-32496 indicated that radioactivity levels (AUC0-90min, SUV×min) accumulated in the brains of P-gp/BCRP knockout mice at a 8-fold higher rate than in the brains of wild-type mice.
    Bioorganic & medicinal chemistry letters. 06/2014;
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    ABSTRACT: Oncoimaging using positron emission tomography (PET) with a specific radioprobe would facilitate individualized cancer management. Evidence indicates that ectopically expressed metabotropic glutamate 1 (mGlu1) receptor independently induces melanocyte carcinogenesis, and it is therefore becoming an important target for personalized diagnosis and treatment strategies for melanomas. Here, we report the development of an oncoprotein-based PET imaging platform in melanomas for noninvasive visualization and quantification of mGlu1 with a novel mGlu1-specific radioprobe, 4-(18) F-fluoro-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide ((18) F-FITM). (18) F-FITM shows excellent pharmacokinetics, namely the dense and specific accumulation in mGlu1-positive melanomas versus mGlu1-negative hepatoma and normal tissues. Furthermore, the accumulation levels of radioactivity corresponded to the extent of tumor and to levels of mGlu1 protein expression in melanomas and melanoma metastasis. The (18) F-FITM PET imaging platform, as a noninvasive personalized diagnostic tool, is expected to open a new avenue for defining individualized therapeutic strategies, clinical trials, patient management and understanding mGlu1-triggered oncologic events in melanomas. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 03/2014; · 6.20 Impact Factor
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    ABSTRACT: After administration of the (99m)Tc complex with N,N'-1,2-ethylenediylbis-L-cysteine diethyl ester ((99m)Tc-ECD), a brain perfusion imaging agent, the radioactive metabolite is trapped in primate brain, but not in mouse and rat. Here, we investigate the involvement of metabolite extrusion by organic anion transporter 3 (OAT3), which is highly expressed at the blood-brain barrier in mice, in this species difference. The efflux rate of radioactivity in the cerebrum of Oat3(-/-) mice at later phase was 20% of that of control mice. Thus, organic anion transporters in mouse brain would be involved in the low brain retention of radioactivity after (99m)Tc-ECD administration.Journal of Cerebral Blood Flow & Metabolism advance online publication, 5 February 2014; doi:10.1038/jcbfm.2014.20.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 02/2014; · 5.46 Impact Factor
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    ABSTRACT: We developed the novel PET ligand 2-[5-(4-[(11) C]methoxyphenyl)-2-oxo-1,3-benzoxazol-3(2H)-yl]-N-methyl-N-phenylacetamide ([(11) C]MBMP) for translocator protein (18 kDa, TSPO) imaging and evaluated its efficacy in ischemic rat brains. [(11) C]MBMP was synthesized by reacting desmethyl precursor (1) with [(11) C]CH3 I in radiochemical purity of ≥ 98% and specific activity of 85 ± 30 GBq/μmol (n = 18) at the end of synthesis. Biodistribution study on mice showed high accumulation of radioactivity in the TSPO-rich organs, e.g., the lungs, heart, kidneys, and adrenal glands. The metabolite analysis in mice brain homogenate showed 80.1 ± 2.7% intact [(11) C]MBMP at 60 min after injection. To determine the specific binding of [(11) C]MBMP with TSPO in the brain, in vitro autoradiography and PET studies were performed in an ischemic rat model. In vitro autoradiography indicated significantly increased binding on the ipsilateral side compared with that on the contralateral side of ischemic rat brains. This result was supported firmly by the contrast of radioactivity between the ipsilateral and contralateral sides in PET images. Displacement experiments with unlabelled MBMP or PK11195 minimized the difference in uptake between the two sides. In summary, [(11) C]MBMP is a potential PET imaging agent for TSPO and, consequently, for the up-regulation of microglia during neuroinflammation. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 01/2014; · 3.97 Impact Factor
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    ABSTRACT: Liver damage induced by drug toxicity is an important concern for both medical doctors and patients. The aim of this study was to noninvasively visualize acute liver damage using positron emission tomography (PET) with N-benzyl-N-methyl-2-[7,8-dihydro-7-(2-[(18)F]fluoroethyl)-8-oxo-2-phenyl-9H-purin-9-yl]acetamide ([(18)F]FEDAC), a radiotracer specific for translocator protein (18 kDa, TSPO) as a biomarker for inflammation, and to determine cellular sources enriching TSPO expression in the liver. A mild acute liver damage model was prepared by a single intraperitoneal injection of cycloheximide (CHX) into rats. Treatment with CHX induced apoptosis and necrotic changes in hepatocytes with slight neutrophil infiltration. The uptake of radioactivity in the rat livers was measured with PET after injection of [(18)F]FEDAC. The uptake of [(18)F]FEDAC increased in livers damaged from treatment with CHX compared to the controls. Presence of TSPO was examined in the liver tissue using quantitative reverse transcriptase-polymerase chain reaction and immunohistochemical assays. mRNA expression of TSPO was elevated in the damaged livers compared to the controls, and the level was correlated with the [(18)F]FEDAC uptake and severity of damage. TSPO expression in the damaged liver sections was mainly found in macrophages (Kupffer cells) and neutrophils, but not in hepatocytes. The elevation of TSPO mRNA expression was derived from the increase of the number of macrophages with TSPO and neutrophils with TSPO in damaged livers. From this study we considered that PET imaging with [(18)F]FEDAC represented the mild liver damage through the enhanced TSPO signal in inflammatory cells. We conclude that this method may be a useful tool for diagnosis in early stage of acute liver damage.
    PLoS ONE 01/2014; 9(1):e86625. · 3.53 Impact Factor
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    ABSTRACT: Because of its role in multiple central nervous system (CNS) pathways, metabotropic glutamate receptor type 1 (mGluR1) is a crucial target in the development of pharmaceuticals for CNS disorders. N-[4-[6-(isopropylamino)-pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methyl-4-[(11)C]-methylbenzamide ([(11)C]ITDM) was recently developed as a positron emission tomography (PET) ligand for mGluR1. To devise a method for measurement of the binding potential (BPND) of [(11)C]ITDM to mGluR1, reference tissue methods aimed at replacing measurement of the arterial input function are desirable. In this study, we evaluated a noninvasive quantification method of mGluR1 with [(11)C]ITDM, demonstrating its accuracy using Huntington disease model R6/2 mice. The BPND measurements based on the Logan reference (Logan Ref) method have closely approximated that based on the arterial input method. We performed PET analysis with Logan Ref to assess its accuracy in quantifying the decline of mGluR1 expression in R6/2 mice. Significant decreases in BPND values in R6/2 mice were detected in cerebellum, thalamus, striatum, and cingulate cortex. We compared autoradiographs of R6/2 mouse brain sections with immunohistochemical images, and found a close correlation between changes in radioactive signal intensity and degree of mGluR1 expression. In conclusion, [(11)C]ITDM-PET is a promising tool for in vivo quantification of mGluR1 expression.Journal of Cerebral Blood Flow & Metabolism advance online publication, 8 January 2014; doi:10.1038/jcbfm.2013.243.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 01/2014; · 5.46 Impact Factor
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    ABSTRACT: The metabotropic glutamate receptor type 1 (mGluR1) is a novel target protein for the development of new drugs against central nervous system disorders. Recently, we have developed (11)C-labeled PET probes (11)C-ITMM and (11)C-ITDM, which demonstrate similar profiles, for imaging of mGluR1. In the present study, we compared (11)C-ITMM and (11)C-ITDM PET imaging and quantitative analysis in the monkey brain. Respective PET images showed similar distribution of uptake in the cerebellum, thalamus, and cingulate cortex. Slightly higher uptake was detected with (11)C-ITDM than with (11)C-ITMM. For the kinetic analysis using the two-tissue compartment model (2-TCM), the distribution volume (VT) in the cerebellum, an mGluR1-rich region in the brain, was 2.5 mL∙cm(-3) for (11)C-ITMM and 3.6 mL∙cm(-3) for (11)C-ITDM. By contrast, the VT in the pons, a region with negligible mGluR1 expression, was similarly low for both radiopharmaceuticals. Based on these results, we performed noninvasive PET quantitative analysis with general reference tissue models using the time-activity curve of the pons as a reference region. We confirmed the relationship and differences between the reference tissue models and 2-TCM using correlational scatter plots and Bland-Altman plots analyses. Although the scattergrams of both radiopharmaceuticals showed over- or underestimations of reference tissue model-based the binding potentials against 2-TCM, there were no significant differences between the two kinetic analysis models. In conclusion, we first demonstrated the potentials of (11)C-ITMM and (11)C-ITDM for noninvasive PET quantitative analysis using reference tissue models. In addition, our findings suggest that (11)C-ITDM may be superior to (11)C-ITMM as a PET probe for imaging of mGluR1, because regional VT values in PET with (11)C-ITDM were higher than those of (11)C-ITMM. Clinical studies of (11)C-ITDM in humans will be necessary in the future.
    American Journal of Nuclear Medicine and Molecular Imaging 01/2014; 4(3):260-9.
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    ABSTRACT: [(11)C]ABP688 is a promising positron emission tomography (PET) ligand for imaging of metabotropic glutamate receptor subtype 5 (mGlu5 receptor). Of the two geometric isomers of ABP688, (E)-ABP688 has a greater affinity towards mGlu5 receptors than (Z)-ABP688. Therefore, a high ratio of E-isomer is required when using [(11)C]ABP688 as a PET probe for imaging and quantification of mGlu5 receptors. The aim of this study was to evaluate the effect (Z)-[(11)C]ABP688 on the synthesis of [(11)C]ABP688 to be used for binding (E)-[(11)C]ABP688 in the brain. We synthesized and separated (E)- and (Z)-[(11)C]ABP688 by purification using an improved preparative high-performance liquid chromatography (HPLC) method equipped with a COSMOSIL Cholester column. We performed an in vitro binding assay in rat brain homogenates and PET studies of the rat brains using (E)- and (Z)-[(11)C]ABP688. (E)- and (Z)-[(11)C]ABP688 were successfully obtained with suitable radioactivity for application. In the in vitro assay, the Kd value of (E)-[(11)C]ABP688 (5.7 nmol/L) was higher than that of (Z)-[(11)C]ABP688 (140 nmol/L). In the PET study of the rat brain, high radioactivity after injection of (E)-[(11)C]ABP688 was observed in regions rich in mGlu5 receptors such as the striatum and hippocampus. In contrast, after injection of (Z)-[(11)C]ABP688, radioactivity did not accumulate in the brain. Furthermore, BPND in the striatum and hippocampus was highly correlated (R(2) = 0.99) with the percentage of (E)-[(11)C]ABP688 of the total radioactivity of (E)- and (Z)-[(11)C]ABP688 in the injection. We demonstrated that including (Z)-[(11)C]ABP688 in the [(11)C]ABP688 injection can decrease BPND in regions rich in mGlu5 receptors. Routine production of (E)-[(11)C]ABP688 will be helpful for imaging and quantification of mGlu5 receptors in clinical studies.
    Nuclear Medicine and Biology 10/2013; · 2.52 Impact Factor
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    ABSTRACT: Recent pharmacological evidence shows that antagonists for the metabotropic glutamate 1 (mGlu1) receptor exhibit neuroprotective effects in an ischemic brain. The aim of this study was to visualize the mGlu1 receptor and to monitor neuroprotective effects in a rat model of mild focal ischemia using positron emission tomography (PET) with N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-4-[(11)C]methoxy-N-methylbenzamide ([(11)C]ITMM), a radiotracer for mGlu1. Rats were subjected to a 30-minute transient right middle cerebral artery occlusion. Saline or minocycline, a neuroprotective agent, was intravenously injected immediately after surgery and then daily during the subsequent 7 days. PET imaging with [(11)C]ITMM was performed on the rats on days 1 to 7 after ischemia. In vitro autoradiography and histopathologic staining were conducted to confirm the results of in vivo PET. PET with [(11)C]ITMM demonstrated a gradual decrease of radioactivity in the ipsilateral sides of the ischemic brains. The radioactivity uptake ratio between the ipsilateral and contralateral sides also decreased with time. Minocycline treatment slowed down the decrease in the radioactivity level in the ipsilateral sides. Pretreatment with JNJ16259685, an mGlu1-selective ligand, significantly reduced brain radioactivity, confirming that the uptake of [(11)C]ITMM primarily reflects mGlu1 levels in the brain regions, including the ischemic area. In vitro autoradiography and histopathology confirmed the changes in mGlu1 levels in the brains. [(11)C]ITMM-PET may be a useful technique for characterizing the change in mGlu1 level during the occurrence and progression of neuronal damage and for evaluating the neuroprotective effects of drugs after ischemia.
    Stroke 08/2013; · 6.16 Impact Factor
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    ABSTRACT: Metabotropic glutamate 7 (mGlu7) receptor is a crucial target protein for the development of pharmaceuticals against central nervous system disorders. In the present study, we synthesized [11C]MMPIP, a putative radioligand for mGlu7 (binding constant KB = 30 nM), and evaluated its potential for imaging of mGlu7 via in vitro and in vivo techniques. [11C]MMPIP was synthesized by the reaction of phenol precursor 3 with [11C]CH3I. In vitro autoradiography using [11C]MMPIP was performed on rat brain sections. To determine in vitro specific binding of [11C]MMPIP with mGlu7, a blocking study was conducted by co-incubation with excess AMN082, a selective antagonist for mGlu7, or unlabeled MMPIP. Positron emission tomography (PET) studies and ex vivo metabolite analysis were carried out on rat brains. [11C]MMPIP was obtained with two specific activity (SA) levels of average 58 (conventional) and 3,800 (high SA) GBq/mumol, respectively. High radioactive signals derived from conventional [11C]MMPIP in the in vitro autoradiography were seen in the thalamus, medulla oblongata, and striatum, corresponding with comprehensive brain distributions of mGlu7. Co-incubation with ANM082 or unlabeled MMPIP reduced the radioactive signals in the brain sections, respectively. In the PET studies with [11C]MMPIP, no specific uptake relative to mGlu7 was found in the examined brain regions. Despite in vitro specific binding of [11C]MMPIP with mGlu7, visualization of mGlu7 in the living brain using PET was not successful. Development of new ligand candidates with higher affinity for mGlu7 is necessary.
    EJNMMI research. 07/2013; 3(1):54.
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    ABSTRACT: 1-[2-(4-Methoxyphenyl)phenyl]piperazine (4) is a potent serotonin 5-HT7 receptor antagonist (Ki=2.6nM) with a low binding affinity for the 5-HT1A receptor (Ki=476nM). As a potential positron emission tomography (PET) radiotracer for the 5-HT7 receptor, [(11)C]4 was synthesized at high radiochemical yield and specific activity, by O-[(11)C]methylation of 2'-(piperazin-1-yl)-[1,1'-biphenyl]-4-ol (6) with [(11)C]methyl iodide. Autoradiography revealed that [(11)C]4 showed in vitro specific binding with 5-HT7 in the rat brain regions, such as the thalamus which is a region with high 5-HT7 expression. Metabolite analysis indicated that intact [(11)C]4 in the brain exceeded 90% of the radioactive components at 15min after the radiotracer injection, although two radiolabeled metabolites were found in the rat plasma. The PET study of rats showed moderated uptake of [(11)C]4 in the brain (1.2SUV), but no significant regional difference in radioactivity in the brain. Pretreatment with 5-HT7-selective antagonist SB269970 (3) did not decrease the uptake of [(11)C]4 in the rat brain. Further studies are warranted that focus on the development of PET ligand candidates with higher binding affinity for 5-HT7 and higher in vivo stability in brain than 4.
    Bioorganic & medicinal chemistry 06/2013; · 2.82 Impact Factor
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    ABSTRACT: INTRODUCTION: Irinotecan is a semisynthetic derivative of camptothecin that exerts potent antitumor activity by inhibiting topoisomerase I. Despite much research into the complex pharmacokinetic profile and pharmacodynamic effects of irinotecan, unpredictable and severe side effects are still commonly observed. In this study, we synthesized [(11)C]irinotecan as a positron emission tomography (PET) probe, performed the metabolite analysis, and evaluated the biodistribution and kinetics of [(11)C]irinotecan using small animal PET. METHODS: [(11)C]Irinotecan was synthesized by two routes using [(11)C]phosgene and [(11)C]carbon dioxide fixation. Metabolites in the plasma of mice following injection of [(11)C] irinotecan were investigated using a combination of column-switching high-performance liquid chromatography (HPLC) and on-line solid-phase extraction (SPE). Whole-body PET studies were conducted in wild-type mice and P-glycoprotein and breast cancer resistance protein (Pgp/Bcrp) knockout mice. RESULTS: [(11)C]Irinotecan was successfully synthesized by the two abovementioned routes. Decay-corrected radiochemical yields based on [(11)C]carbon dioxide using [(11)C]phosgene and [(11)C]carbon dioxide fixation were 8.8±2.0% (n=8) and 16.9±2.9 % (n=5), respectively. Metabolite analysis of the plasma of mice following injection of [(11)C]irinotecan was successfully performed using the column-switching HPLC and on-line SPE combination resulting in greater than 87 % recovery of radioactivity from HPLC. In the PET study in mice, the radioactivity levels in the brain, liver, and small intestine were slightly increased by inhibition of the Pgp/Bcrp function for more than 30min after [(11)C]irinotecan injection. This result demonstrated that in vivo behavior of [(11)C] irinotecan and radioactive metabolites are influenced by the Pgp/Bcrp function. CONCLUSION: PET studies using [(11)C]irinotecan combined with metabolite analysis may be a useful tool for evaluating irinotecan pharmacokinetics and toxicity.
    Nuclear Medicine and Biology 04/2013; · 2.52 Impact Factor
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    ABSTRACT: Three novel 4-substituted benzamides have been synthesized as potential ligands for the positron emission tomography (PET) imaging of metabotropic glutamate 1 (mGlu1) receptors in the brain. Of these compounds, N-(4-(6-(isopropylamino)pyrimidin-4-yl)-1,3-thiazol-2-yl)-N,4-dimethylbenzamide (4) exhibited the highest binding affinity (Ki = 13.6 nM) for mGlu1 receptors and was subsequently labeled with carbon-11. In vitro autoradiography using rat brain sections showed that [(11)C]4 binding was consistent with the distribution of mGlu1, with high specific binding in the cerebellum and thalamus. PET studies with [(11)C]4 in monkey showed a high brain uptake and a kinetic profile suitable for quantitative analysis. Pretreatment with a mGlu1-selective ligand 16 largely decreased the brain uptake, indicating high in vivo specific binding of [(11)C]4 to mGlu1. In metabolite analysis, only unchanged [(11)C]4 was found in the brain. [(11)C]4 is a useful PET ligand for the imaging and quantitative analysis of mGlu1 in monkey brain and merits further evaluation in humans.
    Journal of Medicinal Chemistry 11/2012; · 5.61 Impact Factor
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    ABSTRACT: Metabotropic glutamate receptor subtype 1 (mGluR1) is a crucial molecular target in the central nervous system disorders. 4-(18)F-fluoro-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide ((18)F-FITM) has been recently developed as a useful PET ligand for mGluR1 imaging in our laboratory. In this study, we aimed to measure the affinity and density of mGluR1 using PET with (18)F-FITM in rat brain under the in vivo conditions. Binding potentials (BP(ND)) and amounts of specific binding (bound ligand concentration) at equilibrium state in brain regions were noninvasively estimated using the equilibrium analysis combined with the receptor-blocked approach (EA RBA) for kinetic analysis of (18)F-FITM PET results in place of reference tissue methods. Using BP(ND) and specific binding values of rats treated with multidose ligand, we performed Scatchard analyses for in vivo measurements of mGluR1 density (maximum number of binding sites, or B(max)) and ligand affinity (dissociation constant, or K(d)) in brain regions, respectively. The pretreatment of rats with unlabeled FITM (1 mg/kg) occupied an mGluR1 binding site of (18)F-FITM by more than 99% and did not affect the input function. Hence, we used the tissue time-activity curve for receptor-blocked rats as representative of the nondisplaceable (free and nonspecific binding of radioligand) compartment. The BP(ND) based on EA RBA showed a high correlation with the BP(ND) based on invasive Logan plot graphical analysis in the thalamus, hippocampus, striatum, and cingulate cortex. The K(d) (nM) and B(max) (pmol/mL) obtained by the Scatchard analyses with the multidose ligand assays were 2.1 and 36.3, respectively, for the thalamus; 2.1 and 27.5, respectively, for the hippocampus; 1.5 and 22.2, respectively, for the striatum; and 1.5 and 20.5, respectively, for the cingulate cortex with a high confidence. Our study is the first to our knowledge to measure the in vivo affinity (K(d) and binding potential) of (18)F-FITM and mGluR1 density (B(max)) with a high correlation to in vitro values in rat brain regions. This measurement using PET with (18)F-FITM would be a useful index for research about mGluR1 functions in central nervous system disorders and development of new pharmaceuticals.
    Journal of Nuclear Medicine 08/2012; 53(10):1601-7. · 5.77 Impact Factor
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    ABSTRACT: Mitochondrial dysfunction is responsible for liver damage and disease progression in non-alcoholic fatty liver disease (NAFLD). Translocator protein (18kDa) (TSPO), a mitochondrial transmembrane protein, plays important roles in modulating mitochondrial function. This study explored whether TSPO can be used as an imaging biomarker of non-invasive diagnosis and staging of NAFLD, monitored using positron emission tomography (PET) with a TSPO radioligand [(18)F]FEDAC. PET with [(18)F]FEDAC, non-enhanced computerized tomography (CT), autoradiography, histopathology, and gene analysis were performed to evaluate and quantify TSPO levels and NAFLD progression in methionine and choline-deficient diet-fed mice. Correlations were analyzed between uptake ratio of radioactivity and NAFLD activity score (NAS) in the liver. Uptake of [(18)F]FEDAC obviously increased with disease progression from simple steatosis to non-alcoholic steatohepatitis (NASH) (p<0.01). A close correlation was identified between [(18)F]FEDAC uptake ratio and NAS in the liver (Pearson's r=0.922, p=0.000). Specific binding of [(18)F]FEDAC to TSPO in the NAFLD livers was assessed in competition studies with the unlabelled TSPO-selective ligand PK11195. Autoradiography and histopathology confirmed the PET imaging results. Further, the mRNA levels of the functional macromolecular signaling complex composed of TSPO were obviously higher compared to controls. TSPO expression increases in NAFLD and closely correlates with NAFLD progression. TSPO as a specific molecular imaging biomarker may open a novel avenue for non-invasive, reliable, and quantitative diagnosis and staging of NAFLD.
    Journal of Hepatology 07/2012; 57(5):1076-82. · 9.86 Impact Factor
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    ABSTRACT: N-(2-{3-[3,5-Bis(trifluoromethyl)]phenylureido}ethyl)glycyrrhetinamide (2), an ureido-substituted derivative of glycyrrhetinic acid (1), has been reported to display potent inhibitory activity for proteasome and kinase, which are overexpressed in tumors. In this study, we labeled this unsymmetrical urea 2 using [(11)C]phosgene ([(11)C]COCl(2)) as a labeling agent with the expectation that [(11)C]2 could become a positron emission tomography ligand for the imaging of proteasome and kinase in tumors. The strategy for the radiosynthesis of [(11)C]2 was to react hydrochloride of 3,5-bis(trifluoromethyl)aniline (4·HCl) with [(11)C]COCl(2) to possibly give isocyanate [(11)C]6, followed by the reaction of [(11)C]6 with N-(2-aminoethyl)glycyrrhetinamide (3).
    Bioorganic & medicinal chemistry letters 04/2012; 22(11):3594-7. · 2.65 Impact Factor
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    ABSTRACT: We designed three novel positron emission tomography ligands, N-(4-(6-(isopropylamino)pyrimidin-4-yl)-1,3-thiazol-2-yl)-4-[(11)C]methoxy-N-methylbenzamide ([(11)C]6), 4-[(18)F]fluoroethoxy-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide ([(18)F]7), and 4-[(18)F]fluoropropoxy-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide ([(18)F]8), for imaging metabotropic glutamate receptor type 1 (mGluR1) in rodent brain. Unlabeled compound 6 was synthesized by benzoylation of 4-pyrimidinyl-2-methylaminothiazole 10, followed by reaction with isopropylamine. Removal of the methyl group in 6 gave phenol precursor 12 for radiosynthesis. Two fluoroalkoxy analogues 7 and 8 were prepared by reacting 12 with tosylates 13 and 14. Radioligands [(11)C]6, [(18)F]7, and [(18)F]8 were synthesized by O-[(11)C]methylation or [(18)F]fluoroalkylation of 12. Compound 6 showed high in vitro binding affinity for mGluR1, whereas 7 and 8 had weak affinity. Autoradiography using rat brain sections showed that [(11)C]6 binding is aligned with the reported distribution of mGluR1 with high specific binding in the cerebellum and thalamus. PET study with [(11)C]6 in rats showed high brain uptake and a similar distribution pattern to that in autoradiography, indicating the usefulness of [(11)C]6 for imaging brain mGluR1.
    Journal of Medicinal Chemistry 03/2012; 55(5):2342-52. · 5.61 Impact Factor
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    ABSTRACT: Neuroimaging measures have potential for monitoring neuroinflammation to guide treatment before the occurrence of significant functional impairment or irreversible neuronal damage in multiple sclerosis (MS). N-Benzyl-N-methyl-2-(7-[(11)C]methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin-9-yl) acetamide ([(11)C]DAC), a new developed positron emission tomography (PET) probe for translocator protein 18 kDa (TSPO), has been adopted to evaluate the neuroinflammation and treatment effects of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. [(11)C]DAC-PET enabled visualization of neuroinflammation lesion of EAE by tracing TSPO expression in the spinal cords; the maximal uptake value reached in day 11 and 20 EAE rats with profound inflammatory cell infiltration compared with control, day 0 and 60 EAE rats. Biodistribution studies and in vitro autoradiography confirmed these in vivo imaging results. Doubling immunohistochemical studies showed the infiltration and expansion of CD4+ T cells and CD11b+ microglia; CD68+ macrophages were responsible for the increased TSPO levels visualized by [(11)C]DAC-PET. Furthermore, mRNA level analysis of the cytokines by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) revealed that TSPO+/CD4 T cells, TSPO+ microglia and TSPO+ macrophages in EAE spinal cords were activated and secreted multiple proinflammation cytokines to mediate inflammation lesions of EAE. EAE rats treated with an immunosuppressive agent: 2-amino-2-[2-(4-octylphenyl)ethyl] propane-1,3-diolhydrochloride (FTY720), which exhibited an absence of inflammatory cell infiltrates, displaying a faint radioactive signal compared with the high accumulation of untreated EAE rats. These results indicated that [(11)C] DAC-PET imaging is a sensitive tool for noninvasively monitoring the neuroinflammation response and evaluating therapeutic interventions in EAE.
    Journal of Neuroimmune Pharmacology 03/2012; 7(1):231-42. · 3.80 Impact Factor