Junko Noguchi

National Institute of Radiological Sciences, Chiba-shi, Chiba-ken, Japan

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Publications (13)37.36 Total impact

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    ABSTRACT: The aim of this study was to characterize the in vitro binding of [(11)C]raclopride with ultrahigh specific activity (SA) in the striatum and cerebral cortex of rat brain. [(11)C]Raclopride, a dopamine D(2) receptor ligand, with an ultrahigh SA of 4880+/-2360 GBq/micromol (132+/-64 Ci/micromol, n=25) was synthesized. In vitro binding experiment was performed using brain homogenate assay and autoradiography (ARG). In vitro homogenate assay demonstrated that high SA [(11)C]raclopride (2520-6340 GBq/micromol; 68-171 Ci/micromol) had two-affinity (high and low) binding sites in the striatum and cerebral cortex of rat brain. In the striatum, K(d,high) and B(max,high) values were 0.005+/-0.002 nM and 0.19+/-0.04 fmol/mg tissue, respectively, while K(d,low) and B(max,low) values were 2.2+/-1.0 nM and 35.8+/-16.4 fmol/mg tissue, respectively. In the cerebral cortex, K(d,high) and B(max,high) values were 0.061+/-0.087 nM and 0.2+/-0.2 fmol/mg tissue, respectively, while K(d,low) and B(max,low) values were 2.5+/-3.2 nM and 5.5+/-4.8 fmol/mg tissue, respectively. On the other hand, only one binding site was found in the striatum and no binding site was identified in the cerebral cortex using low SA [(11)C]raclopride (44 GBq/micromol; 1.2 Ci/micromol). In vitro ARG for the rat brain using high SA [(11)C]raclopride (6212 GBq/micromol; 168 Ci/micromol) gave a coronal image of the striatum and cerebral cortex with a higher signal/noise ratio than using low SA [(11)C]raclopride (40 GBq/micromol; 1.1 Ci/micromol). Using ultrahigh SA [(11)C]raclopride for the in vitro homogenate assay, we succeeded in detecting two-affinity binding sites of [(11)C]raclopride, not only in the striatum but also in the cerebral cortex of rat brain.
    Nuclear Medicine and Biology 02/2008; 35(1):19-27. · 2.52 Impact Factor
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    ABSTRACT: To image the peripheral-type benzodiazepine receptor (PBR) in vivo, we previously developed two positron emission tomography (PET) ligands, N-(2-[11C],5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamide ([11C]1a) and its [18F]fluoroethyl analogue ([18F]1b), for the investigation of PBR in the living human brain. This time, using 1a as a leading compound, we designed two novel iodinated analogues, N-(5-fluoro-2-phenoxyphenyl)-N-(2-iodo-5-methoxybenzyl)acetamide (3a) and N-(2,5-dimethoxybenzyl)-N-(5-iodo-2-phenoxyphenyl)acetamide (3b) for the PBR imaging. Ligands 3 were synthesized by the iodination of tributystannyl precursors 10. Radiolabeling for 3 with 131I was carried out by the reaction of 10 with [131I]NaI using H2O2 as an oxidizing agent. In vitro competition experiments determined that 3a exhibited both high affinity and selectivity for PBR (IC50: 7.8 nM) vs CBR (>1 microM). Biodistribution study in mice determined that [131I]3a had a high radioactivity level (1.69% dose/g) in the brain, and its distribution pattern in the brain was consistent with the known distribution of PBR in rodents. Ex vivo autoradiography of the rat brain gave visual evidence that [131I]3a was a potent and specific radioligand for PBR.
    Journal of Medicinal Chemistry 03/2007; 50(4):848-55. · 5.61 Impact Factor
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    ABSTRACT: 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.
    Nuclear Medicine and Biology 12/2006; 33(8):971-5. · 2.52 Impact Factor
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    ABSTRACT: 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.
    Journal of Medicinal Chemistry 06/2006; 49(9):2735-42. · 5.61 Impact Factor
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    ABSTRACT: The purpose of this study is to compare the histopathological radiation effect and the growth fraction determined by MIB-1 immunostaining between radiation alone and concurrent chemoradiotherapy. Twenty-eight patients treated with radiotherapy (RT) alone or weekly cisplatin and RT (CRT) for uterine squamous cell carcinoma were studied. Specimens from cervical tumors were obtained before treatment and at 9 Gy of irradiation. Histopathological radiation effects were evaluated by hematoxylin and eosin staining at 9 Gy. The MIB-1 labeling indices were calculated before treatment and at 9 Gy. There were no significant differences in histopathological radiation effect at 9 Gy or MIB-1 index before treatment between RT alone and CRT. However, the MIB-1 index at 9 Gy of CRT was significantly higher than that of RT alone. These results suggest that the increment of the growth fraction in the early period of CRT can be increased by the addition of cisplatin.
    11/2005; 4.
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    ABSTRACT: 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.
    Bioorganic & Medicinal Chemistry 04/2005; 13(5):1811-8. · 2.90 Impact Factor
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    ABSTRACT: 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.
    Journal of Medicinal Chemistry 05/2004; 47(9):2228-35. · 5.61 Impact Factor
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    ABSTRACT: We performed in vitro and in vivo assays of the metabolism of [(11)C]Ro15-4513 over time in the plasma of mice, rats, monkeys and humans, using a radio-HPLC equipped with a sensitive positron detector, in order to compare the metabolic rates of the radiopharmaceutical agent among the different animal species and to establish a highly sensitive analytical method for the radiotracer agent. We also examined the metabolism of [(11)C]Ro15-4513 in the brain tissue of mice and rats. The analytical method used in this study permitted detection of even extremely low levels of radioactivity (approximately 5,000 dpm). In vitro experiments revealed that [(11)C]Ro15-4513 in the blood was metabolized to hydrolysate [(11)C]A. The species were classified in descending order of the metabolic rate of the radiotracer in vitro as follows; mice, rats, and monkeys/humans. In the in vitro experiment, the percentage of the unchanged drug in the plasma at 60 minutes postdose was 9% in mice, 70% in rats, 97% in monkeys, and 98% in humans. In vivo metabolite analysis in the blood showed the presence of two radioactive metabolites, consisting of one hydrolysate [(11)C]A and another unidentified substance. The species were classified in descending order of the metabolic rate of the radiotracer in vivo as follows; mice, rats/humans, and monkeys. The percentage of the unchanged drug in the plasma was 6% in mice, 21% in rats, 26% in humans, and 40% in monkeys. Furthermore, the in vitro and in vivo experiments conducted to analyze the metabolism of [(11)C]Ro15-4513 in the brain tissue of mice and rats revealed that the radiotracer was metabolized to some extent in the brain tissue of these animals. In the in vivo experiment, the percentage of the unchanged drug at 60 min postdose was 86% in the brain tissue of mice and 88% in the brain tissue of rats, while in the in vitro experiment, the corresponding percentage was 93% in mice, and 91% in rats.
    Nuclear Medicine and Biology 11/2003; 30(7):779-84. · 2.52 Impact Factor
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    ABSTRACT: DAA1106 (N-(2,5-Dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamide), is a potent and selective ligand for peripheral benzodiazepine receptors (PBR) in mitochondrial fractions of rat (K(i)=0.043 nM) and monkey (K(i)=0.188 nM) brains. This compound was labeled by [(11)C]methylation of a corresponding desmethyl precursor (DAA1123) with [(11)C]CH(3)I in the presence of NaH, with a 72+/-16% (corrected for decay) incorporation yield of radioactivity. After HPLC purification, [(11)C]DAA1106 was obtained with > or =98% radiochemical purity and specific activity of 90-156 GBq/micromol at the end of synthesis. After iv injection of [(11)C]DAA1106 into mice, high accumulations of radioactivity were found in the olfactory bulb and cerebellum, the high PBR density regions in the brain. Coinjection of [(11)C]DAA1106 with unlabeled DAA1106 and PBR-selective PK11195 displayed a significant reduction of radioactivity, suggesting a high specific binding of [(11)C]DAA1106 to PBR. Although this tracer was rapidly metabolized in the plasma, only [(11)C]DAA1106 was detected in the brain tissues, suggesting the specific binding in the brain due to the tracer itself. These findings revealed that [(11)C]DAA1106 is a potential and selective positron emitting radioligand for PBR.
    Nuclear Medicine and Biology 07/2003; 30(5):513-9. · 2.52 Impact Factor
  • J Noguchi, K Suzuki
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    ABSTRACT: We have designed and constructed an automated device for the production of ultra-high specific activity (11)C-labeled compounds via [(11)C]CH(3)I synthesized by the single pass I(2) method. The optimum condition for the production of [(11)C]CH(3)I was determined to be 630 degrees C for oven-1 (reaction column), 50 degrees C for oven-2 (iodine column) and 50 ml/min for the He gas flow rate, and gave the maximum conversion ratio of [(11)C]CH(3)I, 44%. [(11)C]Ro15-4513, known as an inverse agonist of the benzodiazepine receptor, was produced under optimized conditions. An i.v. injectable [(11)C]Ro15-4513 solution of 1500 +/- 490 MBq (n = 6) with specific activity 4700 +/- 2500 GBq/micromol and a radiochemical purity of 98.2 +/- 2% was obtained automatically within 25 minutes (from EOB) by irradiating nitrogen gas containing 5% H(2) with 18 MeV protons (14.2 MeV on target) at 20 microA for 20 minutes. The highest specific activity of 9700 GBq/micromol (at EOS) could be achieved, although the radiochemical purity was 92.4%. By the use of the ultra-high specific activity [(11)C]Ro15-4513, the super high affinity binding sites in the rat brain hippocampus could be clearly visualized even at the extremely low concentration of 0.66 pM Ro15-4513 by in vitro autoradiography.
    Nuclear Medicine and Biology 05/2003; 30(3):335-43. · 2.52 Impact Factor
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    ABSTRACT: N-[18F]Fluoroethyl-4-piperidyl acetate ([18F]FEtP4A), an analog of [11C]MP4A for mapping brain acetylcholineseterase (AchE) activity, was prepared by reacting 4-piperidyl acetate (P4A) with [18F]fluoroethyl bromide ([18F]FEtBr) using a newly developed automated system. Preliminary evaluation showed that the initial uptake of [18F]FEtP4A in the mouse brain was > 8% injected dose/g tissue. The distribution pattern of [18F]FEtP4A in the brain was striatum>cerebral cortex>cerebellum within 10-120 min post-injection, which reflected the distribution rank pattern of AchE activity in the brain. Moreover, chemical analysis of in vivo radioactive metabolites in the mouse brain indicated that 83% of [18F]FEtP4A was hydrolyzed to N-[18F]fluoroethyl-4-piperidinol ([18F]FEtP4OH) after 1 min intravenous injection. From these results, [18F]FEtP4A may become a promising PET tracer for mapping the AchE in vivo.
    Nuclear Medicine and Biology 05/2002; 29(4):463-8. · 2.52 Impact Factor
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    ABSTRACT: Two benzamide derivatives as dopamine D4 receptor antagonists, YM-50001(4) and N- [2-[4-(4-chlorophenyl]piperizin-1-yl]ethyl]-3-methoxybenzamide (9), were labeled by positron-emitter (11C), and their pharmacological specificities to dopamine D4 receptors were examined by quantitative autoradiography and positron emission tomography (PET). Radiosyntheses were accomplished by O-methylation of corresponding phenol precursors (5 and 10) with [11C]CH3I followed by HPLC purifications. In vitro binding on rat brain slices showed different distribution patterns and pharmacological properties between the two radioligands. The [11C]4 showed the highest binding in the striatum, which was inhibited not only by 10 microM 4 but also by 10 microM raclopride, a selective dopamine D2 receptor antagonist. In contrast, [11C]9 showed the highest binding in the cerebral cortex, which was inhibited by several D4 receptor antagonists (9, RBI-254, L-745,870), but not by any other receptor ligands (D1/D5, D2/D3, 5-HT1A, 5-HT2A, sigma1 and alpha1) tested. In vivo brain distribution of [11C]9 in rat showed the highest uptake in the frontal cortex, a region that has a high density of D4 receptors. These results indicate that the pharmacological property of [11C]9 matches the rat brain D4 receptors, but that of [11C]4 rather appears to match the rat brain D2 receptors. The results for the benzamide [11C]9 prompted us to further evaluate its potential as a PET radioligand for D4 receptors by employing PET on monkey brain. Unfortunately, in contrast to rats, neither specific binding nor differences in regional uptake of radioactivity were observed in monkey brain after intravenous 11C]9 injection. Based on that specific activities of radioligands might be critical in mapping the neurotransmitter receptors if they are only faintly expressed in the brain, 11C]9 with an extremely high specific activity (1810 GBq/micromol) was used for PET study. However, the effort to determine the specific binding for D4 failed. These results indicate that both of the benzamide derivatives would not be suitable radioligands for D4 receptors with PET.
    Nuclear Medicine and Biology 03/2002; 29(2):233-41. · 2.52 Impact Factor
  • J. Noguchi, M. Mutoh, K. Suzuki
    Journal of Labelled Compounds 05/2001; 44(S1).