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National Institutes for Quantum Science and Technology (QST), formerly known as the National Institute of Radiological Sciences (NIRS), has been engaged in work on radiopharmaceutical science using cyclotrons since 1974. Eight pioneering researchers founded the basis of this field of research at NIRS, and to the present, many researchers and technicians have accumulated both scientific and technical achievements, as well as inherited the spirit of research. Besides, in recent years, we have developed production systems with AVF-930 cyclotron for various ‘non-standard’ radioisotopes applied in both diagnosis and therapy. Here, we review the past 50 years of our activities on radioisotope and radiopharmaceutical development, as well as more recent activities.

In the midst of growing interdependence among countries, there are an increasing number of cases in which the socioeconomic heterogeneities of nations have given cause for frictions. Currently, such frictions between the USA and China are the subject of much attention. Although each friction is special and contextual to the dyad of nations involved, certain aspects of the increasing risks associated with heterogeneities can be generalized to some extent. For this purpose, this chapter considers the precedent of structural tensions between the USA and Japan and looks at how these structural differences developed into intense diplomatic issues. It also seeks to clarify the precise nature of heterogeneity-related risks by examining the role played by the economic interdependence between two nations. The analysis presented here confirms that, while the problems associated with heterogeneities between the USA and Japan had long existed, the risks were heightened only after the interdependence had been deepened. Nonetheless, these differences and the deepening of interdependence were not, in and of themselves, sufficient to produce a crisis.

Surface-textured morphology of transparent conductive oxide (TCO) substrates enhances light absorption in Si thin films by scattering and trapping light, which results in an increase in the current density of Si thin film solar cells. However, the highly textured morphology often induces the formation of structural defects within the Si layer, which decreases the photovoltaic performance parameters of solar cells such as the open-circuit voltage (VOC) and fill factor (FF). To overcome this trade-off, we propose a flattened light-scattering TCO substrate based on a strongly light-scattering metal-oxide nanoparticle (NP) layer in conjunction with a surface TCO layer of low surface roughness. Individual layers of ZnO, TiO2, and stacked TiO2/ZnO metal-oxide nanoparticles (NP-TiO2/NP-ZnO), which functioned as a light-scattering layer, were formed between a glass substrate and a low-resistivity Al-doped zinc oxide (AZO) layer to serve as substrates for Si thin film solar cells. After deposition of the AZO film, the nanoparticle AZO substrate demonstrated good flatness and high haze values, which were nearly equivalent to the haze values of the nanoparticle layers before coating by AZO. For thin film hydrogenated amorphous Si (a-Si:H) solar cells fabricated on the stacked AZO/NP-TiO2/NP-ZnO substrate, the short-circuit current increased with no corresponding decrease in the VOC or FF. We attribute this result to an improved spectral response in a wavelength range λ > 500 nm and a decrease in the structural defects within the Si layers.

To improve the light-scattering capacity of transparent conductive oxide (TCO) films without increasing in surface roughness, we formed a stacked nanoparticle layers of ZnO (NP-ZnO) and TiO2 (NP-TiO2), which serve as light-scattering and surface-modifying layers, respectively, between the glass substrate and low-resistive TCO layers. The stacked TCO/NP/glass (NP-TCO) substrate indicated strong light-scattering capacity, with a relatively low surface root mean roughness of approximately 10nm. In addition, the haze value of NP-TCO substrates increased with an increase in the component particle diameter of the underlying NP-ZnO layers from about 20% (33nm) to 40% (96nm) at a wavelength of 550nm. [doi:10.2320/matertrans.M2014208]

Thin film Si solar cells based on hydrogenated amorphous Si and hydrogenated microcrystalline Si have been considered to have a reduced manufacturing cost compared with crystal type Si solar cells due to their reduced use of Si materials. However, the conversion efficiency of thin film Si solar cells is much lower than that of crystal Si solar cells owing to their lower photo absorption in the near infrared region which can be attributed to their indirect-transition type absorption and thin Si layer thickness. In order to increase in the conversion efficiency of thin film Si solar cells, improvement in the optical path length in the near infrared region is necessary. In order to confine the light and thereby increase the optical path length within the solar cells, a textured morphology has been formed on a transparent

A (11)C molecular production/separation system (CMPS) has been developed as part of an isotope separation on line system for simultaneous positron emission tomography imaging and heavy-ion cancer therapy using radioactive (11)C ion beams. In the ISOL system, (11)CH4 molecules will be produced by proton irradiation and separated from residual air impurities and impurities produced during the irradiation. The CMPS includes two cryogenic traps to separate specific molecules selectively from impurities by using vapor pressure differences among the molecular species. To investigate the fundamental performance of the CMPS, we performed separation experiments with non-radioactive (12)CH4 gases, which can simulate the chemical characteristics of (11)CH4 gases. We investigated the separation of CH4 molecules from impurities, which will be present as residual gases and are expected to be difficult to separate because the vapor pressure of air molecules is close to that of CH4. We determined the collection/separation efficiencies of the CMPS for various amounts of air impurities and found desirable operating conditions for the CMPS to be used as a molecular separation device in our ISOL system.

A new calibration technique, referred to as e-trace, has been developed by the National Institute of Advanced Industrial Science and Technology (AIST). The e-trace technique enables rapid remote ca...

We observed that the two-photon excitation of a v3 hot band (6s Rydberg ) in methyl iodide is promising for isotopic laser separation, because the isotope shift of the multiphoton ionization (MPI) resonance is resolvable. To estimate the excitation cross section, which gives the enrichment factor (final isotope ratio per initial isotope ratio) of the separation method, we devised a method based on a pump-probe MPI procedure. By probing the material remaining after irradiation with the pump pulse, we estimated the cross section of the ground-state transition (6s Rydberg 3;0-0) to be 4.1+/-1.4x10-48 (cm4 s). The enrichment factor predicted from this cross section indicates that a high-performance laser system (20 mJ/pulse, 200 Hz, 10 ns duration) was capable of achieving an enrichment of over 1000-fold in view of the dissociation efficiency under low-pressure gas conditions. Thus, laser separation (elimination) appears to be a promising tool to create positron-emission tomography molecular probes. \n

We have developed an efficient synthesis method for the rapid and high-yield automated synthesis of 4-(2′-methoxyphenyl)-1-[2′-(N-2″-pyridinyl)-p-[18F]fluorobenzamido]ethylpiperazine (p-[18F]MPPF). No-carrier-added [18F]F− was trapped on a small QMA cartridge and eluted with 70% MeCN(aq) (0.4 mL) containing Kryptofix 222 (2.3 mg) and K2CO3 (0.7 mg). The nucleophilic [18F]fluorination was performed with 3 mg of the nitro-precursor in DMSO (0.4 mL) at 190 °C for 20 min, followed by the preparative HPLC purification (column: COSMOSIL Cholester, Nacalai Tesque, Kyoto, Japan; mobile phase: MeCN/25 mm AcONH4/AcOH = 200/300/0.15; flow rate: 6.0 mL/min) to afford p-[18F]MPPF (retention time = 9.5 min). p-[18F]MPPF was obtained automatically with a radiochemical yield of 38.6 ± 5.0% (decay corrected, n = 5), a specific activity of 214.3 ± 21.1 GBq/µmol, and a radiochemical purity of >99% within a total synthesis time of about 55 min. Copyright © 2012 John Wiley & Sons, Ltd.

To investigate a possible means of achieving isotopic enrichment of methyl iodide (CH3I), we studied the 6s Rydberg states of 13,12CH3I by (2 + 1) resonance-enhanced multiphoton ionization. For band (v3 hot band) excitation (at a full width at half maximum of 14 cm−1), we observed a well-resolved isotope shift of +16 cm−1. The band shape, which has a broad shoulder on the red side and an abrupt decrease on the blue side, indicates that this resonance is ideal for enriching the concentration of the desired lighter isotope (the isotopomer).

The aim of this study was to develop an efficient fully automated synthesis method to achieve a high radiochemical yield of [(18)F]FAZA with a small amount of precursor. A small cartridge containing 25mg of the QMA resin was prepared and evaluated to obtain [(18)F]F(-) in a small quantity of base (K(2)CO(3)), which might allow the use of a small amount of precursor. The labeling and hydrolyzing conditions for [(18)F]FAZA synthesis were also investigated manually. No-carrier-added [(18)F]F(-) was trapped on the small QMA cartridge and eluted with a mixture of Krytofix 222 (2.26 mg, 6.0 μmol) and K(2)CO(3) (0.69 mg, 5.0 μmol) in 70% MeCN (0.4 mL). The automated synthesis of [(18)F]FAZA was optimally performed with a modified NIRS original synthesis system for clinical use, by labeling 2.5mg (5.2 μmol) of the precursor in DMSO (0.4 mL) at 120°C for 10 min, and then by hydrolyzing the (18)F-labeled intermediate with 0.1M NaOH (0.5 mL) at room temperature for 3 min. Using the above condition, the [(18)F]FAZA injection was obtained with a high radiochemical yield of 52.4±5.3% (decay-corrected, n=8) within 50.5±1.5 min.

Although the progression of cancer is a leading cause of death, oncologic medicine is adapting its strategy regarding cancer therapy and contributing to a personalized medicine approach. Because of its ability to measure therapeutic efficacy in vivo rapidly, molecular imaging has received growing attention and has shed light onto new avenues for assessing the therapeutic effect and determining the progression of disease (1,2). Successful chemotherapy or radiotherapy induces apoptosis in neoplastic cells, which can be a predictive indicator of a good therapy outcome in oncology (3,4). An early hallmark of apoptosis is the externalization of anion phospholipids including phosphatidylserine and phosphatidylinositide (5,6). Noninvasive imaging of cell death has been successfully applied in tumor models and clinical trials to determine whether apoptosis imaging could be a surrogate marker for monitoring therapeutic efficacy (7–12). C2A domain of synaptotagmin I is an approximate 120–amino-acid segment with a common fold, an 8-strand anti-parallel β sandwich connected by variable loops. In many C2 domains, binding of 2 or 3 Ca2+ ions in the 3 variable loops creates a substantial electrostatic potential that accelerates a protein’s association. The C2A domain also binds anionic phospholipids with relatively high affinity (13). Our previous studies demonstrated that the technetium-labeled C2A-based molecular imaging probe 99mTc-C2A could target apoptotic cells not only in acute myocardial infarction but also in a tumor model (14–18). However, the biodistribution of 99mTc-C2A-glutathione-S-transferase (GST) is not optimal, and its main drawback is high uptake of radioactivity in the kidneys and abdomen, severely hampering its clinical application, especially for imaging of abdominal tumors. It has been reported that 18F-annexin V showed favorable characteristics of biodistribution and kinetics, compared with 99mTc-annexin V derivatives (19–21). Meanwhile, PET with higher spatial resolution and easily quantified calculation of standardized uptake value (SUV) may have more advantages in detecting apoptotic cells than other modalities including SPECT. The current study aimed to synthesize and develop 18F-labeled C2A-GST as a molecular imaging probe for detecting apoptosis and to assess the feasibility of early evaluation of paclitaxel chemotherapy outcome in a rabbit VX2 lung cancer model.

The aim of this study was to visualize early infarction in the rat brain after ischemia using a translocator protein (TSPO) (18 kDa) PET ligand [ 11 C]DAC with ultra-high specific activity (SA) of 3670–4450 GBq/μmol. An infarction model of rat brain was prepared by ischemic surgery and evaluated 2 days after ischemia using small-animal PET and in vitro autoradiography. Early infarction with a small increase of TSPO expression in the brain was visualized using PET with high SA [ 11 C]DAC (average 4060 GBq/μmol), but was not distinguished clearly with usually reported SA [ 11 C]DAC (37 GBq/μmol). Infarction in the rat brain 4 days after ischemia was visualized using high and usually reported SAs [ 11 C]DAC. Displacement experiments with unlabeled TSPO-selective AC-5216 or PK11195 diminished the difference in radioactivity between ipsilateral and contralateral sides, confirming that the increased uptake on the infracted brain was specific to TSPO. In vitro autoradiography with high SA [ 11 C]DAC showed that the TSPO expression increased on early infarction in the rat brain. High SA [ 11 C]DAC is a useful and sensitive biomarker for the visualization of early infarction and the characterization of TSPO expression which was slightly elevated in the infarcted brain using PET.

The nitroaldol reaction of nitro[11C]methane and formaldehyde, which yields 2-(hydroxymethyl)-2-nitro[2-11C]propane-1,3-diol, is explored. The fluoride-ion-assisted nitroaldol reaction using (C4H9)4NF was rapid and provided the desired nitrotriol in more than 97% radiochemical conversion (decay-corrected) in 3 min at room temperature. Neither 2-nitro[2-11C]ethanol nor 2-nitro[2-11C]propane-1,3-diol was observed under the reaction conditions. The preparation of 2-amino-2-(hydroxymethyl)-[2-11C]propane-1,3-diol ([11C]Tris) was described, which was followed by the nitro-group reduction using NiCl2 and NaBH4 in aqueous MeOH. The decay-corrected radiochemical conversion to [11C]Tris was 68.0±6.5% in two steps. Copyright © 2010 John Wiley & Sons, Ltd.

Introduction High specific radioactivity is preferable in the measurement of neuroreceptor bindings with positron emission tomography (PET) because receptor occupancy by mixed cold ligand hampers the accurate estimation of receptor binding. Recently, we succeeded in synthesizing [ 11 C]raclopride, a dopamine D 2 receptor ligand, with ultra-high specific radioactivity, i.e., several thousand GBq/μmol. In the present study, we compared the [ 11 C]raclopride bindings to dopamine D 2 receptors between radioligands with ultra-high specific radioactivity and ordinary high specific radioactivity in healthy human subjects. Methods Two PET studies using [ 11 C]raclopride with ultra-high specific radioactivity (4302–7222 GBq/μmol) or ordinary high specific radioactivity (133-280 GBq/μmol) were performed on different days in 14 healthy men. Binding potential (BP) was calculated by the simplified reference tissue method, peak equilibrium method, and area-under-the-curve method for each region-of-interest using time-activity data in the cerebellum as a reference brain region. Results BP values for radioligands with ultra-high specific radioactivity and ordinary high specific radioactivity calculated by the simplified reference tissue method were 4.06±0.29 and 4.10±0.25 in the putamen, 0.44±0.07 and 0.47±0.07 in the thalamus and 0.37±0.06 and 0.38±0.06 in the temporal cortex, respectively (mean±S.D.). No significant difference in BP was observed between ultra-high specific radioactivity and ordinary high specific radioactivity in any of the brain regions. Conclusion BP values of [ 11 C]raclopride with ultra-high specific radioactivity did not differ from those with ordinary high specific radioactivity in the measured brain regions, including striatal and extrastriatal regions.

The catecholamine, dopamine (DA), is synthesized from 3,4-dihydroxy-L-phenylalanine (L-DOPA) by aromatic L-amino acid decarboxylase (AADC). Dopamine metabolism is regulated by monoamine oxidase (MAO) and catechol- O-methyltransferase (COMT). To measure dopaminergic metabolism, we used microdialysis with radiometric detection to monitor L-[β-11C]DOPA metabolites in the extracellular space of the rat striatum. We also evaluated the effects of AADC, MAO, and COMT inhibitors on metabolite profiles. The major early species measured after administration of L-[β-11C]DOPA were [11C]3,4-dihydroxyphenylacetic acid ([11C]DOPAC) and [11C]homovanillic acid ([11C]HVA) in a 1:1 ratio, which shifted toward [11C]HVA with time. An AADC inhibitor increased the uptake of L-[β-11C]DOPA and L-3- O-methyl-[11C]DOPA and delayed the accumulation of [11C]DOPAC and [11C]HVA. The MAO and COMT inhibitors increased the production of [11C]3-methoxytyramine and [11C]DOPAC, respectively. These results reflect the L-DOPA metabolic pathway, suggesting that this method may be useful for assessing dopaminergic metabolism.

The present study is aimed to propose the establishment of the plan of the drainage and vent system of the low-rise house and the design method and testing method of flow capacity. It is necessary to attempt the accumulation of the test data that shows a necessary drainage performance to propose the examination method. A concrete research method is as follows. 1) The condition at the edge of the stack vent pipe where it influences the flow capacity for drainage system most is presented. 2) The drainage system influence on the drain load condition is understood. It reports on the result of experimenting on these examining it.

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-[mu]m 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.

The aim of this study was to evaluate N-benzyl-N-[11C]methyl-2-(7-methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin-9-yl)acetamide ([11C]DAC) as a new translocator protein (18 kDa) [TSPO, formerly known as the peripheral-type benzodiazepine receptor (PBR)] positron emission tomography (PET) ligand in normal mice and unilateral kainic acid (KA)-lesioned rats. DAC is a derivative of AC-5216, which is a potent and selective PET ligand for the clinical investigation of TSPO. The binding affinity and selectivity of DAC for TSPO were similar to those of AC-5216, and DAC was less lipophilic than AC-5216. The distribution pattern of [11C]DAC was in agreement with TSPO distribution in rodents. No radioactive metabolite of [11C]DAC was found in the mouse brain, although it was metabolized rapidly in mouse plasma. Using small-animal PET, we examined the in vivo binding of [11C]DAC for TSPO in KA-lesioned rats. [11C]DAC and [11C]AC-5216 exhibited similar brain uptake in the lesioned and nonlesioned striatum, respectively. The binding of [11C]DAC to TSPO was increased significantly in the lesioned striatum, and [11C]DAC showed good contrast between the lesioned and nonlesioned striatum (the maximum ratio was about threefold). In displacement experiments, the uptake of [11C]DAC in the lesioned striatum was eventually blocked using an excess of either unlabeled DAC or PK11195 injected. [11C]DAC had high in vivo specific binding to TSPO in the injured rat brain. Therefore, [11C]DAC is a useful PET ligand for TSPO imaging, and its specific binding to TSPO is suitable as a new biomarker for brain injury. Synapse 63:961–971, 2009. © 2009 Wiley-Liss, Inc.

Glutamine synthetase (GS) is selectively localized in astrocytes and has important roles in the central nervous system (CNS). Cerebral extracellular excess ammonia and glutamate are taken up by astrocytes and converted to glutamine via GS to protect the CNS against neurotoxicity. In this study, we monitored cerebral extracellular 13N-glutamine derived from 13N-ammonia as a potential marker for astroglial metabolism using in vivo microdialysis combined with ultra performance liquid chromatography-radiometric detection. This method allowed rapid and highly sensitive radiometric analysis of 13N-ammonia and its metabolite, 13N-glutamine, in striatal extracellular fluid with good time resolution. Inhibition of GS with methionine sulfoximine resulted in a decrease of extracellular 13N-glutamine accompanied by an increase of 13N-ammonia as compared with control. Fluorocitrate, a selective inhibitor of glial metabolism, also decreased 13N-glutamine production and increased unmetabolized 13N-ammonia. In contrast, 13N-glutamine was increased with 5 mmol/kg of ammonium acetate without significant changes in 13N-ammonia as compared with control. These results suggest that the concentration of extracellular 13N-glutamine strongly reflects the biological changes in the metabolic activity of astroglial cells.

In this study, we synthesized and evaluated several amino 4-hydroxy-2(1H)-quinolone (4HQ) derivatives as new PET radioligand candidates for the glycine site of the NMDA receptors. Among these ligands, we discovered that 7-chloro-4-hydroxy-3-{3-(4-methylaminobenzyl) phenyl}-2-(1H)-quinolone (12) and 5-ethyl-7-chloro-4-hydroxy-3-(3-methylaminophenyl)-2(1H)-quinolone (32) have high affinity for the glycine site (K(i) values; 11.7 nM for 12 and 11.8 nM for 32). In vitro autoradiography experiments indicated that [(11)C]12 and [(11)C]32 showed high specific binding in the brain slices, which were strongly inhibited by both glycine agonists and antagonists. In vivo brain uptake of these (11)C-labeled 4HQs were examined in normal mice. Cerebellum to blood ratio of accumulation, of both [(11)C]12 and [(11)C]32 at 30 min were 0.058, which were slightly higher than those of cerebrum to blood ratio (0.043 and 0.042, respectively). These results indicated that [(11)C]12 and [(11)C]32 have poor blood brain barrier permeability. Although the plasma protein-binding ratio of [(11)C]32 was much lower than methoxy analogs (71% vs 94-98%, respectively), [(11)C]32 still binds with plasma protein strongly. It is conjectured that still acidic moiety and high affinity with plasma protein of [(11)C]32 may prevent in vivo brain uptake. In conclusion, [(11)C]12 and [(11)C]32 are unsuitable for imaging cerebral NMDA receptors.

(R)-(−)-2-[11C]Methoxy-N-n-propylnorapomorphine ([11C]MNPA ([11C]2)) is an agonist radioligand of interest for imaging D2/D3 receptors in vivo. Here we sought to develop an improved radiosynthesis of this radioligand. Reference 2 was synthesized in nine steps with an overall yield of about 5%, starting from codeine. Trimethylsilyldiazomethane proved to be a practical improvement in comparison to diazomethane in the penultimate methylation step. A protected precursor for radiolabeling ((R)-(−)-2-hydroxy-10,11-acetonide-N-n-propylnoraporphine, 4) was prepared from (R)-(−)-2-hydroxy-N-n-propylnorapomorphine (1) in 30% yield. [11C]2 was prepared from 4 via a two-step one-pot radiosynthesis. The first step, methylation of 4 with [11C]methyl triflate, occurred in quantitative radiochemical yield. The second step, deprotection of the catechol moiety with HCl and heat, yielded 60–90% of [11C]2 giving an overall incorporation yield from [11C]methyl triflate of 60–90%. In a typical run more than 1 GBq of [11C]2, was produced from carbon-11 generated from a 10-min proton irradiation (16 MeV; 35 µA) of nitrogen–hydrogen target gas. The radiochemical purity of [11C]2 was > 99% and specific radioactivity at the time of injection was 901±342 GBq/µmol (n=10). The total synthesis time was 35–38 min from the end of radionuclide production. The identity of [11C]2 was confirmed by comparing its LC-MS/MS spectrum with those of reference 2 and (R)-(−)-10-methoxy-2,11-dihydroxy-N-n-propylnoraporphine. Copyright © 2009 John Wiley & Sons, Ltd.

The aim of this study was to develop a practical labeling method of [13N]ligands using no-carrier-added [13N]NH3 with high specific activity. [13N]urea analogues [13N]1a and [13N]2a or [13N]carbamate [13N]3a were synthesized by reacting isocyanate 5a, carbamoyl chloride 6a or chloroformate 7a with [13N]NH3. The precursors 5a–7a were prepared by treating amines 8a and 9a and alcohol 10a with triphosgene in situ. These reaction mixtures were not purified and were used directly for [13N]ammonolysis, respectively. Using the one-pot method, we synthesized [13N]carbamazepine ([13N]4), a putative positron emission tomography ligand for brain imaging. Copyright © 2009 John Wiley & Sons, Ltd.

An improved method for isolation of (61)Cu(2+) from a (nat)Co target using cation exchange was developed. (61)Cu(2+) was eluted from a cation exchange resin column by 0.2 M HCl with 90% acetone, while Co(2+) remained on the column. The whole separation process was completed within 50 min at more than 72% yield. The Co(2+) impurity level in (61)Cu(2+) solution was reduced to less than 0.1 ppm. Highly pure (61)Cu(2+) solution was then applied to prepare (61)Cu-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-human serum albumin (HSA) which showed good blood pool imaging properties.

[(18)F]FEAC ([(18)F]4a) and [(18)F]FEDAC ([(18)F]4b) were developed as two novel positron emission tomography (PET) ligands for peripheral-type benzodiazepine receptor (PBR). [(18)F]4a and [(18)F]4b were synthesized by fluoroethylation of precursors 8a and 8b with [(18)F]FCH(2)CH(2)Br ([(18)F]9), respectively. Small-animal PET scan for a neuroinflammatory rat model showed that the two radioligands had high uptakes of radioactivity in the kainic acid-infused striatum, a brain region where PBR density was increased.

[1-(11)C]Acetyl chloride ([(11)C]AcCl), an important [(11)C]acylating agent, was synthesized by reacting [(11)C]CO(2) with methylmagnesium bromide coated on the inner surface of a polyethylene loop (loop method). By optimizing the reaction conditions and synthesis parameters, [1-(11)C]phenylacetate and [1-(11)C]benzylacetate were produced from [(11)C]AcCl in high radiochemical yield and specific activity.

Earlier in vivo PET experiments have demonstrated the binding of the neuroprotective alkaloid vinpocetine to the peripheral benzodiazepine receptor (PBR) or, with other terminology, the TSPO (18kDa translocator protein). With the aim of demonstrating the direct binding of vinpocetine to TSPO in vitro, two different ionidated versions of the novel TSPO ligand DAA1106 were used in autoradiographic experiments on human postmortem whole hemisphere brain slices. Vinpocetine effectively blocked the binding of both [125I]desmethoxy-DAA1106 and [125I]desfluoro-DAA1106 to TSPO, the decrease in binding reaching 30 % to 64 % in various brain structures. This present findings yield further evidence to vinpocetines direct binding to the TSPO in the human brain in vitro as well as to the possible use of its radiolabelled versions as imaging biomarkers. The results also support the usefulness of two ionidated versions of DAA1106 as biomarkers of TSPO for in vitro and in vivo studies in neurological diseases accompanied with microglia activation.

The binding of two radiolabelled analogues (N-(5-[125I]Iodo-2-phenoxyphenyl)-N-(2,5-dimethoxybenzyl)acetamide ([125I]desfluoro-DAA1106) and N-(5-[125I]Fluoro-2-phenoxyphenyl)-N-(2-[125I]Iodo-5-methoxybenzyl)acetamide ([125I]desmethoxy-DAA1106) of the peripheral benzodiazepine receptor (PBR) (or TSPO, 18kDa translocator protein) ligand DAA1106 was examined by in vitro autoradiography on human post mortem whole hemisphere brain slices obtained from Alzheimer's disease (AD) patients and age-matched controls. Both [(125)I]desfluoro-IDAA1106 and [(125)I]desmethoxy-IDAA1106 were effectively binding to various brain structures. The binding could be blocked by the unlabelled ligand as well as by other PBR specific ligands. With both radiolabelled compounds, the binding showed regional inhomogeneity and the specific binding values proved to be the highest in the hippocampus, temporal and parietal cortex, the basal ganglia and thalamus in the AD brains. Compared with age-matched control brains, specific binding in several brain structures (temporal and parietal lobes, thalamus and white matter) in Alzheimer brains was significantly higher, indicating that the radioligands can effectively label-activated microglia and the up-regulated PBR/TSPO system in AD. Complementary immunohistochemical studies demonstrated reactive microglia activation in the AD brain tissue and indicated that increased ligand binding coincides with increased regional microglia activation due to neuroinflammation. These investigations yield further support to the PBR/TSPO binding capacity of DAA1106 in human brain tissue, demonstrate the effective usefulness of its radio-iodinated analogues as imaging biomarkers in post mortem human studies, and indicate that its radiolabelled analogues, labelled with short half-time bioisotopes, can serve as prospective in vivo imaging biomarkers of activated microglia and the up-regulated PBR/TSPO system in the human brain.

Excitation functions of the reactions natTe (p,xn)120g,121,123,124,125,126,128,13I were measured from their respective thresholds up to 63 MeV via the stacked foil technique. Thin targets were prepared by a vacuum deposition method. Irradiations were performed using AVF 930 cyclotron at the National Institute of Radiological Sciences. The concord and conflict between our excitation studies and the available literature data are shown. The high values of our cross sections for 125I in comparison to some literature data are discussed. Our cross sections measurements validated some of the literature data obtained using enriched target isotopes. The integral yields of iodine radionuclides were deduced from the measured excitation curves. The estimated yield of 124I via the natTe(p,xn) process over the energy range E p= 57 → 53 MeV is 16.7 MBq/μA h. The level of the radionuclidic impurities 125I and 126I is, however, rather high, so that it is not meaningful to produce 124I using natTe as target material.

We demonstrate the significance of peripheral benzodiazepine receptor (PBR) imaging in living mouse models of Alzheimer's disease (AD) as biomarkers and functional signatures of glial activation. By radiochemically and immunohistochemically analyzing murine models of the two pathological hallmarks of AD, we found that AD-like Aβ deposition is concurrent with astrocyte-dominant PBR expression, in striking contrast with nonastroglial PBR upregulation in accumulations of AD-like phosphorylated tau. Because tau-induced massive neuronal loss was distinct from the marginal neurodegeneration associated with Aβ plaques in these models, cellular localization of PBR reflected deleterious and beneficial glial reactions to tau versus Aβ pathologies, respectively. This notion was subsequently examined in models of various non-AD neuropathologies, revealing the following reactive glial dynamics underlying differential PBR upregulation: (1) PBR(−) astrogliosis uncoupled with microgliosis or coupled with PBR(+) microgliosis associated with irreversible neuronal insults; and (2) PBR(+) astrogliosis coupled with PBR(− or ±) microgliosis associated with minimal or reversible neuronal toxicity. Intracranial transplantation of microglia also indicated that nontoxic microglia drives astroglial PBR expression. Moreover, levels of glial cell line-derived neurotrophic factor (GDNF) in astrocytes were correlated with astroglial PBR, except for increased GDNF in PBR(-) astrocytes in the model of AD-like tau pathology, thereby suggesting that PBR upregulation in astrocytes is an indicator of neurotrophic support. Together, PBR expressions in astrocytes and microglia reflect beneficial and deleterious glial reactions, respectively, in diverse neurodegenerative disorders including AD, pointing to new applications of PBR imaging for monitoring the impact of gliosis on the pathogenesis and treatment of AD.

18F-fluoroethyl-SPA-RQ (18F-FE-SPA-RQ) was recently developed as a radioligand for the measurement of neurokinin 1 (NK1) receptor with PET. In this study, we used 18F-FE-SPA-RQ with PET to visualize and quantify NK1 receptor in the human brain. Methods: PET scans were performed on 7 healthy men after intravenous injection of 18F-FE-SPA-RQ. Binding potential (BPND) was calculated by the indirect kinetic, simplified reference tissue model (SRTM), and ratio methods. The indirect kinetic method was used as the gold standard method and was compared with the SRTM method, with scan times of 180, 270, and 330 min, and with the ratio method, with time integration intervals of 120–180, 210–270, and 300–330 min. The cerebellum was used as the reference brain region. Results: Regional radioactivity was highest in the caudate head and putamen; mid level in the parahippocampus, cerebral cortex, and thalamus; and lowest in the cerebellum. BPND values by the indirect kinetic method were 3.15 ± 0.36, 3.11 ± 0.66, 1.17 ± 0.25, and 0.46 ± 0.14 in the caudate, putamen, parahippocampal region, and thalamus, respectively. For cerebral cortical regions, BPND values by the indirect kinetic method were 0.94 ± 0.23, 0.82 ± 0.15, 0.76 ± 0.15, and 0.69 ± 0.16 in the occipital, temporal, frontal, and anterior cingulate cortices, respectively. BPND values by the SRTM and ratio methods were in good agreement with those by the indirect kinetic method (r = 0.94–0.98). Conclusion: The regional distribution of 18F-FE-SPA-RQ was in agreement with previous PET studies and postmortem studies of NK1 receptor in the human brain. The ratio method will be useful for clinical research of psychiatric disorders, for the estimation of NK1 receptor without arterial blood sampling and long dynamic PET.

The aim of this study was how to introduce radioactive chlorine (*Cl) isotope into a benzene ring to afford *Cl-labeled chlorobenzene ([*Cl] 1 ). Using tributylphenylstannyl compound ( 2 ) as a starting material, we determined two routes for introducing *Cl into the benzene ring: reaction of [*Cl]Cl − with 2 in the presence of chloramine-T and nucleophilic reaction of [*Cl]Cl − with diphenyliodonium tosylate ( 3 ). The two routes provide suitable tools to prepare [*Cl] 1 without electron-abstracting group in the benzene ring.

A sensitive quality control method is often required in positron emission tomography (PET) radiopharmaceutical analysis due to the high specific radioactivity of synthetic products. The applicability of a radio high-performance liquid chromatography (HPLC) method with fluorescence detection was evaluated for a wide variety of PET radiopharmaceuticals. In 29 different radiopharmaceuticals studied, 20 compounds exhibited native fluorescence. These properties enabled sensitive determination of their chemical masses by direct fluorimetric detection after separation by HPLC. For some substances, detection limits were below nanograms per milliliter level, at least 40 times better than current UV absorbance detection. Sufficient reproducibility and linearity were obtained for the analysis of pharmaceutical fluid. Post-column fluorimetric derivatization was also established for the quantitative determination of FDG and ClDG in [ 18 F]FDG samples. These methods could be applied successfully to the analysis of PET radiopharmaceuticals with ultra-high specific radioactivity.

Thick target yields of the nat S(α,x) 34m Cl nuclear reaction were measured in the energy region from 14.2 to 69.5 MeV. Our results were also compared to the only available literature dataset. Cross-sections of the above reaction were also estimated from the obtained thick target yields. Pure natural sulfur used as a target material resulted in a thick target saturation yield of 1557 ± 18 MBq (42.1 ± 0.5 mCi)/μA at 69.5 MeV. The estimated excitation function curve of the nat S(α,x) 34m Cl process showed a maximum cross-section of 122 mbarn at about 27.5 MeV.

Oseltamivir phosphate (Tamiflu, 1.H(3)PO(4) is an orally active anti-influenza drug, which is hydrolyzed by esterase to its carboxylate metabolite Ro 64-0802 (2) with potent activity inhibiting neuraminidase. In this study, for the first time, we synthesized carbon-11-labeled oseltamivir ([(11)C]1) and Ro 64-0802 ([(11)C]2) as two novel positron emission tomography probes and demonstrated that [(11)C]1 had twofold higher radioactivity concentration in the mouse brains than [(11)C]2.

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.

This study reports on the radiosynthesis and feasibility studies of 4'-[methyl-(11)C]thiothymidine ([methyl-(11)C]S-dThd) as a tumor proliferation imaging agent. [Methyl-(11)C]S-dThd was synthesized by rapid methylation of corresponding 5-trimethylstannyl- or 5-tributylstannyl-precursor via a palladium-promoted Stille cross-coupling reaction with [(11)C]methyl iodide. The decay-corrected radiochemical yields of [methyl-(11)C]S-dThd synthesized by the corresponding 5-trimethylstannyl-precursor and 5-tributylstannyl-precursor based on [(11)C]CO(2) were 18.9% and 14.5%, respectively. The radiochemical purity of [methyl-(11)C]S-dThd was always greater than 99%. The specific activities of [methyl-(11)C]S-dThd synthesized by the corresponding 5-trimethylstannyl-precursor and 5-tributylstannyl-precursor were 47 GBq/mumol and 121 GBq/mumol, respectively, at the end of the synthesis. The total synthesis time was 30 min after the end of bombardment. The comparison between in vivo distribution of [methyl-(14)C]S-dThd and that of [methyl-(3)H]FLT showed that tracer uptake was comparable in nonproliferating tissues. In contrast, [methyl-(14)C]S-dThd showed significantly higher uptake in proliferating tissues than did [methyl-(3)H]FLT. [Methyl-(11)C]S-dThd uptake levels in five different tumor tissues were well correlated with the DNA synthesis levels determined by [2-(14)C]thymidine DNA incorporation. At 30 min after injection, plasma analysis found 95% of the activity in unmetabolized form. The microPET imaging of the C6 glioma xenograft showed significantly high uptake in the tumor and urinary bladder, followed by the intestine and marrow. Our results demonstrated that the tumor uptake of [methyl-(11)C]S-dThd was higher than that of [methyl-(3)H]FLT and was well correlated with the DNA synthesis level. Consequently, 4'-[methyl-(11)C]thiothymidine has promise for the imaging of tumor cell proliferation by positron emission tomography.

Objective 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. Methods [ 11 C]Raclopride, a dopamine D 2 receptor ligand, with an ultrahigh SA of 4880±2360 GBq/μmol (132±64 Ci/μmol, n =25) was synthesized. In vitro binding experiment was performed using brain homogenate assay and autoradiography (ARG). Results In vitro homogenate assay demonstrated that high SA [ 11 C]raclopride (2520–6340 GBq/μmol; 68–171 Ci/μmol) 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/μmol; 1.2 Ci/μmol). In vitro ARG for the rat brain using high SA [ 11 C]raclopride (6212 GBq/μmol; 168 Ci/μmol) 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/μmol; 1.1 Ci/μmol). Conclusion 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.

The aim of this study was to develop a practical route for preparing a fluorine-18 ([18F]) labelled ligand ([18F]1) containing [18F]fluorobenzene ring by employing the reaction of diphenyliodonium salt with [18F]F−. Diphenyliodonium tosylate (2) was synthesized from tributylphenylstannyl compound (6) with [hydroxy(tosyloxy)iodo]benzene (7). Using this method, [18F]DAA1106 ([18F]3a), a positron emission tomography ligand for imaging peripheral-type benzodiazepine receptor, was prepared.

AC-5216 was reported as a novel ligand for peripheral-type benzodiazepine receptor (PBR) with a different chemical structure from DAA1106 analogues. This ligand had potent affinity for PBR and selectivity for PBR over other neurotransmitters. We have previously labeled AC-5216 using positron-emitter 11 C. The aim of this study was to evaluate [ 11 C]AC-5216 in a rat brain model with neuroinflammation using an autoradiography (ARG) technique. In vitro ARG of normal rat brain showed that [ 11 C]AC-5216 accumulated highly in the olfactory bulb, choroid plexus and cerebellum. The distribution pattern agreed with the localization of PBR in the rodent brain. Infusion of kainic acid (KA: 1, 2.5 and 5 nmol) into the rat striatum resulted in neuroinflammation. In vitro and ex vivo ARG revealed that the radioactivity level of [ 11 C]AC-5216 was increased significantly in the KA-lesioned striatum compared to the non-lesioned striatum. Increasing the amount of KA infused into the striatum augmented radioactivity in the striatum as well as the cerebral cortex and hippocampus of the lesioned side. Treatment with a large amount of non-radioactive AC-5216 or PK11195 inhibited the binding of [ 11 C]AC-5216 and diminished the difference of radioactivity levels between the lesion and non-lesioned sides. These results demonstrated that [ 11 C]AC-5216 had high specific binding to PBR in the KA-lesioned rat brain. Thus, [ 11 C]AC-5216 is a promising PET ligand for imaging PBR in a brain with neuroinflammation.

Developing a PET ligand for imaging of the peripheral benzodiazepine receptor (PBR; Translocator Protein [18 kDa] TSPO) is of great importance for studying its role in glial cells in the injured brain and in neurodegenerative disorders, such as Alzheimer9s disease. The aim of this study was to synthesize and evaluate N-benzyl-N-ethyl-2-(7-11C-methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin-9-yl)acetamide (11C-AC-5216) as a PET ligand for imaging PBR in the primate brain. Methods: AC-5216 and its desmethyl precursor (compound 1) were synthesized starting from commercially available compounds. The radiosynthesis of 11C-AC-5216 was performed through the reaction of compound 1 with 11C-CH3I in the presence of NaH. The in vivo brain regional distribution was determined in mice (dissection) and a monkey (PET). Results:11C-AC-5216 (800–1,230 MBq; n = 25) was obtained with a radiochemical purity of 98% and a specific activity of 85–130 GBq/μmol at the end of synthesis. After injection of 11C-AC-5216 into mice, a high accumulation of radioactivity was found in the lungs, heart, adrenal glands, and other PBR-rich organs. In the mouse brain, high radioactivity was observed in the olfactory bulb and cerebellum. Radioactivity in these regions was inhibited by nonradioactive AC-5216 or PK11195 but was not decreased by central benzodiazepine receptor–selective flumazenil and Ro15-4513. A PET study of the monkey brain determined that 11C-AC-5216 had a relatively high uptake in the occipital cortex, a rich PBR-dense area in the primate brain. Pretreatment with nonradioactive AC-5216 and PK11195 reduced the radioactivity of 11C-AC-5216 in the occipital cortex significantly, suggesting its high specific binding with PBR in the brain. Metabolite analysis demonstrated that 11C-AC-5216 was stable in vivo in the mouse brain, although it was metabolized in the plasma of mice and the monkey. Conclusion:11C-AC-5216 is a promising PET ligand for imaging PBR in rodent and primate brains.

Fluorine-18 ((18)F, beta(+); 96.7%, T(1/2)=109.8 min) is of considerable importance for developing positron emission tomography (PET) ligands for imaging receptor, enzyme, gene expression etc. in brain, tumor, myocardium and other regions or organs due to its optimal decay characteristics. To synthesize (18)F-labeled PET ligands, reliable labeling techniques inserting (18)F into a target molecule are necessary. [(18)F]Fluoroalkylation is a useful way of introducing (18)F into target molecules containing amino, phenol, thiophenol, and amide functional groups. Here, we review the preparation, reactivity and application of [(18)F]fluoroalkyl agents for the development of (18)F-labeled PET ligands in molecular imaging. [(18)F]Fluoroalkyl agents have been synthesized by reacting [(18)F]F(-) with the corresponding alkyl derivatives containing halogen and sulfonate as leaving groups. After the fluorination reaction, the radiolabeled products with relatively low boiling points were distilled from the reaction mixtures, sometimes added by Sep-Pak or gas chromatography separation. The [(18)F]fluoromethyl agents have high reactivity with nucleophilic substrates, but many [(18)F]fluoromethylated compounds are in vitro unstable. To increase the efficiency of [(18)F]fluoroethylation, [(18)F]FCH2CH2Br, the most frequently used [(18)F]fluoroethyl agent, was converted into [(18)F]FCH2CH2I or [(18)F]FCH2CH2OTf in situ. Most [(18)F]fluoromethylated ligands were found to be in vivo unstable due to defluorination. Deuterium substitution for the fluoromethyl group reduced defluorination to an extent. A number of [(18)F]fluoroethylated PET ligands have been developed for animal evaluation and clinical investigation.

The lung is one of the key organs for determining the distribution of drugs in the human body. Various factors influence the accumulation of drugs. In this study, we investigated the effects of smoking on drug distribution to the lung using radiolabeled drugs. We measured the lung uptake of [11C](+)McN5652, a radioligand for serotonin transporter (5-HTT), and inactive enantiomer [11C](−)McN5652 in 19 healthy men (12 nonsmokers and 7 smokers) using positron emission tomography. Pretreatment study was performed by the administration of clomipramine (50 mg), a potent 5-HTT inhibitor. The mean lung uptake of [11C](+)McN5652 and [11C](−)McN5652 was significantly higher in smokers than in nonsmokers. The lung uptake of [11C](+)McN5652 decreased after pretreatment with clomipramine, whereas that of [11C](−)McN5652 was not affected by clomipramine. Lung uptake of [11C](−)McN5652 was influenced by smoking, possibly because the probable nonspecific binding accumulation was changed as [11C](−)McN5652 was reported to have negligible affinity to 5-HTT. Smoking might be one of the important factors when distribution of radioligands is considered.

Elevated levels of peripheral benzodiazepine receptor (PBR) in glia have been documented in diverse nervous system injuries, while the identity and spatiotemporal characteristics of the cells showing upregulation of PBR remain elusive. We examined the astrocytic and microglial expressions of PBR in rat brains during the duration of ethanol-induced neuronal insults in order to clarify the significance of PBR as a biomarker capable of detecting a distinctive subpopulation of these glial cells involved in the impairment and protection of neurons. The levels of PBR, as determined by autoradiographic analysis using a specific radioligand, [11C]DAA1106, began to significantly increase at 3 days after intrastriatal injection of ethanol, and peaked at 7 days. This was consistent with the results of double immunofluorescence staining and high-resolution emulsion autoradiography, which revealed upregulation of PBR in both microglia and astrocytes proliferating in nonoverlapping compartments of the injury site. Notably, increased expression of PBR in astrocytes was transiently observed in a manner parallel to the centripetal migration of these cells to the inflammatory lesion, which may be a response indispensable to the protection of intact tissue. Thereafter, astrocytic PBR was barely detectable, despite the presence of numerous glial fibrillary acidic protein-immunoreactive astrocytes forming glial scarring. By contrast, intense PBR signals were persistently present in microglia localized to the injury epicenter up to 90 days, notwithstanding a gradual reduction in the number of ionized calcium binding adapter molecule-1-positive amoeboid microglia between 7 and 90 days. The long-lasting PBR expression in microglia was finally supported by in vivo positron emission tomography imaging, and suggests that inflammatory tissue damage is potentially expandable unless it is tightly sealed by astrocytic scar. The present findings collectively support the utility of PBR in identifying a unique temporal pattern of astrocytic and microglial activation that conventional glial markers hardly pursue.

PET用放射性薬剤の放射能強度に関する品質保証のため, 実用標準器を導入し, 性能評価を行うと共に18F-FDG溶液による校正を実施した。実用標準器には, 国家標準機関である産総研が遠隔校正用として開発を指導し, 日本アイソトープ協会 (協会) が校正用に用いているALOKA製IGC-7と同型のキュリーメータを採用した。協会の校正用仲介キュリーメータ及び放医研の実用標準器であるキュリーメータにて製造直後の18F-FDGを測定することで相互比較を行った。18F-FDGは, 協会に搬送され, 協会保有の特定二次標準器による校正値を得た。その結果, 放医研の基準用キュリーメータの18F-FDGに対する指示値はその不確かさ3.2%の範囲内で一致し, 国家標準とのトレーサビリティが確立した。そして本実用標準器を基準とし放医研内のキュリーメータの校正体系を整えた。