Objective: Antihistamines often have sedative side effects. This was the first study to measure regional cerebral glucose (energy) consumption and hemodynamic responses in young adults during cognitive tests after antihistamine administration. Methods: In this double-blind, placebo-controlled, three-way crossover study, 18 healthy young Japanese men received single doses of levocetirizine 5 mg and diphenhydramine 50 mg at intervals of at least six days. Subjective feeling, task performances, and brain activity were evaluated during three cognitive tests (word fluency, two-back, and Stroop). Regional cerebral glucose consumption changes were measured using positron emission tomography with [ 18 F]fluorodeoxyglucose. Regional hemodynamic responses were measured using near-infrared spectroscopy. Results: Energy consumption in prefrontal regions was significantly increased after antihistamine administration, especially diphenhydramine, whereas prefrontal hemodynamic responses, evaluated with oxygenated hemoglobin levels, were significantly lower with diphenhydramine treatment. Stroop test accuracy was significantly impaired by diphenhydramine, but not by levocetirizine. There was no significant difference in subjective sleepiness. Conclusions: Physiological “coupling” between metabolism and perfusion in the healthy human brain may not be maintained under pharmacological influence due to antihistamines. This uncoupling may be caused by a combination of increased energy demands in the prefrontal regions and suppression of vascular permeability in brain capillaries after antihistamine treatment. Further research is needed to validate this hypothesis.

Objective. The aim of this study was to investigate changes in brain and muscle glucose metabolism that are not yet known, using positron emission tomography with [18F]fluorodeoxyglucose ([18F]FDG PET). Methods. Twenty-one male volunteers were recruited for the present study. [18F]FDG PET scanning was performed twice on each subject: once after the spinal manipulation therapy (SMT) intervention (treatment condition) and once after resting (control condition). We performed the SMT intervention using an adjustment device. Glucose metabolism of the brain and skeletal muscles was measured and compared between the two conditions. In addition, we measured salivary amylase level as an index of autonomic nervous system (ANS) activity, as well as muscle tension and subjective pain intensity in each subject. Results. Changes in brain activity after SMT included activation of the dorsal anterior cingulate cortex, cerebellar vermis, and somatosensory association cortex and deactivation of the prefrontal cortex and temporal sites. Glucose uptake in skeletal muscles showed a trend toward decreased metabolism after SMT, although the difference was not significant. Other measurements indicated relaxation of cervical muscle tension, decrease in salivary amylase level (suppression of sympathetic nerve activity), and pain relief after SMT. Conclusion. Brain processing after SMT may lead to physiological relaxation via a decrease in sympathetic nerve activity.

Objective Antihistamines are often used for treating allergic rhinitis. However, many older antihistamines cause sedative side effects. The sedative effects of antihistamines on car-driving have been investigated. This has not been investigated for levocetirizine, a new-generation antihistamine, in Asian populations, and so we evaluated its sedative effects in healthy Japanese subjects. Methods In this double-blind, placebo-controlled, four-way crossover study, healthy volunteers received single doses of levocetirizine 5 mg, fexofenadine 60 mg, diphenhydramine 50 mg, and placebo at intervals of at least 6 days. Simple brake reaction time and choice brake reaction time task (CBRT), a lateral tracking (LT) task, and a multiple task, a mixture of CBRT and LT task, were used to compare driving performance between the four drugs. Subjective sedation was also assessed. Results The simple brake reaction time and CBRT, and the CBRT component of the multiple task, did not show any significant differences between the drugs. In contrast, the LT, both as a single parameter and as a component of the multiple task, showed significant differences between diphenhydramine and the newer-generation antihistamines in a manner that corresponds with subjective sedation. Conclusions Levocetirizine and fexofenadine did not impair psychomotor performance in subjects performing simulated car-driving tasks, while diphenhydramine did impair psychomotor performance in the subjects.

Imaging of neurofibrillary pathology in the brain helps in diagnosing dementia, tracking disease progression, and evaluating the therapeutic efficacy of antidementia drugs. The radiotracers used in this imaging must be highly sensitive and specific for tau protein fibrils in the human brain. We developed a novel tau PET tracer, 18FTHK5351, through compound optimization of arylquinoline derivatives. Methods: The in vitro binDing properties, pharmacokinetics, and safety of 18F-THK5351 were investigated, and a clinical study on Alzheimer disease (AD) patients was performed. Results: 18FTHK5351 demonstrated higher binDing affinity for hippocampal homogenates from AD brains and faster dissociation from whitematter tissue than did 18F-THK5117. The THK5351 binDing amount correlated with the amount of tau deposits in human brain samples. Autoradiography of brain sections revealed that THK5351 bound to neurofibrillary tangles selectively and with a higher signal-tobackground ratio than did THK5117. THK5351 exhibited favorable pharmacokinetics and no defluorination in mice. In first-in-human PET studies in AD patients, 18F-THK5351 demonstrated faster kinetics, higher contrast, and lower retention in subcortical white matter than18F-THK5117. Conclusion: 18F-THK5351 is a useful PET tracer for the early detection of neurofibrillary pathology in AD patients.

Background: The biodistribution and radiation dosimetry of the 18F-labelled amyloid imaging probe ([18F] FACT) was investigated in humans. Methods: Six healthy subjects (three males and three females) were enrolled in this study. An average of 160.8 MBq of [18F] FACT was intravenously administered, and then a series of whole-body PET scans were performed. Nineteen male and 20 female source organs, and the remainder of the body, were studied to estimate time-integrated activity coefficients. The mean absorbed dose in each target organ and the effective dose were estimated from the time-integrated activity coefficients in the source organs. Biodistribution data from [18F] FACT in mice were also used to estimate absorbed doses and the effective dose in human subjects; this was compared with doses of [18F] FACT estimated from human PET data. Results: The highest mean absorbed doses estimated using human PET data were observed in the gallbladder (333 ± 251 μGy/MBq), liver (77.5 ± 14.5 μGy/MBq), small intestine (33.6 ± 30.7 μGy/MBq), upper large intestine (29.8 ± 15.0 μGy/MBq) and lower large intestine (25.2 ± 12.6 μGy/MBq). The average effective dose estimated from human PET data was 18.6 ± 3.74 μSv/MBq. The highest mean absorbed dose value estimated from the mouse data was observed in the small intestine (38.5 μGy/MBq), liver (25.5 μGy/MBq) and urinary bladder wall (43.1 μGy/MBq). The effective dose estimated from the mouse data was 14.8 μSv/MBq for [18F] FACT. Conclusions: The estimated effective dose from the human PET data indicated that the [18F] FACT PET study was acceptable for clinical purposes. © 2013 Shidahara et al.; licensee Springer.

Molecular imaging in neuroscience is a new research field that enables visualization of the impact of molecular events on brain structure and function in humans. While magnetic resonance-based imaging techniques can provide complex information at the level of system, positron emission tomography (PET) enables determination of the distribution and density of receptor and enzyme in the human brain. Previous studies using [ 11C]raclopride and [ 11C]FLB457 revealed that the release of neuronal dopamine was increased in human brain by psychostimulants or reward stimuli. Following on from these previous [ 11C]raclopride studies, we examined whether the levels of neuronal release of histamine might change [ 11C]doxepin binding to the H1 receptors under the influence of physiological stimuli. The purpose of the present study was to evaluate the test-retest reliability of quantitative measurement of [ 11C]doxepin binding between morning and afternoon and between resting and attentive waking conditions in healthy human subjects. There was a trend for a decrease in [ 11C]doxepin binding during attentive calculation tasks compared with that in resting conditions, but the difference (less than 10%) was not significant. Similarly, the binding potential of [ 11C]doxepin in the cerebral cortex was slightly higher in the morning than that in the afternoon, but it was also insignificant. These data suggest that higher histamine release during wakefulness could not decrease the [ 11C]doxepin binding in the brain. This study confirmed the reproducibility and reliability of [ 11C]doxepin in the previous imaging studies to measure the H1 receptor. © 2012 Shibuya,Funaki, Hiraoka, Yoshikawa, Naganuma, Miyake, Watanuki, Sato, Tashiroand Yanai.

In this report, PEM scanner using a Pr:LuAG scintillator crystal will be discussed. We have developed the PEM scanner with planer detectors which can change the angle and the distance depending on the condition of diagnosis. The planer detectors were composed of four units respectively and one unit consisted of a 20 × 64 pixels scintillator array optically coupled with three H8500 multi anode photomultipliers. As a scintillator Pr:LuAG was installed which possesses interesting properties such as a very fast decay time of 20 ns and a good energy resolution of 4.2 %. The Pr:LuAG pixel size was 2.1 mm × 2.1 mm × 15 mm and the BaSO4-type reflector was used for the array assembly. Based on this PEM system we have performed the clinical studies and compared with the images detected by the PET scanner. Because the spatial resolution of PEM is better than PET, advantages of PEM scanner were clearly shown. © 2012 IEEE.

A Positron Emission Mammograph (PEM) with a pair of planer detectors dedicated for breast cancer detection is developed under collaborations of Tohoku University, Kobe City Collage of Technology, and Furukawa Co., Ltd. It uses thin crystals made of a scintillator Pr:Lu3Al5O12 (Pr:LuAG) of 2.1×2.1×15.0 mm in size combined with H8500 position sensitive Photo multi tubes (PMTs) from Hamamatsu. The PEM system is comprised of two opposing detectors that have 140×200 cm2 field of view (FOV). We present its basic architecture with fundamental performance, such as spatial resolution, time resolution, energy resolution, and data acquisition count rate. The Spatial resolution measured using a 22Na point sauce was found to be 1.1 mm FWHM for image planes parallel to the detector faces. Time resolution was 3.1 ns FWHM. And, energy resolution was 11.6 % FWHM (@511 keV) at the center of detector blocks. Coincident count rate was improved dramatically for optimizing energy windows level and implementation a new offset correction method. © 2012 IEEE.

In this report, PEM scanner using a Pr:LuAG scintillator crystal will be discussed. We have developed the PEM scanner with planer detectors which can change the angle and the distance depending on the condition of diagnosis. The planer detectors were composed of four units respectively and one unit consisted of a 20 x 64 pixels scintillator array optically coupled with three H8500 multi anode photomultipliers. As a scintillator Pr: LuAG was installed which possesses interesting properties such as a very fast decay time of 20 ns and a good energy resolution of 4.2 %. The Pr:LuAG pixel size was 2.1 mm x 2.1 mm x 15 mm and the BaSO4-type reflector was used for the array assembly. Based on this PEM system we have performed the clinical studies and compared with the images detected by the PET scanner. Because the spatial resolution of PEM is better than PET, advantages of PEM scanner were clearly shown.

CYRIC Annual Report 2010/2011

Objective: Positron emission tomography (PET) scanners require periodic monitoring in order to maintain scanner performance. The aim of the present study was to examine the deterioration of PET scanner performance caused by aging. Methods: We retrospectively examined PET scanner performance alterations in terms of sensitivity, spatial resolution, false coincidences due to scatter and random coincidences based on 13 years of follow-up data, including data when the PET scanner underwent an overhaul at the 10th year after installation. Sensitivity and scatter fraction were calculated by using cross calibration factor (CCF) measurement data, which are collected routinely. Efficacy of the examining the sensitivity and scatter was confirmed by NEMA measurements. Trans-axial resolution was measured as full width at half-maximum (FWHM) and full width at tenth-maximum (FWTM) at 0-20 cm offset from the field of view (FOV) center at the time of installation, 8 years after installation, and immediately after the overhaul. Random coincidence rate fraction was measured in a wide range of count rates before and after the overhaul. Results and discussion: The results indicated that the total reduction of sensitivity during the first 10 years was 41% of the initial value in terms of NEMA measurement, and that the annual reduction of sensitivity progressed at a rate of 4.7% per year in terms of CCF measurement data. The changes in sensitivity can be calculated using CCF measurement data. Regarding the spatial resolution, mean FWHM and FWTM values were increased by 1.7 and 3.6%, respectively, in 8 years after installation. The relative scatter fraction was significantly increased compared with that before the overhaul. The random fraction decreased by 10-15% after the overhaul within a certain range of random count rates (1-120 kcps). In the case of our scanner, the parameter that displayed the largest change was the sensitivity, and this change was thought to be caused by the reduction of photomultiplier tube (PMT) gain, although the changes in PMT gain can cause various types of performance deterioration, as investigated in this study. Conclusion: We observed that the sensitivity of our PET scanner generally deteriorated due to aging. Sensitivity monitoring using CCF measurements can be an easy and useful method for monitoring and maintaining the performance of PET scanners against aging. Since the data were obtained from a single scanner, the authors would encourage the initiation of a follow-up study involving various scanners. © 2010 The Japanese Society of Nuclear Medicine.

In order to detect the breast cancer at the early stage with high efficiency, we intend to develop positron emission mammography (PEM), using Pr:LuAG single crystal as a scintillator of this scanner. PEM has the same mechanism of PET, where two 511 keV annihilation gamma-rays are detected by two gamma cameras at opposite side, and reconstruction of the data shows the position of the cancer with malignancy grades. After cutting and polishing processes for each crystal to a physical dimensions of 2.1 × 2.1 × 15 mm3, Pr:LuAG array covered with BaSO4 reflector was used as a sensor head. The one camera unit consisted of 20 × 64 pixels optically coupled with three H8500-03 multi anode PMTs. Our PEM required four cameras at each side. Finally, eight cameras were installed in both sides of the prototype instrument and the spatial resolution was evaluated using the 18F in the breast phantom. © 2010 IEEE.

Positron emission tomography (PET) is widely used in the fields of clinical and basic medicine. The PET device utilizes coincidence logic to detect annihilation photons emitted from positrons and estimates physiological functions of human organs in vivo. Radiopharmaceutical 18F- fluorodeoxyglucose (FDG), an analogue of glucose, is trapped metabolically in cells after being administered into the body, and can be substantially used for evaluating physiological and biochemical functions in vivo. Here, we attempted to describe the basics of PET as well as to apply the technique together with 18F-FDG as a tracer for evaluating organ glucose metabolism induced by exercise. Three-dimensional (3D) FDG-PET was applied to normal volunteers who performed exercise to evaluate whole-body glucose metabolism. Regions of interest analysis were drawn on visually defined regions (i.e., lower limbs, thigh, liver, intestine, brain, heart, etc.) to determine radioactivity distribution. FDG-PET clearly showed the recruitment of energy resources from abdominal organs to lower limb skeletal muscles to balance energy expenditures. The results suggested that 3D FDG-PET can be applied as an imaging tool to physical medicine.

Nowadays, the neural receptor study has been reported in many research papers. Human studies related with neural receptors have made progress by the technological improvement of positron emission tomography (PET) and development of various radiopharmaceuticals that can specifically bind to neuroreceptors. A previous study by Koepp et al. revealed, in 1998, that the release of neuronal dopamine had been increased in human brain during performing a "goal-directed task" (video game). Given an idea from this previous study, we hypothesized that the release of histamine, another neurotransmitter in the brain, might change under the influence of physiological factors such as stress and circadian rhythm. The purpose of our present study was to evaluate the change of brain histamine release induced by stress and circadian rhythm in the healthy human subjects by using [11C]doxepin and PET method. In results, there was a trend for decreased BP in the condition of calculation task, but the difference was not significant, demonstrating that the histamine release in the brain would not be influenced so much by psychological stress. However, the BP was higher in the morning than in the afternoon. The result indicates that histamine release in human brain would be higher in the afternoon than in the morning. © 2010 International Federation for Medical and Biological Engineering.

Ce2%: 6LiCaAlF6 (6LiCAF) single crystal (nominal composition) with 2 mm in diameter and 50 mm in length was grown by the micro-pulling-down method. Emission from the perturbed Ce3+ centers was observed in an a-ray excited radioluminescence. The neutron response was compared with Li-glass (GS20, Saint-Gobain) using. The scintillation decay time of Ce2% : 6LiCAF is 38 nsec, which is twice as short as that of GS20. Using Hamamatsu photomultiplier H7416 the photoelectron yield about a half of that of GS20 has been measured for the single crystal. Considering the light yield of GS20 (6000 phot/neutron) and the spectral correction due to the different emission peak position in both materials, the light yield of single crystal is estimated about 4200 phot/neutron. © 2009 IEEE.

Eu1% LiCaAlF6 (LiCAF) single crystal (nominal composition) with 2 mm in diameter and 35 mm in length was grown by the micro-pulling-down (mu-PD) method. Emission from Eu2+ centers were observed in alpha-ray excited luminescence. Neutron response was compared with Li-glass (GS20, Saint-Gobain) using Cf-252. It is found that the decay time of Eu1%:LiCAF is 1.6 mu sec, which is slower than that of GS20. Light yield of the Eu:LiCAF single crystal indicated from 1.5 times to twice as large as that of GS20. Therefore, when light yield of GS20 is 6000 photon s/neutron, that of Eu:LiCAF single crystal is estimated from 9000 to 13000 photons/neutron.

Ce3+ doped LiYF4 [Li(Y1-xCex)F-4] single crystals with various substitution level x were grown by micro pulling down method and the optical properties and neutron responses were investigated. Transparent Li(Y1-xCex)F-4 single crystals with x = 0.001, 0.005, 0.01 could be grown without visible cracks and inclusions. The transmittances indicated over 70% above 310 nm and emission spectrum originated from 5d-4f transition on Ce3+ ion were observed at 309, 325 nm. The pulse-height of the crystals by alpha-ray irradiation indicated the crystal with x = 0.001 was the largest light yield and the decay times systematically decreased with an increase of x, which was shorter than Li-glass(GS20). Neutron responses revealed the light yield of the crystal with x = 0.005 was quarter taht of Li-glass.

Ce2%: (6)LiCAF single crystal (nominal composition) with 2 mm in diameter and 50 mm in length was grown by the micro-pulling-clown method. Emission from the perturbed Ce3+ centers was observed in alpha-ray excited radioluminescence. Neutron response was compared with Liglass (GS20, Saint-Gobain) using Cf-252. Scintillation decay time of Ce2%: LiCAF is 38nsec, which is twice faster than that of GS20. Using Hamamatsu photomultiplier H7416 the photoelectron yield of the Ce: (6)LiCAF single crystal is measured about half of that of GS20.

CYRIC Annual Report 2009

The incidence of breast cancer is in the first place as a cause of death among Japanese women. The breast cancer is a type of cancer which can be cured relatively easily when detected early. However, it is now clear that the detection of breast cancer is difficult without imaging modalities such as X-ray mammography and/or ultrasonic echography. These imaging devices are useful, however, morphological information only are not enough for differentiating cancer from other benign diseases. Positron emission tomography (PET) for whole-body diagnosis can give us functional information regarding the degree of malignancy. But still there remain various problems such as limited spatial resolution and motion artifacts due to respiratory movement, as well as an issue of the high costs. To compensate these weak points, we have started development of the positron emission mammography (PEM) dedicated for the local diagnosis of the breast tissue. We had developed a test device, "PEM simulator" last year. And we have developed a prototype PEM scanner. In the present paper, basic features are introduced regarding a gantry, chair, detector unit and measurement system of the PEM scanner, as well as our first results obtained by using this prototype scanner. © 2009 International Federation of Medical and Biological Engineering.

Our purpose was to evaluate exercise-induced organ glucose metabolism using 18F-2-fluoro-2-deoxyglucose ([18F]FDG and three-dimensional positron emission tomography technique (3D-PET), comparing two analytical procedures. Eleven healthy male subjects were studied as controls (n=6) and exercise group (n=5). Exercise group subjects performed ergometer bicycle exercise for 40 minutes at 40% and 70% VSO2max. [18F]FDG (39.2 2.6 MBq) was injected 10 min after exercise. A whole body 3D-PET scan was performed immediately after exercise using PET scanner (SET-2400W, Shimadzu Co. Kyoto, Japan). PET image data was reconstructed by filtered 3D back projection algorithm with supercomputer (SX-4/128H4, Synergy Center, Tohoku Univ). Controls were studied using identical study criteria with exercise group. Two analytical procedures, semiquantitative (standardized uptake value; SUV) and quantitative (regional metabolic rate of glucose; rMRGlc) [Autoradiographic method (Phelps et al.)] were applied to assess organ glucose metabolism. ROIs (regions of interest) were drawn on lower limb muscles (e.g., thigh and lumbar/gluteal muscles) and viscera (e.g., liver, heart and brain). To compare analytical procedures, correlation coefficient analysis was done between SUV and rMRGlc data of lower limb muscles, brain and heart. Quantitative analysis revealed that rMRGlc was increased (p<0.05) in skeletal muscles of thigh and lumbar/gluteal region, and decreased in brain (p<0.05) at mild or moderate exercise loads. Semiquantitative analysis revealed the identical results except in lumbar/gluteal muscles. It was found a correlation between SUV and rMRGlc at thigh, brain and heart, however; correlation was not suggestive at lumbar/gluteal muscles. We validated the semiquantitative procedure (SUV) taking absolute quantification method of glucose metabolic rate as a standard. It was observed, the rMRGlc was increased in thigh muscles and decreased in brain at mild or moderate workloads. However, discrepancies between SUV and rMRGlc in one organ demonstrate, semiquantitative approach needs a great care when metabolic rate of glucose utilization changes at wholebody level. © 2009 International Federation of Medical and Biological Engineering.

Objective: Our aim was to evaluate changes in glucose metabolism of skeletal muscles and viscera induced by different workloads using 18F-2-fluoro-2-deoxyglucose ([18F]FDG) and three-dimensional positron emission tomography (3-D PET). Methods: Five male volunteers performed ergometer bicycle exercise for 40 min at 40% and 70% of the maximal O2 consumption ( V̇O2max). [ 18F]FDG was injected 10 min later following the exercise task. Wholebody 3-D PET was performed. Five other male volunteers were studied as a control to compare with the exercise group. The PET image data were analyzed using manually defined regions of interest to quantify the regional metabolic rate of glucose (rMRGlc). Group comparisons were made using analysis of variance, and significant differences (P < 0.05) were determined using Scheffe's test (post hoc analysis). Results: Quantitative analysis demonstrated that rMRGlc increased (P < 0.05) in the skeletal muscles of the thigh at mild or moderate workloads when compared with the resting controls. For visceral organs such as the liver and brain, metabolic reduction was significant (P < 0.05) at mild and/or moderate exercise workload. Conclusions: The present study demonstrated linear increases or decreases in glucose uptake by skeletal muscles and viscera with mild and moderate exercise workloads, suggesting the presence of homeostatic energy metabolism. This result supports the finding that [ 18F]FDG-PET can be used as an index of organ energy metabolism for moderate exercise workloads (70% V̇O2max). The results of this investigation may contribute to sports medicine and rehabilitation science. © 2009 The Japanese Society of Nuclear Medicine.

Aims: The strength of sedation due to antihistamines can be evaluated using positron emission tomography (PET). The purpose of the present study is to measure histamine H1 receptor (H1R) occupancy following oral administration of cetirizine (10 and 20 mg) in order to examine dose dependency. Methods: Fifteen healthy male volunteers (age range, 20-35 years) were divided into 3 subgroups and were studied following single oral administration of cetirizine at 10 mg (n = 5) and 20 mg (n = 5) or hydroxyzine at 30 mg (n = 5) using PETwith 11C-doxepin. Each subject was scanned also following the administration of placebo. Binding potential and H 1RO values were calculated in the prefrontal and anterior cingulate cortices. Subjective sleepiness was also measured, and the correlation to H 1RO was examined for each antihistamine. Results: The averaged H 1ROs of cetirizine 10 mg, 20 mg, and hydroxyzine 30 mg in the prefrontal and cingulate cortices was 12.6%, 25.2%, and 67.6%, respectively. The H1RO of hydroxyzine 30 mg correlated well with subjective sleepiness (p < 0.001); however, those of cetirizine 10 and 20 mg showed no correlation with subjective sleepiness. Conclusion: It was demonstrated that the brain penetration of orally administered cetirizine was dose-dependent. Cetirizine 10 mg, with its low H1RO and thus minimal sedation, could be more safely used than cetirizine 20 mg for the treatment of various allergic disorders. Copyright © 2009 John Wiley & Sons, Ltd.

AIMS: Antihistamines are frequently used for treating various allergic diseases, but often induce sedation. The degree of sedation can be evaluated by measuring histamine H1 receptor occupancy (H1RO) in the brain using positron emission tomography (PET). The aim was to measure H 1RO of bepotastine, a new second-generation antihistamine, and to compare it with that of diphenhydramine. METHODS: Eight healthy male volunteers (mean age ± SD 24.4 ± 3.3 years) were studied after single oral administration of bepotastine (10 mg), diphenhydramine (30 mg) or placebo, by PET imaging with 11C-doxepin in a crossover study design. Binding potential ratio and H1ROs were calculated using placebo data and were compared between bepotastine and diphenhydramine in the anterior and posterior cingulate gyri (ACG and PCG, respectively), superior and inferior frontal cortices (SFC and IFC, respectively), orbitofrontal cortex (OFC), insular cortex (IC), lateral and medial temporal cortices (LTC and MTC, respectively), parietal cortex (PC), occipital cortex (OC) and sensorimotor cortex (SMC). Plasma concentration of each antihistamine was measured, and its correlation to H1RO was examined. RESULTS: H1RO after bepotastine treatment was significantly lower than that after diphenhydramine treatment in all cortical regions (P < 0.001). Mean H1ROs of bepotastine and diphenhydramine were 14.7% and 56.4%, respectively. H1ROs of both bepotastine and diphenhydramine correlated to their respective drug plasma concentration (P < 0.001). CONCLUSION: Oral bepotastine (10 mg), with its relatively low H1RO and thus minimal sedation, has the potential for use as a mildly or slightly sedative antihistamine in the treatment of various allergic disorders. © 2008 The Authors.

CYRIC Annual Report 2008

Ce3+ doped LiYF4 [Li(Y1-xCe x)F4] single crystals with various substitution level x were grown by micro-pulling down method and the optical properties and neutron responses were investigated. Transparent Li(Y1-xCex)F 4 single crystals with x= 0.001, 0.005, 0.01 could be grown without visible cracks and inclusions. The transmittances indicated over 70% above 310 nm and emission spectrum originated from 5d-4f transition on Ce3+ ion were observed at 309, 325 nm. The pulse-height of the crystals by aray irradiation indicated the crystal with x=0.001 was the largest light yjeld and the decay times systematically decreased with an increase of x which was shorter than Li-glass(GS20). Neutron responses revealed the light yjeld of the crystal with x =0.005 was quarter taht of Li-glass. © 2008 IEEE.

Eul% LiCaAlF6 (LiCAF) single crystal (nominal composition) with 2 mm in diameter and 35 mm in length was grown by the micro-pulling-down (μ-PD) method. Emission from Eu2+ centers were observed in α-ray excited luminescence. Neutron response was compared with Li-glass (GS20, SaintGobain) using 252Cf.It is found that the decay time of Eul%LiCAF is 1.6 μSec, which is slower than that of GS20. Light yield of the Eu:LiCAF single crystal indicated from 1.5 times to twice as large as that of GS20. Therefore, when light yield of GS20 is 6000 photons/neutron, that of Eu:LiCAF single crystal is estimated from 9000 to 13000 photons/neutron. © 2008 IEEE.

Ce2%:6LiCAF single crystal (nominal composition) with 2 mm in diameter and 50 mm in length was grown by the micro-pulling-down method. Emission from the perturbed Ce3+ centers was observed in α-ray excited radioluminescence. Neutron res~onse was compared with Liglass (GS20, Saint-Gobain) using 252Cf. Scintillation decay time of Ce2%:LiCAF is 38nsec, which is twice faster than that of GS20. Using Hamamatsu photomultiplier H7416 the photoelectron yield of the Ce:6LiCAF single crystal is measured about half of that of GS20. © 2008 IEEE.

Background and aims: Histamine H1 receptor (H1R) antagonists, or antihistamines, are often used for treatment of allergic disorders such as seasonal rhinitis. Antihistamines mainly act on the peripheral tissues but can induce sedation. This undesirable central side effect is caused by blockade of nerve transmission in the histaminergic neuron system. First-generation antihistamines such as diphenhydramine can easily penetrate blood-brain barrier (BBB) and tend to occupy a large proportion of post-synaptic H1Rs. Second-generation antihistamines such as fexofenadine and olopatadine can slightly penetrate BBB and H1Rs are slightly occupied. Thus, variation in cerebral H1R occupancy (H1RO) of antihistamines results mainly from their different BBB permeability. The aim of the present study was to compare the sedative property of a new antihistamine, bepotastine, in terms of H1RO using PET and [11C]doxepin. Methods: Eight healthy male volunteers (mean age +/- s.d.: 24.4 +/- 3.3 years old) were studied after single oral administration of bepotastine 10 mg, diphenhydramine 30 mg (a typical sedative antihistamine), or placebo, using PET and [11C]doxepin in a crossover study-design. Binding potential ratio and H1R occupancy values were calculated using placebo data, and were compared between bepotastine and diphenhydramine. PET brain images were reconstructed with a filtered back projection algorithm. The brain images were then normalized by plasma radioactivity at 10 min post-injection to yield static distribution volume (DV) images. H1RO of bepotastine was compared to that of diphenhydramine. The present study was approved by the Committee on Clinical Investigation at Tohoku University Graduate School of Medicine, Japan. All experiments were performed at the Cyclotron and Radioisotope Centre, Tohoku University. Results: Brain images following administration of bepotastine demonstrated slightly lower binding potential in comparison to those following placebo, and images following diphenhydramine administration demonstrated significantly lower binding potential in comparison to both placebo and bepotastine. Overall cortical mean H1RO of bepotastine and diphenhydramine were 15% and 57%, respectively. H1R occupancy of both bepotastine and diphenhydramine correlated well with their respective drug plasma concentration (p< 0.001). Conclusions: In the present study, H1ROs following oral administration of bepotastine 10 mg or diphenhydramine 30 mg were calculated as 14.8% and 56.8%, respectively. In our previous studies, our previous PET studies demonstrated that first-generation antihistamines occupied more than 50% of available H1Rs. The result of bepotastine (15%) is in accordance with the categorization of bepotastine as a second-generation antihistamine. Previous studies have demonstrated H1ROs of other second-generation antihistamines such as terfenadine 60 mg (12-17%), fexofenadine 120 mg (1%) and ebastine 10 mg (10%). As a whole, second-generation antihistamines seem to occupy around 0 to 20% of brain H1Rs. In conclusion, PET and [11C]doxepin is useful for evaluating sedative side effects of various psychoactive drugs with antihistamine effects. Collection of more H1RO data is encouraged for establishment of a reliable international database for evaluation of the sedative profile of psychoactive drugs.

Background and Aims: Car-driving is a combination of complex neural tasks such as attention, perception, integration of visual and somatosensory inputs, generation of motor outputs and action controls. Though the car-driving is not a difficult task for many experienced drivers, all drivers might sometimes encounter potentially-dangerous situations induced by cognitive and psychomotor deficits due to aging, neurological disorders, sedative drugs and mobile phone use. Therefore, elucidation of the brain mechanism during car-driving is important and might lead to development of an effective system to prevent accidents. The present study aims at identifying the brain activation during actual car-driving on the road, and at comparing the result to those of previous studies on simulated car-driving. Methods: Thirty normal volunteers, aged 20 to 56 years, were divided into three subgroups, active driving, passive driving and control groups, for examination by positron emission tomography (PET) and [18F]2-deoxy-2-fluoro-D-glucose (FDG). The active driving subjects (n=10) drove for 30 minutes on quiet normal roads with a few traffic signals. The passive driving subjects (n=10) participated as passengers on the front seat. The control subjects (n=10) remained to be seated in a lit room with their eyes open. Voxel-based t-statistics were applied using SPM2 to search of brain activation among the subgroups mentioned above. Results: Significant brain activation was detected during active driving in the primary and secondary visual cortices, primary sensorimotor areas, premotor area, the parietal association area, the cingulate gyrus, the parahippocampal gyrus as well as in the thalamus and cerebellum. The passive driving manifested a similar-looking activation pattern, lacking activations in the premotor area, the cingulate and parahippocampal gyri and in the thalamus. Direct comparison of the active and passive driving conditions revealed activation in the cerebellum. Conclusions: So far, several activation studies during simulated car-driving have been conducted using functional MRI and PET with [15O]H2O. The result of actual driving seemed to be similar to that of simulated driving, suggesting that visual perception and visuomotor coordination were the main brain functions while driving. In terms of attention and autonomic arousal, however, it seems there was a significant difference between simulated and actual driving possibly due to risk of accidents. Autonomic and emotional aspects of driving should be studied using actual driving study-design. Functional neuroimaging using actual and simulated car-driving task will be a useful tool in the filed of transportation medicine.

CYRIC Annual Report 2007

CYRIC Annual Report 2007

CYRIC Annual Report 2007

CYRIC Annual Report 2007

CYRIC Annual Report 2007

CYRIC Annual Report 2007

ISBN 978-4-904157-00-8

CYRIC Annual Report 2006

This study applied the FDG-PET technique to visually analyze brain activity during actual car-driving. Subjects were total 10 normal volunteers who drove a testing car for 30 min on ordinary roads. Ten additional subjects participated as a passenger during the actual driving. Ten additional subjects performed as the controls remained seated in a room. Data analysis was made to find possible brain activation between the 3 groups using Statistical Parametric Mapping (SPM). The results demonstrated an increased activity mainly in the sensorimotor areas and visual areas. The result of actual driving looked similar to that of previous studies of simulated driving, suggesting that visual perception and visuomotor coordination were the main brain functions while driving.

We have implemented an automatic registration algorithm for PET to CT or MR images and measured the accuracy of image matching with both simulated and real images. The algorithm utilizes multi-resolution scheme to improve calculation speed. In the examination of the performance of the algorithm, randomly mismatched images were processed with the present method, and the computation time and matching error were measured with various operation parameters. The mean matching error was observed increasing as initial image resolution decreases. For an acceptable range of errors (less than the spatial resolution of input image), the typical computation time for PET-MR head image was about 1 min using moderate performance PC.

Our aim was to evaluate homeostatic regulation of organ energy metabolism after exercise using F-18-FDG and 3D-PET. Five male subjects were studied after exercise task of two different intensities (40% and 70% VO2max). Other 5 males were studied as control. ROls were drawn to quantify organ glucose metabolism (rMRGlc). ANOVA was applied among groups, and significant differences (p < 0.05) were determined by post-hoc analysis (Scheffe's test). Present study with mild and moderate exercise loads demonstrated linear increases or decreases in glucose uptake by skeletal muscles and viscera, suggestive of homeostatic energy regulation. This supports, (18)FDG-3DPET method can be used as one index of organ energy metabolism up to 70% VO2max, which might have contributions in rehabilitation science.

Aims: This study aims at identifying the brain activation during actual car-driving on the road, and at comparing the results to those of previous studies on simulated car-driving. Methods: Thirty normal volunteers, aged 20 to 56 years, were divided into three subgroups, active driving, passive driving and control groups, for examination by positron emission tomography (PET) and [ 18F]2-deoxy-2-fluoro-D-glucose (FDG). The active driving subjects (n = 10) drove for 30 minutes on quiet normal roads with a few traffic signals. The passive driving subjects (n = 10) participated as passengers on the front seat. The control subjects (n = 10) remained seated in a lit room with their eyes open. Voxel-based t-statistics were applied using SPM2 to search brain activation among the subgroups mentioned above. Results: Significant brain activation was detected during active driving in the primary and secondary visual cortices, primary sensorimotor areas, premotor area, parietal association area, cingulate gyrus, the parahippocampal gyrus as well as in thalamus and cerebellum. The passive driving manifested a similar-looking activation pattern, lacking activations in the premotor area, cingulate and parahippocampal gyri and thalamus. Direct comparison of the active and passive driving conditions revealed activation in the cerebellum. Conclusion: The result of actual driving looked similar to that of simulated driving, suggesting that visual perception and visuomotor coordination were the main brain functions while driving. In terms of attention and autonomic arousal, however, it seems there was a significant difference between simulated and actual driving possibly due to risk of accidents. Autonomic and emotional aspects of driving should be studied using an actual driving study-design.

CYRIC Annual Report 2005

CYRIC Annual Report 2005

CYRIC Annual Report 2005

CYRIC Annual Report 2005

CYRIC Annual Report 2005

The momentum dependences of the nuclear spin polarization P and alignment A of B-12 (I-pi = 1(+), T-1/2 = 20.20 ms) [B-13 (I-pi = 3/2(-), T-1/2 = 17.36 ms)] produced in 100A MeV C-13 [N-15] + Be collisions have been measured by detecting the beta-ray asymmetry. Because both the P and A were significantly smaller than the prediction from a simple kinematical model, some depolarization mechanisms must be taken into account related with the collision process itself. Comparing the signs of the observed alignment of B-12 and B-13, the sign of the quadrupole moment Q(B-13) was determined to be positive.

CYRIC Annual Report 2004

Our aim was to evaluate regional differences between brain activity in two resting control conditions measured by 3D PET after administration of FDG through either the intravenous (i.v.) or the oral route. Ten healthy male volunteers engaged in the study as the i.v. group (mean age, 26 ± 9.3 years, ± S.D.) who received FDG intravenously and another 10 volunteers as the oral group (mean age, 27.9 ± 11.3 years, ± S.D.) who received FDG per os. A set of 3D-PET scans (emission and transmission scans) were performed in both groups. To explore possible functional differences between the brains of the two groups, the SPM-96 software was used for statistical analysis. The results revealed that glucose metabolism was significantly higher in the superior frontal gyrus, superior parietal lobule, lingual gyrus and left cerebellar hemisphere in the i.v. group than in the oral group. Metabolically active areas were found in the superior, middle and inferior temporal gyrus, parahippocampal gyrus, amygdaloid nucleus, pons and cerebellum in the oral group when compared with the i.v. group. These differences were presumably induced by differences between FDG kinetics and/or time-weighted behavioral effects in the two studies. This study suggests the need for extreme caution when selecting a pooled control population for designated activation studies.

CYRIC Annual Report 2000

PET with three-dimensional data acquisition using 18F- fluorodeoxyglucose (FDG) was applied to evaluate skeletal muscle activity in runners. Methods: Seven healthy adult male volunteers were studied. They ran for a total of 35 min, 15 min before and 20 min after intravenous injection of FDG. Another 7 adult male control subjects were also examined at rest. Images obtained through a set of whole-body PET scans were analyzed. Regions of interest (ROIs) were manually drawn on images of muscles of both thighs, legs and feet, and the standardized uptake ratio (SUR) and total radioactivity distribution (TRD) for each region were calculated. Results: The work load was below the anaerobic threshold. SUR of foot, leg and thigh were low at rest but during running increased 5.19, 4.30 and 1.74 times, respectively. The SUR of posterior-to- anterior compartment of the leg was 1.1 ± 0.1 at rest and 1.6 ± 0.5 (P < 0.01) during running. The laterality index of both SUR and TRD changed significantly only in the foot of the dominant side during running. TRD of the leg, less than half that of the thigh at rest, became equivalent to that of the thigh during running. TRD of the foot did not change significantly. Conclusion: Sole muscles showed highest metabolic activation per unit volume during running, which was higher in the dominant side. Comparison of whole muscle activity during running indicated the highest metabolic activation was in the posterior compartment of the leg, whereas thigh muscles showed relatively little changes during running. Our data indicate that whole-body FDG PET, especially three- dimensional data acquisition, is a useful tool for the investigation of muscular activity during exercise.

Whole-body PET scanning for an oncology study produces a large number of transaxial images by data acquisition over multiple bed positions. The sagittal and coronal reformatted images are often used for better understanding of radioisotope distribution. We reduced the number of PET images by calculating projection images and evaluated the merit of additional data processing for the visualization and detection of tumors. After reconstructing whole-body 18F-FDG PET images (6-8 bed positions) of eight cancer patients, antero-posterior and lateral projection images were calculated by the maximum intensity projection (MIP) algorithm, the standard deviation projection (SD) algorithm and the summed voxel projection (SUM) algorithm. The projection images were compared with 2D whole-body images for visualizing loci. The focal uptakes of various positions in original whole- body PET data (294-392 transaxial images) were visualized on only two MIP reformatted images when superimposition of hot spots did not occur. Even if one hot spot was superimposed over the other hot spot, we could recognize the existence of at least one focus and determine the true positions of the hot spots from corresponding transaxial images. The SD image was found inferior for showing a contrast of small loci to the corresponding MIP images in the neck, mediastinum and abdomen. The SUM image failed to visualize many metastatic lesions. MIP is a promising technique for the easy preliminary assessment of tumor distribution in oncologic whole-body PET study.

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L-[Methyl-11C]-methionine (11C-methionine) is proposed as a useful radiotracer for tumour diagnosis. Human biodistribution data of cumulated activities and absorbed doses estimated by the MIRD (medical internal radiation dosimetry) method for 11C-methionine are not available in the literature. In this study we measured the organ activity for 11C-methionine by using whole-body positron emission tomography (PET) and estimated the absorbed doses to 25 organs by the MIRD method. Whole-body dynamic PET scans were performed on five normal volunteers to measure the time course of the organ activity concentration (activity/volume) after intravenous administration of 11C-methionine. Cumulated activities of the ten source organs were calculated from the time-activity curves, obtained from the dynamic PET data. Absorbed dose estimates were performed by the MIRD method for the Caucasian reference man and for the Japanese reference man. The organs which received the highest absorbed doses for the Caucasian reference man were found to be the bladder wall (2.7 x 10-2 mGy/MBq), the pancreas (1.9 x 10-2 mGy/MBq), the liver (1.8 x 10-2 mGy/MBq) and the kidney (1.1 x 10-2 mGy/MBq). The effective doses for the Caucasian reference man and the Japanese reference man were calculated as 5.2 x 10-3 and 5.0 x 10-3, mSv/MBq, respectively.

The purpose of this study was to measure the cumulated activity and absorbed dose in organs after intravenous administration of 2-[F-18]fluoro-2-deoxy-D-glucose (18F-FDG) using whole-body positron emission tomography (PET) and magnetic resonance imaging (MRI). Whole-body dynamic emission scans for 18F-FDG were performed in six normal volunteers after transmission scans. The total activity of a source organ was obtained from the activity concentration of the organ measured by whole-body PET and the volume of that organ measured by whole-body T1-weighted MRI. The cumulated activity of each source organ was calculated from the time-activity curve. Absorbed doses to the individuals were estimated by the MIRD (medical internal radiation dosimetry) method using S-values adjusted to the individuals. Another calculation of cumulated activities and absorbed doses was performed using the organ volumes from the MIRD phantom and the 'Japanese reference man' to investigate the discrepancy of actual individual results against the phantom results. The cumulated activities of 18 source organs were calculated, and absorbed doses of 27 target organs estimated. Among the target organs, bladder wall, brain and kidney received the highest doses for the above three sets of organ volumes. Using measured individual organ volumes, the average absorbed doses for those organs were found to be 3.1 x 10-1, 3.7 x 10-2 and 2.8 x 10-2 mGy/MBq, respectively. The mean effective doses in this study for individuals of average body weight (64.5 kg) and the MIRD phantom of 70 kg were the same, i.e. 2.9 x 10-2 mSv/MBq, while for the Japanese reference man of 60 kg the effective dose was 2.1 x 10-2 mSv/MBq. The results for measured organ volumes derived from MRI were comparable to those obtained for organ volumes from the MIRD phantom. Although this study considered 18F-FDG, combined use of whole-body PET and MRI might be quite effective for improving the accuracy of estimations of the cumulated activity and absorbed dose of positron-labelled radiopharmaceuticals.

We have developed a miniature γ-ray endoscopic probe consisting of dual BGO detector probes for tumor detection inside the body cavities. The dual detector system was coupled with random coincidence to decrease the distant background radiation and to improve its spatial resolution for tumor localization. Method: The performance of the probe was investigated with a point source and a water phantom. A solution of positron emitting 18F isotope was used as the source. Clinical trials of the probe were done to localize tumors on the skin surface of four subjects carrying tumors close to the body surfaces, into whom 67Ga-citrate and 18F-FDG radiopharmaceuticals were injected. Results: Measurements indicated that the spatial resolution of the dual detector probes is around 1.5 times better than the single detector probe, and both single and dual detector endoscopic probe systems are capable of localizing a tumor on a large photon background. Conclusion: The endoscopic probe may be easier to insert inside body cavities due to the small crystal size and the flexible light guides. A single detector probe with higher sensitivity may be useful in searching for tumors over a wide intracavity area but a dual detector probe can be used for precise tumor localization. The detector probe may also be suitable for intraoperative observation.

The SET-2400W is a newly designed whole-body PET scanner with a large axial field of view (20 cm). Its physical performance was investigated and evaluated. The scanner consists of four rings of 112 BGO detector units (22.8 mm in-plane x 50 mm axial x 30 mm depth). Each detector unit has a 6 (in- plane) x 8 (axial) matrix of BGO crystals coupled to two dual photomultiplier tubes. They are arranged in 32 rings giving 63 two-dimensional image planes. Sensitivity for a 20-cm cylindrical phantom was 6.1 kcps/kBq/ml (224 kcps/μCi/ml) in the 2D clinical mode, and to 48.6 kcps/kBq/ ml (1.8 Mcps/μCi/ml) in the 3D mode after scatter correction. In-plane spatial resolution was 3.9 mm FWHM at the center of the field-of-view, and 4.4 mm FWHM tangentially, and 5.4 mm FWHM radially at 100 mm from the center. Average axial resolution was 4.5 mm FWHM at the center and 5.8 mm FWHM at a radial position 100 mm from the center. Average scatter fraction was 8% for the 2D mode and 40% for the 3D mode. The maximum count rate was 230 kcps in the 2D mode and 350 kcps in the 3D mode. Clinical images demonstrate the utility of an enlarged axial field-of-view scanner in brain study and whole- body PET imaging.

A noninvasive blood radioactivity monitor system for Positron Emission Tomography (PET) study has been developed. This system has dual plastic scintillators to detect positrons from the wrist artery. One is for monitoring the blood radioactivity in artery and tissue, and another is for monitoring only in tissue, in order to subtract background radiation from tissue. We carried out phantom experiments for evaluating basic characteristics of this monitor system. Clinical experiments using 15O-labeled water were also done to compare this system with a conventional invasive monitor. © 1995 IEEE.