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Objective To investigate differences in uptake regions between methyl-11C-L-methionine positron emission tomography (11C-MET PET) and gadolinium (Gd)-enhanced MRI, and to examine the effects on dose distribution of changing the threshold value for definition of tumor boundaries.Methods Twenty consecutive patients with grade 3 or 4 glioma who had recurrence after postoperative RT between April 2016 and October 2017 were examined in the study. This study is simulation study assuming all patients received RT. Clinical target volume (CTV) was contoured using the Gd-enhanced region (CTV-Gd), T2-high region (CTV-T2), tumor/normal tissue (T/N) ratios of 11C-MET PET of 1.3 and 2.0 (CTV (T/N 1.3), CTV (T/N 2.0)), and the PET-edge method (CTV(P-E)) for stereotactic radiotherapy planning for recurrent malignant glioma after radiotherapy. Differences among CTVs were evaluated and the dose distribution for the normal brain was simulated for each CTV.Results The Jaccard index (JI) for concordance of CTV (Gd) with CTVs using 11C-MET PET was highest for CTV (T/N 2.0), with a value of 0.7. In a comparison of pixel values of MRI and PET, the correlation coefficient for cases with higher JI was significantly greater than that for lower JI cases (0.37 vs. 0.20, P = 0.007). D50% and D33% of the brain in radiotherapy planning using each CTV differed significantly (P = 0.03, P = 0.02) and those using CTV (T/N 1.3) were higher than with use of CTV (Gd). V90% and V95% for each CTV differed in a simulation study for actual treatment using CTV (Gd) (P = 1.0×10− 7, P = 3.0×10− 9) and those using CTV (T/N 1.3) and CTV (P-E) were lower than with CTV (Gd). Comparing with CTV (T2), the JI showed no significant difference with any CTV using PET. D50% and D33% of the brain were significantly higher than any CTV using PET.Conclusions The region of 11C-MET accumulation is not necessarily similar to the Gd-enhanced or T2 high region. A change of the tumor boundary using 11C-MET PET can cause significant changes in doses to the brain and the CTV.

The activation of microglia in various brain pathologies is accompanied by an increase in the expression of peripheral benzodiazepine receptor/18 kDa translocator protein (PBR/TSPO). However, whether activated microglia have a neuroprotective or neurotoxic effect on neurons in the brain is yet to be determined. In this study, we investigated the ability of the novel PBR/TSPO ligand FEPPA to detect activated microglia in an animal model of primary neurotoxic microglia activation. [18F] FEPPA positron emission tomography (PET) imaging was performed before and after intraperitoneal administration of lipopolysaccharide (LPS) (LPS group) or saline (control group) in a unilateral 6-hydroxydopamine (6-OHDA) lesion rat model of Parkinson’s disease. Images were compared between these groups. After imaging, the brains were collected, and the activated microglia at the disease sites were analyzed by the expression of inflammatory cytokines and immunohistochemistry staining. These results were then comparatively examined with those obtained by PET imaging. In the unilateral 6-OHDA lesion rat model, the PBR/TSPO PET signal was significantly increased in the LPS group compared with the saline group. As the increased signal was observed 4 h after the injection, we considered it an acute response to brain injury. In the post-imaging pathological examination, activated microglia were found to be abundant at the site where strong signals were detected, and the expression of the inflammatory cytokines TNF-α and IL-1β was increased. Intraperitoneal LPS administration further increased the expression of inflammatory cytokines, and the PBR/TSPO PET signal increased concurrently. The increase in inflammatory cytokine expression correlated with enhanced signal intensity. PET signal enhancement by PBR/TSPO at the site of brain injury correlated with the activation of microglia and production of inflammatory cytokines. Furthermore, because FEPPA enables the detection of neurotoxic microglia on PET images, we successfully constructed a novel PET detection system that can monitor neurodegenerative diseases.

We conducted the present phase I/IIa positron emission tomography (PET) imaging study with 89Zr conjugated with desferroxamine-IAB2M (89Zr-Df-IAB2M), an anti-prostate-specific membrane-antigen minibody, to assess its safety and feasibility in patients with urological cancer. 89Zr-Df-IAB2M was synthetized by IBA Molecular (Somerset, NJ, USA) and transported by air to Tsukuba Molecular Imaging Center (Tsukuba, Ibaraki, Japan).17 patients received 74 MBq (2 mCi) of 89Zr-Df-IAB2M at total mass doses of 10 mg. Whole-body and plasma clearance, normal-organ and lesion uptake, and radiation absorbed dose were estimated. We also preliminarily tested the performance of 89Zr-immuno-PET imaging for 13 patients with prostate cancer and 4 patients with other urological cancer. The administration of 89Zr-Df-IAB2M was well-tolerated, and no infusion-related reactions were observed in any patient. No adverse events were noted in the laboratory parameters, vital signs, or other parameters. The plasma clearance was biphasic, with an initial rapid phase (t 1/2 fast: 10.1 ± 3.4 h) followed by a slow phase (t 1/2 slow: 49.0 ± 22.7 h). The half-life of radioactivity in the whole body (WB t1/2) was 237 ± 9 h. The highest absorbed radiation dose was 1.67 mGy/MBq, observed in the liver and kidney. The effective dose was 0.68 ± 0.08 mSv/MBq. The radiation dose rate at 0.5 m distance from the patient was 8.67 µSv/h on day 1, and decreased to 2.26 µSv/h at 5 days after injection. Both bone and lymph node metastases were detected with 89Zr-Df-IAB2M by 24 or 48 h imaging. Administration of 89Zr-Df-IAB2M was well-tolerated and safe in terms of adverse events and radiation exposure and protection. 89Zr-Df-IAB2M is feasible for usage by long-distance transportation. Further studies are warranted for analysis of its use for tumor lesion detection (UMIN000015356).

Tumor angiogenesis has attracted increasing attention because of its potential as a valuable marker in the differential diagnosis of brain tumors as well as a novel therapeutic target. Prostate-specific membrane antigen (PSMA) is expressed by the neovasculature endothelium of some tumors, with little to no expression by the tumor cells or normal vasculature endothelium. The aim of this study was to investigate the potential of PSMA for the evaluation of the tumor neovasculature of various brain tumors and the possibility of detecting PSMA expression in brain tumors using PET imaging with 89Zr-Df-IAB2M (anti-PSMA minibody). Eighty-three tissue specimens including gliomas, metastatic brain tumors, primary central nervous system lymphomas (PCNSL), or radiation necroses were analyzed by immunohistochemical staining with PSMA antibody. 89Zr-Df-IAB2M PET scans were performed in three patients with recurrent high-grade gliomas or metastatic brain tumor. PSMA was highly expressed in the vascular endothelium of high-grade glioma and metastatic brain tumor, whereas PSMA was poorly expressed in the vascular endothelium of PCNSL and radiation necrosis. PSMA expression in high-grade gliomas and a metastatic brain tumor was clearly visualized by PET imaging with 89Zr-Df-IAB2M. Furthermore, a trend toward a positive correlation between the degree of 89Zr-Df-IAB2M uptake and PSMA expression levels in tumor specimens was observed. PET imaging of PSMA using 89Zr-Df-IAB2M may have potential value in the differential diagnosis of high-grade glioma from PCNSL or radiation necrosis as well as in the prediction of treatment efficacy and assessment of treatment response to bevacizumab therapy for high-grade glioma.

Recently, small hydroelectric generators have gained attention as a further development in water turbine technology for ultra low head drops in open channels. The authors have evaluated the application of cross-flow water turbines in open channels as an undershot type after removing the casings and guide vanes to substantially simplify these water turbines. However, because undershot cross-flow water turbines are designed on the basis of cross-flow water turbine runners used in typical pipelines, it remains unclear whether the number of blades has an effect on the performance or flow fields. Thus, in this research, experiments and numerical analyses are employed to study the performance and flow fields of undershot cross-flow water turbines with varying number of blades. The findings show that the turbine output and torque are lower, the fluctuation is significantly higher, and the turbine efficiency is higher for runners with 8 blades as opposed to those with 24 blades.

The effective utilization of various biomolecules for creating a series of mesoporous boehmite (γ-AlOOH) and gamma-alumina (γ-Al2 O3 ) nanosheets with unique hierarchical multilayered structures is demonstrated. The nature and concentration of the biomolecules strongly influence the degree of the crystallinity, the morphology, and the textural properties of the resulting γ-AlOOH and γ-Al2 O3 nanosheets, allowing for easy tuning. The hierarchical γ-AlOOH and γ-Al2 O3 multilayered nanosheets synthesized by using biomolecules exhibit enhanced crystallinity, improved particle separation, and well-defined multilayered structures compared to those obtained without biomolecules. More impressively, these γ-AlOOH and γ-Al2 O3 nanosheets possess high surface areas up to 425 and 371 m2 g-1 , respectively, due to their mesoporous nature and hierarchical multilayered structure. When employed for molybdenum adsorption toward medical radioisotope production, the hierarchical γ-Al2 O3 multilayered nanosheets exhibit Mo adsorption capacities of 33.1-40.8 mg g-1 . The Mo adsorption performance of these materials is influenced by the synergistic combination of the crystallinity, the surface area, and the pore volume. It is expected that the proposed biomolecule-assisted strategy may be expanded for the creation of other 3D mesoporous oxides in the future.

We conducted the present phase I/IIa positron emission tomography (PET) imaging study withThe administration ofAdministration of

Tumor angiogenesis has attracted increasing attention because of its potential as a valuable marker in the differential diagnosis of brain tumors as well as a novel therapeutic target. Prostate-specific membrane antigen (PSMA) is expressed by the neovasculature endothelium of some tumors, with little to no expression by the tumor cells or normal vasculature endothelium. The aim of this study was to investigate the potential of PSMA for the evaluation of the tumor neovasculature of various brain tumors and the possibility of detecting PSMA expression in brain tumors using PET imaging with

PURPOSE: Evaluation of translocator protein (TSPO) overexpression is considered an attractive research tool for monitoring neuroinflammation in several neurological and psychiatric disorders. [11C]PK11195 PET imaging has been widely used for this purpose. However, it has a low sensitivity and a poor signal-to-noise ratio. For these reasons, [11C]CB184 was evaluated as a potentially more sensitive PET tracer.METHODS: A model of herpes simplex encephalitis (HSE) was induced in male Wistar rats. On day 6 or 7 after virus inoculation, [11C]CB184 PET scans were acquired followed by ex vivo evaluation of biodistribution. In addition, [11C]CB184 and [11C]PK11195 PET scans with arterial blood sampling were acquired to generate input for pharmacokinetic modelling. Differences between the saline-treated control group and the virus-treated HSE group were explored using volumes of interest and voxel-based analysis.RESULTS: The biodistribution study showed significantly higher [11C]CB184 uptake in the amygdala, olfactory bulb, medulla, pons and striatum (p 2 = 0.71). Pretreatment with 5 mg/kg of unlabelled PK11195 effectively reduced (p 11C]CB184 uptake in the whole brain. Both, [11C]CB184 and [11C]PK11195, showed similar amounts of metabolites in plasma, and the binding potential (BPND) was not significantly different between the HSE rats and the control rats. In HSE rats BPND for [11C]CB184 was significantly higher (p 11C]PK11195 was only detected in the medulla.CONCLUSION: [11C]CB184 showed nonspecific binding to healthy tissue comparable to that observed for [11C]PK11195, but it displayed significantly higher specific binding in those brain regions affected by the HSE. Our results suggest that [11C]CB184 PET is a good alternative for imaging of neuroinflammatory processes.

Background N,N-di-n-propyl-2-[2-(4-[11C]methoxyphenyl)-6,8-dichloroimidazol[1,2-a]pyridine-3-yl]acetamide ([11C]CB184) is a novel selective radioligand for the 18-kD translocator protein (TSPO), which is upregulated in activated microglia in the brain, and may be useful in positron emission tomography (PET). We examined the safety, radiation dosimetry, and initial brain imaging with [11C]CB184 in healthy human volunteers. Results Dynamic [11C]CB184 PET scans (90 min) were performed in five healthy male subjects. During the scan, arterial blood was sampled at various time intervals, and the fraction of the parent compound in plasma was determined with high-performance liquid chromatography. No serious adverse events occurred in any of the subjects throughout the study period. [11C]CB184 was metabolized in the periphery: 36.7% ± 5.7% of the radioactivity in plasma was detected as the unchanged form after 60 min. The total distribution volume (V T) was estimated with a two-tissue compartment model. The V T of [11C]CB184 was highest in the thalamus (5.1 ± 0.4), followed by the cerebellar cortex (4.4 ± 0.2), and others. Although regional differences were small, the observed [11C]CB184 binding pattern was consistent with the TSPO distribution in the normal human brain. Radiation dosimetry was determined in three healthy male subjects using a serial whole-body PET scan acquired over 2 h after [11C]CB184 injection. [11C]CB184 PET demonstrated high uptake in the gallbladder at a later time (>60 min). In urine obtained approximately 100 min post-injection, 0.3% of the total injected radioactivity was recovered, indicating hepatobiliary excretion of radioactivity. The absorbed dose (μGy/MBq) was highest in the kidneys (21.0 ± 0.5) followed by the lungs (16.8 ± 2.7), spleen (16.6 ± 6.6), and pancreas (16.5 ± 2.2). The estimated effective dose for [11C]CB184 was 5.9 ± 0.6 μSv/MBq. Conclusions This initial evaluation indicated that [11C]CB184 is feasible for imaging of TSPO in the brain. Electronic supplementary material The online version of this article (doi:10.1186/s13550-017-0271-6) contains supplementary material, which is available to authorized users.

Thalidomide is a TNF-alpha inhibitor and has been administrated for erythema nodosum leprosum (ENL, Type II leprosy reaction) which is one of leprosy reactions and can cause serious illness to patients oflepromatous pole among the immune spectrum. Twenty live cases (at May, 2011) were identified to whom thalidomide had been administrated since 1978 for their ENL reactions. Data were collected from their clinical records in order to evaluate the usage and effectiveness of thalidomide in National Sanatorium Oku-Komyoen, Okayama, Setouchi-city, Japan. Individual data includes bacillary index (BI), total dose, average daily dose, maximum daily dose, minimum daily dose, methods of thalidomide administration and change of symptoms of ENL. Results: No adverse effect was found among 20 cases. Average daily dose of 20 cases was 19 mg. Regarding to the maximum daily dose, in 3 cases (15%) more than 100 mg, in 3 cases (15%) 50 mg, and in 14 cases (70%) less than 40 mg was administrated. Dose was gradually tapered in most cases. From clinical records, thalidomide was found effective for ENL in 19 cases and clinicians concerned were trying to adjust the proper dose of the drug carefully depending on the current symptoms, because there was no guideline of thalidomide administration for ENL. This data suggests that even less than 50-100 mg as the initial daily dose was still effective, though 50-100 mg daily dose is recommended in the current guideline of Japan (2011) and more dose had been administrated in USA and India.

ad hoc committee of Japanese Leprosy Association recommends revised standard treatment protocol of leprosy in Japan, which is a modification of World Health Organization's multidrug therapy (WHO/MDT, 2010). For paucibacillary (PB) leprosy, 6 months treatment by rifampicin and dapsone (MDT/PB) is enough. However, for high bacterial load multibacillary (MB) leprosy, 12 months treatment seems insufficient. Thus, (A) For MB with bacterial index (BI)3 before treatment, 2 years treatment by rifampicin, dapsone and clofazimine (MDT/MB) is necessary. When BI becomes negative and active lesion is lost within 2 years, no maintenance therapy is necessary. When BI is still positive, one year of MDT/MB is added (3 years in total), followed by maintenance therapy by dapsone and clofazimine until BI negativity and loss of active lesions. (B) For MB with BI3 or fresh MB (less than 6 months after the onset of the disease) with BI3, 1 year treatment by MDT/MB is necessary. When BI becomes negative and active lesion is lost within one year, no maintenance therapy is necessary. When BI is still positive or active lesion is remaining, additional therapy with MDT/MB for one more year is recommended. Brief summary of diagnosis, purpose of therapy, character of drugs, and prevention of deformity is also described.

We performed preclinical and first-in-man clinical positron emission tomography (PET) studies in human brain using N,N-di-n-propyl-2-[2-(4-[(11)C]methoxyphenyl)-6,8-dichloroimidazol[1,2-a]pyridine-3-yl]acetamide ([(11)C]CB184) to image the 18-kDa translocator protein (TSPO), which is overexpressed in activated microglia in neuroinflammatory conditions.In vitro selectivity of CB184 was characterized. The radiation absorbed dose by [(11)C]CB184 in humans was calculated from murine distribution data. Acute toxicity of CB184 hydrochloride in rats at a dose of 5.81 mg/kg body weight, which is 10,000-fold higher than the clinical equivalent dose of [(11)C]CB184, was evaluated. Acute toxicity of [(11)C]CB184 injection of a 400-fold dose to administer a postulated dose of 740 MBq [(11)C]CB184 was also evaluated after the decay-out of (11)C. The mutagenicity of CB184 was studied with a reverse mutation test (Ames test). The pharmacological effect of CB184 injection in mice was studied with an open field test. The first PET imaging of TSPO with [(11)C]CB184 in a normal human volunteer was performed.A suitable preparation method for [(11)C]CB184 injection was established. CB184 showed low activity in a 28-standard receptor binding profile. The radiation absorbed dose by [(11)C]CB184 in humans was sufficiently low for clinical use, and no acute toxicity of CB184 or [(11)C]CB184 injection was found. No mutagenicity or apparent effect on locomotor activity or anxiety status was observed for CB184. We safely performed brain imaging with PET following administration of [(11)C]CB184 in a normal human volunteer. A 90-min dynamic scan showed rapid initial uptake of radioactivity in the brain followed by prompt clearance. [(11)C]CB184 was homogeneously distributed in the gray matter. The total distribution volume of [(11)C]CB184 was highest in the thalamus followed by the cerebellar cortex and elsewhere. Although regional differences were small, the observed [(11)C]CB184 binding pattern was consistent with the TSPO distribution in normal human brain. Peripherally, [(11)C]CB184 was metabolized in humans: 30 % of the radioactivity in plasma was detected as the unchanged form after 60 min.[(11)C]CB184 is suitable for imaging TSPO in human brain and provides an acceptable radiation dose. Pharmacological safety was noted at the dose required for PET imaging.

Short-lived radionuclides for positron emission tomography (PET) examinations in medicine are produced mainly using on site small cyclotrons. The operation of the cyclotron generates a significant quantity of neutrons, which will activate the cyclotron and surrounding materials. A new technique is proposed to estimate the neutron fluxes in the cyclotron rooms, in which small bolts in the cyclotron rooms were used as surrogates for neutron detectors. The measurements were carried out at four PET cyclotrons. The induced radioactivity of the bolts was analyzed by gamma-ray spectroscopy and elemental analysis. A gold foil activation method was applied to compare the results. The neutron fluxes in the PET cyclotron rooms were in the range of 105∼106 cm−2 s−1 during 18F production. In the brass bolts, 69mZn, 65Zn, 64Cu, 58Co, and 60Co were detected. In the iron bolts, 56Mn, 54Mn, 59Fe, 60Co, 69mZn, and 65Zn were detected. In the stainless steel bolts, 58Co, 60Co, 56Mn, 54Mn, and 59Fe were detected. Neutron fluxes estimated from the activities of 56Mn agreed well with those by the Au foil method. The feasibility of estimating the neutron fluxes in cyclotron rooms by means of radioactive analysis of bolts in the rooms was proven.

The number of positron emission tomography (PET) examinations has greatly increased world-wide. Since positron emission nuclides for the PET examinations have short half-lives, they are mainly produced using on-site cyclotrons. During the production of the nuclides, significant quantities of neutrons are generated from the cyclotrons. Neutrons have potential to activate the materials around the cyclotrons and cause exposure to the staff. To investigate quantities and distribution of the thermal neutrons, thermal neutron fluxes were measured around a PET cyclotron in a laboratory associating with a hospital. The cyclotron accelerates protons up to 18 MeV, and the mean particle current is 20 μA. The neutron fluxes were measured during both 18F production and C production. Gold foils and thermoluminescent dosimeter (TLD) badges were used to measure the neutron fluxes. The neutron fluxes in the target box averaged 9.3 × 10(6) cm(-2) s(-1) and 1.7 × 10(6) cm(-2) s(-1) during 18F and 11C production, respectively. Those in the cyclotron room averaged 4.1 × 10(5) cm(-2) s(-1) and 1.2 × 10(5) cm(-2) s(-1), respectively. Those outside the concrete wall shielding were estimated as being equal to or less than ∼3 cm s, which corresponded to 0.1 μSv h(-1) in effective dose. The neutron fluxes outside the concrete shielding were confirmed to be quite low compared to the legal limit.

Introduction The nicotinic acetylcholine receptor (nAChR) α7 subtype (α 7 nAChR) is one of the major nAChR subtypes in the brain. We synthesized C-11 labeled α 7 nAChR ligands, ( R )-2-[ 11 C]methylamino-benzoic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester ([ 11 C]( R )-MeQAA) and its isomer ( S )-[ 11 C]MeQAA, for in vivo investigation with positron emission tomography (PET). Then, the potential of ( R )- and ( S )-[ 11 C]MeQAA for in vivo imaging of α 7 nAChR in the brain was evaluated in mice and monkeys. Methods The binding affinity for α 7 nAChR was measured using rat brain. Biodistribution and in vivo receptor blocking studies were undertaken in mice. Dynamic PET scans were performed in conscious monkeys. Results The affinity for α 7 nAChR was 41 and 182 nM for ( R )- and ( S )-MeQAA, respectively. The initial uptake in the mouse brain was high ([ 11 C]( R )-MeQAA: 7.68 and [ 11 C]( S )-MeQAA: 6.65 %dose/g at 5 min). The clearance of [ 11 C]( R )-MeQAA was slow in the hippocampus (α 7 nAChR-rich region) but was rapid in the cerebellum (α 7 nAChR-poor region). On the other hand, the clearance was fast for [ 11 C]( S )-MeQAA in all regions. The brain uptake of [ 11 C]( R )-MeQAA was decreased by methyllycaconitine (α 7 nAChR antagonist) treatment. In monkeys, α 7 nAChRs were highly distributed in the thalamus and cortex but poorly distributed in the cerebellum. The high accumulation was observed in the cortex and thalamus for [ 11 C]( R )-MeQAA, while the uptake was rather homogeneous for [ 11 C]( S )-MeQAA. Conclusions [ 11 C]( R )-MeQAA was successfully synthesized and showed high uptake to the brain. However, since the in vivo selectivity for α 7 nAChR was not enough, further PET kinetic analysis or structure optimization is needed for specific visualization of brain α 7 nAChRs in vivo.

The transition of microglia from the normal resting state to the activated state is associated with an increased expression of peripheral benzodiazepine receptors (PBR). The extent of PBR expression is dependent on the level of microglial activation. A PBR ligand, [11C]PK11195, has been used for imaging of the activation of microglia in vivo. We evaluated whether [11C]PK11195 PET can indicate differences of microglial activation between no treatment and lipopolysaccharide (LPS) treatment in a rat artificial injury model of brain inflammation. On day 1, a small aliquot of absolute ethanol was injected into the rat right striatum (ST) to produce artificial brain injury. On day 3, MRI scans were performed to evaluate and select rats showing a similar degree of brain injury. Then LPS or vehicle was administered intraperitoneally. On day 4, PET scans were performed after a bolus injection of [11C]PK11195. Eleven rats (7 LPS administered rats, 4 LPS non-administered rats) were evaluated. We used uptake ratios of the integral of right and left striatum from 0 to 60 min as an estimate of PBR distribution volume (V 60). The number of activated microglia and mRNA expression of inflammatory cytokines (TNFα, IL-1β) were assessed by isolectin-B4 staining and RT-PCR, respectively. Right/left ST V 60 ratios of LPS group were significantly higher than those of non-LPS group (P

Positron emission tomography (PET) and single photon emission computed tomography (SPECT) are useful for non-invasive investigation of brain receptors. With these imaging techniques, changes in brain receptor densities and distributions during chronic drug treatments and disease progressions can be tracked for a long period. Appropriate radiolabeled imaging agents are necessary for PET and SPECT molecular imaging. Nicotinic acetylcholine receptors (nAChRs) play important roles in brain functions. The alpha4beta2 and alpha7 are the major nAChR subtypes in the brain. To date, several subtype selective radiolabeled ligands for nAChR have been reported. For the alpha4beta2 subtype, some agents are already applied for human studies, but only a few agents are developed for the alpha7 subtype. Here, we overview our results of [(125/123)I]5-iodo-3-(2(S)-azetidinylmethoxy)pyridine and 5-[11C]methyl-3-(2-(S)-azetidinylmethoxy)pyridine ([11C]5MA) for alpha4beta2 subtype imaging, and [11C](R)-2-methylamino-benzoic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester ([11C](R)-MeQAA) for alpha7 subtype imaging.

To investigate whether [(11)C]PK-11195, a specific peripheral benzodiazepine receptors (PBRs) ligand for positron emission tomography (PET), can show activated microglia in a rat brain injury model.On day 1, ethanol was injected into the rat's right striatum (ST) using a stereotaxic operative procedure. On day 3, head magnetic resonance imaging (MRI) scans for surgically treated rats were performed to evaluate ethanol injury morphologically. On day 4, dynamic PET scans (17 injured rats and 7 non-injured controls) were performed for 60 min with an animal PET scanner under chloral hydrate anesthesia following a bolus injection of [(11)C]PK-11195 through tail vein. Because PBRs are present throughout the brain, there is no suitable receptor-free reference region. The reference tissue model may not be applicable because of low target to background ratio for low affinity of [(11)C]PK-11195 to PBRs. We evaluated the PBRs binding with regions of interest (ROIs)-based approach to estimate total distribution volume (V). We used an integral from 0 min to 60 min (V (60)) as an estimate of V. On the coronal PET image, ROIs were placed on bilateral ST. Differences in right/left ST V (60) ratios between lesioned and unlesioned control rats were compared using unpaired t tests. Immunohistochemical staining was performed for confirming the presence of activated microglia following decapitation on the PET experiment day.The right/left ST V (60) ratios in lesioned rats (1.07 +/- 0.08) were significantly higher than those in unlesioned control rats (1.00 +/- 0.06, P0.05). On immunohistochemical staining, activated microglia were exclusively observed in the injured right ST but not in the noninjured left ST of the injury rats and the bilateral ST of the non-injured control rats.These results suggest that [(11)C]PK-11195 PET imaging would be a useful tool for evaluating microglial activation in a rat brain injury model.

Imidazopyridineacetoamide 5-8, a series of novel and potentially selective peripheral benzodiazepine receptor (PBR) ligands with affinities comparable to those of known PBR ligands, was investigated. Radiosyntheses of [11C]5, 6, 7 or 8 was accomplished by N-methylation of the corresponding desmethyl precursors with [11C]methyl iodide in the presence of NaH in dimethylformamide (DMF), resulting in 25% to 77% radiochemical yield and specific activitiy of 20 to 150 MBq/nmol. Each of the labeled compounds was injected in ddY mice, and the radioactivity and weight of dissected peripheral organs and brain regions were measured. Organ distribution of [11C]7 was consistent with the known PBR distribution. Moreover, [11C]7 showed the best combination of brain uptake and PBR binding, leading to its high retention in the olfactory bulb and cerebellum, areas where PBR density is high in mouse brain. Coinjection of PK11195 or unlabeled 7 significantly reduced the brain uptake of [11C]7. These results suggest that [11C]7 could be a useful radioligand for positron emission tomography imaging of PBRs.

The typical leprosy doctor is disappearing in Japan. One of the reasons for this is that no more new cases arise among people of Japanese nationality. Furthermore, among people of other nationality living in Japan, occurrence of the cases has become rare. At the same time, it has become difficult to get a new medical person for leprosy field because the interest for the overseas medical cooperation has become diversified and there is a misunderstanding that the problem of leprosy in the world has been resolved. However we need to keep speaking out that there are still much more to be done. When we fortunately have someone who wishes to become a leprologist, his/her training is only possible in the very site of NGO in developing countries. One may start his/her work by passionate motivation of “living together”, but actually he/she needs to be nurtured by people there. Another way to get involved is to first become a specialist of some sort, and then get in a medical system of a developing country as a narrow range specialist, and while serving them there, one can deepen his/her experiences as a whole leprosy.It is also important for us to think how we accept people who have worked overseas. We need to investigate and construct the supporting system for them. As long as leprosy patients exist in the world who are still suffering, we, as Japanese, need to make efforts in continuously sending people who live with them.

Nicotine injections and nicotine skin patches significantly improve attention, memory, and learning in Alzheimer's disease. In animal studies, nicotine improves the performance of various memory-related tasks, an effect that is thought to be mediated by the neuronal dopaminergic system as systemic administration of nicotine decreased [(11)C]raclopride binding in the anesthetized state. Since high doses of systemically administered nicotine are harmful, we administrated it directly into the rat striatum via microdialysis. We then examined the acute effects of continuous central administration of high doses of nicotine on striatal dopamine concentrations by measuring [(11)C]raclopride binding by positron emission tomography. The concentration of dopamine in the dialysates was significantly increased from basal levels when microdialysis with 100 mM nicotine was initiated. However, contrary to expectations, the binding potential (BP) of [(11)C]raclopride in the nicotine-perfused striatum was significantly higher than that in control striatum. Preinjection of mecamylamine (3 mg/kg), a nicotinic antagonist, had no effect on either extracellular dopamine levels or on the BP of [(11)C]raclopride. These findings suggest that the high dose of local nicotine administration induced mecamylamine-insensitive local increases in extracellular dopamine, but might have decreased the total amount of extracellular dopamine in the striatum.

The radioactive by-products contained in an entire series of target foil, [18O]H2O and synthesis apparatus were identified and quantified. From the perspective of waste management, 60Co induced in Havar foil should be taken into consideration. Because the exempt activity of 60Co in BSS is 0.1 MBq, the used Havar foil should be managed more than for 20 years. The radionuclides in the [18F]-FDG synthesis apparatus are negligible. Equivalent doses at skin and to tissues were estimated assuming a point source at a distance of 30 cm in air. The annual equivalent doses at skin and equivalent dose at deep tissues of such an operating staff will be 56 and 8.3 μSv, respectively, as two times the remove of the target foil and five hundreds times the synthesis of the [18F]-FDG. When proper radiation protection is provided, the exposure from the cyclotron management and the [18F]-FDG synthesis process will not cause meaningful radiological risk to the operating staff. The activity concentration of 3H, 180kBq-cm−3, de...

The association of the alpha(v)beta(3) integrin with tumor metastasis and tumor related angiogenesis has been suggested. Therefore, by imaging the alpha(v)beta(3) receptor with PET, information concerning the tumor status could be obtained. Cyclic peptides including the RGD sequence, were radiolabeled by direct electrophilic fluorination with [(18)F]AcOF. In tumor-bearing mice, the labeled peptides accumulated at the tumor with a high tumor to blood ratio. These findings suggest that an assessment of tumor characteristics may be obtained by using these (18)F-labeled peptides.

The purpose of this study was to determine the functional organization of the human brain involved in cross-modal discrimination between tactile and visual information. Regional cerebral blood flow was measured by positron emission tomography in nine right-handed volunteers during four discrimination tasks; tactile-tactile (TT), tactile-visual (TV), visual-tactile (VT), and visual-visual (VV). The subjects were asked either to look at digital cylinders of different diameters or to grasp the digital cylinders with the thumb and index finger of the right hand using haptic interfaces. Compared with the motor control task in which the subjects looked at and grasped cylinders of the same diameter, the right lateral prefrontal cortex and the right inferior parietal lobule were activated in all the four discrimination tasks. In addition, the dorsal premotor cortex, the ventral premotor cortex, and the inferior temporal cortex of the right hemisphere were activated during VT but not during TV. Our results suggest that the human brain mechanisms underlying cross-modal discrimination have two different pathways depending on the temporal order in which stimuli are presented.

Malfunctions of the dopaminergic system in Parkinson's disease are thought to affect motion, behavior, and cognition through the neural loops connecting the basal ganglia and the cerebral cortices. We investigated the pathophysiology using [F-18]FDOPA (fluorodopa) and [F-18]FDG (fluorodeoxyglucose) positron emission tomography (PET) in Parkinson's disease patients without apparent dementia (PD), PD patients with dementia (PDD), and age-matched normal control subjects (NC). PD patients showed significant declines of influx rate (Ki) values of [F-18]FDOPA in the bilateral striatum (dominant in the posterior and dorsal putamen) and substantia nigra. On the other hand, the PDD patients showed declines of Ki in the extrastriatal regions such as the medial frontal lobe and the hippocampus in addition to the striatum. Multi-volume projection (MVP) displayed that the decline of Ki was more widespread to the medial part of the midbrain in PDD than in PD. This area showing slight decrease of Ki was thought to correspond to the ventral tegmental area. The Ki value in the caudate head correlated with the glucose metabolism in the posterior cingulate, precuneus, and the parietotemporal area. The Ki value in the anterior cingulate correlated with the glucose metabolism in the anterior cingulate and left frontal association area. The results suggest that cerebral cortical functions are influenced by dopaminergic activities depending on its pathway. Cognitive disorder may be caused by the impaired mesolimbic dopaminergic system in Parkinson's disease.

Developing countries have their own unique characteristics, histories, and situation. There are great differences from country to country. From the experiences worked in both Bangladesh and Myanmar which share their border, some similarities and dissimilarities among these two greatly different countries are discussed. Considering this, common problems on leprosy in the developing countries are analyzed. The needs of developing countries in the field of leprosy are studied, and the possible way of corroboration for us, Japanese leprosy workers, are suggested.

N,N-di-n-propyl-2-[2-(4-[11C]methoxyphenyl)-6,8-dichloroimidazol[1,2-a]pyridine-3-yl]acetamide ([11C]CB184) is a novel selective radioligand for the 18-kD translocator protein (TSPO), which is upregulated in activated microglia in the brain, and may be useful in positron emission tomography (PET). We examined the safety, radiation dosimetry, and initial brain imaging with [11C]CB184 in healthy human volunteers. Dynamic [11C]CB184 PET scans (90 min) were performed in five healthy male subjects. During the scan, arterial blood was sampled at various time intervals, and the fraction of the parent compound in plasma was determined with high-performance liquid chromatography. No serious adverse events occurred in any of the subjects throughout the study period. [11C]CB184 was metabolized in the periphery: 36.7% ± 5.7% of the radioactivity in plasma was detected as the unchanged form after 60 min. The total distribution volume (V T) was estimated with a two-tissue compartment model. The V T of [11C]CB184 was highest in the thalamus (5.1 ± 0.4), followed by the cerebellar cortex (4.4 ± 0.2), and others. Although regional differences were small, the observed [11C]CB184 binding pattern was consistent with the TSPO distribution in the normal human brain. Radiation dosimetry was determined in three healthy male subjects using a serial whole-body PET scan acquired over 2 h after [11C]CB184 injection. [11C]CB184 PET demonstrated high uptake in the gallbladder at a later time (>60 min). In urine obtained approximately 100 min post-injection, 0.3% of the total injected radioactivity was recovered, indicating hepatobiliary excretion of radioactivity. The absorbed dose (μGy/MBq) was highest in the kidneys (21.0 ± 0.5) followed by the lungs (16.8 ± 2.7), spleen (16.6 ± 6.6), and pancreas (16.5 ± 2.2). The estimated effective dose for [11C]CB184 was 5.9 ± 0.6 μSv/MBq. This initial evaluation indicated that [11C]CB184 is feasible for imaging of TSPO in the brain.

Major membrane protein II (MMP II) of Mycobacterium leprae ( M. leprae ) is a 22 kDa protein inducing humoral immune response in leprosy patients. MMP II-specific bulk T cell lines were established from leprosy patients to determine major T cell epitopes in MMP II and to evaluate lymphokine production induced by MMP II. These bulk T cell lines reacted to one or more peptides in the locus of amino acid residues from 23 to 109 of MMP II. The proliferative responses of all T cell lines were mainly inhibited by the addition of anti-DRB1 mAb. Many bulk T cell lines induced IFN-γ, IL-5, but not IL-4. However, it was not possible to distinguish the LL or TT types of leprosy based on the pattern of T cell epitopes and the lymphokine productivity in the responses against MMP II. Thus, it appears that T cell response to MMP II is restricted by the HLA-DRB1 molecule, but not by DQ and DP molecules, which results in the induction of IFN-γ production.

Identification of familiar people is essential in our social life. We can identify familiar people by hearing their voices as well as by viewing their faces. By measuring regional cerebral blood flow (rCBF) by positron emission tomography (PET), we identified neural substrates for the recognition of familiar voices. The brain activity during discrimination of voices of the subjects' associates and friends from those of unfamiliar people was compared with that during an analogous discrimination of their own voice from unfamiliar voices as well as during vowel discrimination. The left frontal pole, right temporal pole, right entorhinal cortex, and left precuneus were activated to a greater extent during discrimination of familiar voice than during control discriminations, suggesting that these brain regions are involved in the recognition of familiar voices. Furthermore, the adjusted values of rCBF in the left frontal pole and right temporal pole correlated with the number of subjects' correct identification of familiar voices. The present results suggest that these two regions are coactively associated with matching the currently heard voice to familiar voices in one's memory.

This study aimed to develop a new system, named CD-Well, for mouse PET dynamic study. CD-Well allows the determination of time-activity curves (TACs) for arterial whole blood and plasma using 2-3 µL of blood per sample; the minute sample size is ideal for studies in small animals. The system has the following merits: (1) measures volume and radioactivity of whole blood and plasma separately; (2) allows measurements at 10 s intervals to capture initial rapid changes in the TAC; and (3) is compact and easy to handle, minimizes blood loss from sampling, and delay and dispersion of the TAC. CD-Well has 36 U-shaped channels. A drop of blood is sampled into the opening of the channel and stored there. After serial sampling is completed, CD-Well is centrifuged and scanned using a flatbed scanner to define the regions of plasma and blood cells. The length measured is converted to volume because the channels have a precise and uniform cross section. Then, CD-Well is exposed to an imaging plate to measure radioactivity. Finally, radioactivity concentrations are computed. We evaluated the performance of CD-Well in in vitro measurement and in vivo (18)F-fluorodeoxyglucose and [(11)C]2-carbomethoxy-3β-(4-fluorophenyl) tropane studies. In in vitro evaluation, per cent differences (mean±SE) from manual measurement were 4.4±3.6% for whole blood and 4.0±3.5% for plasma across the typical range of radioactivity measured in mouse dynamic study. In in vivo studies, reasonable TACs were obtained. The peaks were captured well, and the time courses coincided well with the TAC derived from PET imaging of the heart chamber. The total blood loss was less than 200 µL, which had no physiological effect on the mice. CD-Well demonstrates satisfactory performance, and is useful for mouse PET dynamic study.

The aim of this study was to define the mean regional 6-[(18)F]fluoro-l-dopa (FDOPA) uptake rate constant (K(i)) values in the striatal and extrastriatal regions of the brain of normal subjects using magnetic resonance imaging (MRI)-aided spatial normalization of the FDOPA K(i) image and using automatic region of interest (ROI) analysis. Dynamic three-dimensional FDOPA positron emission tomography (PET) and three-dimensional magnetic resonance (MR) images were acquired in 13 aged normal subjects. The FDOPA add image and the K(i) image of each subject were transformed into standard stereotactic space with the aid of individual coregistered MR image. The mean regional K(i) values of the striatal and extrastriatal regions before normalization were compared with the respective values after normalization. Then automatic ROI analysis was performed on the MRI-aided spatially normalized K(i) images of the 13 normal subjects. The K(i) values on original images and those on spatially normalized images were in good agreement, indicating that the spatial normalization technique did not change the regional K(i) values appreciably. Automatic ROI analysis of the spatially normalized FDOPA K(i) images of the normal subjects, showed high K(i) values in ventral and dorsal regions of the midbrain, amygdala, hippocampus, and medial prefrontal cortex, in addition to caudate nucleus and putamen, which correspond to the dopaminergic projections in the brain. Spatial normalization technique helped to establish a database of FDOPA K(i) images of normal subjects and high K(i) values were observed widely besides striatal regions corresponding to the dopaminergic projections in the brain.

Social contact often initially depends on ascertaining the direction of the other person's gaze. We determined the brain areas involved in gaze monitoring by a functional neuroimaging study. Discrimination between the direction of gaze significantly activated a region in the left amygdala during eye-contact and no eye-contact tasks to the same extent. However, a region in the right amygdala was specifically activated only during the eye-contact task. Results confirm that the left amygdala plays a general role in the interpretation of eye gaze direction, and that the activity of the right amygdala of the subject increases when another individual's gaze is directed towards him. This suggests that the human amygdala plays a role in reading social signals from the face.

Ether-linked analogs of fluorine-18 labeled diacylglycerol were synthesized in order to improve their bioavailability in vivo. Compounds were designed to have long chain (having sixteen carbons) alkyl substituent on 1-O-position and short alkyl or acyl group (eight carbons) on 2-O-position of glycerol. Introduction of 18 F into each chain resulted in four labeled tracers. Precursors having tosyloxy or bromo moiety as leaving group were obtained step wise alkylations and/or acylations of 3-O-benzylglycerol. Nucleophilic radiofluorination of the precursors thus obtained gave labeled intermediates in up to 40% radiochemical yield. Ether-linked diacylglycerol analogs were afforded through their deprotection with H2 and Pd/C. Catalytic transfer hydrogenation was also attempted, however, insufficient result was achieved in spite of its usefulness as labeling procedure.

N-(4-Phenylbutyl)-4-(4-fluorobenzoyl)piperidine [4-PBFBP] shows highly selective binding to serotonin 5-HT 2A receptors with high affinity. In this study, we prepared [ 18 F]4-PBFBP for in vivo study of 5-HT 2A receptors in the brain using positron emission tomography (PET). Nucleophilic aromatic displacement of N-(4-phenylbutyl)-4-(4-nitrobenzoyl)piperidine by no carrier added [ 18 F]fluoride which was solubilized by Kryptofix 222 in DMSO produced [ 18 F]4-PBFBP with high specific radioactivity. The product was purified by reversed phase preparative HPLC and was extracted from the collected eluate by SEP-PAK® C18 cartridge prior to formulation. The radiochemical yield of the final product was 15 ± 1.8 % (mean ± S.D. of three experiments) with decay correction and the specific activity was 113 ± 27 GBq/μmol (mean ± S.D. of three experiments) at E.O.S. after a total preparation time of about 160 min. The radiochemical purity of [ 18 F]4-PBFBP was more than 99 %. The regional distribution of [ 18 F]4-PBFBP in mouse brain was also examined.

N,N-Dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine (NE-100) was labeled with 11C in two different positions by the alkylation of an N-despropyl precursor with [11C]propyl iodide and of an O-desmethyl precursor with [11C]methyl iodide and was evaluated for the potential as a tracer for mapping sigma 1 receptors in the CNS and peripheral organs by PET. Following i.v. injection of [N-propyl-11C]NE-100 or [O-methyl-11C]NE-100 into mice, the two tracers showed similar tissue distribution patterns except for the liver and brain. With the coinjected carrier NE-100 or haloperidol, the uptake of [N-propyl-11C]NE-100 by the liver, pancreas and spleen was significantly decreased at 15 min after injection, whereas the effect was not significant for [O-methyl-11C]NE-100. The coinjection of NE-100 enhanced the brain uptake of the two tracers. Haloperidol also enhanced the brain uptake of [N-propyl-11C]NE-100, but not that of [O-methyl-11C]NE-100. The regional brain distribution assessed with [O-methyl-3H]NE-100 was consistent with the distribution pattern of the sigma receptors. Four sigma drugs reduced the regional brain uptake of [O-methyl-3H]NE-100 to 70%-90% of the control. In an ex vivo autoradiographic study of the rat brain, the uptake of [O-methyl-11C]NE-100 was blocked by carrier NE-100 or haloperidol (53%-59% of the control in the cortex), which suggests a receptor-specific distribution. These results show that [O-methyl-11C]NE-100 has limited potential as a PET ligand for mapping sigma 1 receptors in the peripheral organs and the CNS because of high nonspecific binding.

Frontal cortical damage can lead to changes in affective aspects of personality. However, the difficulty of dissociating such abnormalities from cognitive disorders has overshadowed most previous findings. Regional cerebral blood flow (rCBF) was measured with positron emission tomography (PET) while normal subjects were assessing facial attractiveness. Two left frontal regions showed a significant increase in rCBF while assessing facial attractiveness. The increased rCBF in the left anterior frontal cortex correlated with the overall percentage of assessments of a face as unattractive, while that in the left fronto-temporal junction correlated with the percentage of assessments of a face as attractive. These findings provide direct evidence that the left frontal regions are engaged in the assessment of facial attractiveness.

We have examined in leprosy in Bangladesh the change in the rate of peripheral nerve damage before and after the treatment. In the well-organized NGO program where the early diagnose is given, the damage rate improves slightly during the treatment. But among the MB cases, it has been found that the damage rate taken at the time of patient's first check-up still stays high. Furthermore, during the treatment of MB cases, 72% cases show the episode of neuritis, and even during two years of observation period after treatment, 15% cases show the same episode. Among the recurrent cases of last ten years in Oku-Komyo-en, we have looked into the ways of drugs prescribed for the treatment of previous recurrent term in the double recurrent cases. In these prescription, the amount of each dosage was relatively a little and the prescription period was rather long. In RFP, prescription frequency was relatively high, and in DDS and CLF, they were low. We think that the treatment of leprosy in Japan should be based on WHO's regimen. However before making Japanese regimen, it is necessary to discuss more when to finish the treatment.

Regional cerebral blood flow was measured in six healthy volunteers by positron emission tomography during identification of speaker and emotion from spoken words. The speaker identification task activated several audio-visual multimodal areas, particularly the temporal poles in both hemispheres, which may be involved in connecting vocal attributes with the visual representations of speakers. The emotion identification task activated regions in the cerebellum and the frontal lobe, suggesting a functional relationship between those regions involved in emotion. The results suggest that different anatomical structures contribute to the vocal identification of speaker and emotion.