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The low-level radioactivity of a (68)Ge/(68)Ga generator is a suitable tool for measuring radioactive growth and decay after (68)Ga milking due to their desirable nuclear decay properties, such as the EC decay of (68)Ge with no γ-ray emission andthe β(+) decay of (68)Ga with a weak γ-ray emission. To experience andund erstandrad ioactive equilibrium during a university laboratory course, we surveyedandtestedthe production of a small amount of (68)Ge and set up educational programs to manufacture a (68)Ge/(68)Ga generator for measuring the growth andd ecay of (68)Ga. The irradiation of natGa with 25 μA of a 30 MeV proton beam from a cyclotron for 4 h yields ca. 111 MBq of (68)Ge, which was sufficient to supply to several universities. For use as the adsorbent of the generator column, particles of hydrated tin (VI) oxide were prepared from precipitated tin hydroxide gel. Repeated elution of (68)Ga from the handmade (68)Ge/(68)Ga generator gave constant amounts of (68)Ga with acceptable breakthrough of (68)Ge. The feedback from the student's experience with the (68)Ge/(68)Ga generator was evaluatedby annual questionnaire surveys, which were given to all students taking the course every year from 2012 to 2014. It has been made clear that more than half of the students were interested in the (68)Ge/(68)Ga generator program, andthis interest increasedfrom 54.9%in 2012 to 78.6%in 2014. A low-level radioactive (68)Ge/(68)Ga generator is thus expectedto be a suitable experimental tool for demonstrating the phenomenon of radioactivity to students in an intriguing way.

Positron emission tomography (PET) radiotracers have very short physical half-lives. It is hard to complete a bacterial endotoxins test prior to release from medical institutes. For endotoxin quantitative determination, limulus amebocyte lysate (LAL) reagent and kinetic-turbidimetry system were previously developed. We investigated the possibility of a short time test by means of positively charged filters. As a result of this study, the effects of positively charged filters on endotoin removal were over 99.5% for [18F]FDG and [18F]NaF, which were contaminated with the indicated concentration of endotoxin. Combining this filter and the kinetic-turbidimetric method, it was possible to complete a bacterial endotoxins test in 5 min prior to the patient's administration. This test should be required prior to release for PET radiopharmaceutical quality control. It has been suggested that this combination is a good method for this purpose.

6-[18F]Fluoro-L-dopa (L-3,4-dihydroxy-6-[18F]fluorophenylalanine; 6-[18F]FDPA) is useful to assess presynaptic dopamine metabolism in central nervous system. In this paper, we report on the usefulness of the 6-[18F]FDOPA synthesis system developed for the routine synthesis. This system consists of the 6-[18F]FOPA synthesis and the separation units in conjunction with controller using a personal computer. The synthesis time of 6-[18F]FDOPA was 73 minutes. The typical yield and specific activity were 1.4-2.4 GBq and 244-270 MBq/mumol at the end of synthesis, respectively, under the irradiation condition of 50 microA for 130 minutes. The radiochemical yields of 6-[18F]FDOPA were 31.3-38.7% based on the [18F]acetylhypofluorite, and the results were affected with the condition of potassium acetate (AcOK) to produce gaseous [18F]acetylhypofluorite. This system is useful for the routine production of 6-[18F]FDOPA because of its high yield and high specific activity while maintaining AcOK in good condition, and decreasing the radiation exposure for chemist.

We measured regional distribution of the muscarinic cholinergic receptor in the normal human brain with 11C-benztropine (BZT) and positron emission tomography (PET) using an anatomical standardization technique. Seven normal volunteers who gave informed consents were involved in this study. Immediately after intravenous injection of 11C-BZT into the subjects, we started dynamic PET scanning and serial frequent arterial blood sampling. Analyses of plasma metabolites were also performed at selected time points and plasma time activity curves (TAC) of unmetabolized ligand were generated. From these PET and TAC data, we obtained Patlak plot slope calculation images. Using the HBA (human brain atlas) system, the Patlak plot slope calculation image of each subject was transformed into the shape of the standard brain. Mean and standard deviation (SD) calculation images were generated from those anatomically standardized images. On these mean and SD images, we placed regions of interest which were previously outlined on a MR image of the standard brain. From those data, we found the highest receptor distribution in the striatum and occipital cortex, as well as high distribution in the frontal, parietal, and temporal cortices, which were consistent with previous reports. These results suggested that anatomical standardization of PET receptor images with 11C-BZT will be useful for delineating the physiological or pathological alterations of the muscarinic cholinergic receptor in the human brain.

A [15O]water production and infusion system was newly developed for blood flow study with positron emission tomography. The system utilizes a electrostatic cooling unit to liquify [15O]vapor in a coiled plastic tube. Labeled [15O]water is collected into an infusion syringe by a wash of the trapping tube with saline. The system is simple and efficient; the recovery rate of [15O]water is over 90% at 10 degrees C of cooling temperature.

Measurement of cerebral blood flow and energy metabolism using PET with 15O and 18F labeled tracers allows quantitative evaluation of cerebral metabolism that can be perturbed in pathological states. Neurotransmission is a new target that is visualized by labeling of substrates of enzymes that are involved in neurotransmitter synthesis or degradation. Neuronal receptors are mapped by introducing the labeled ligands that are specifically bound to the receptors in question. We developed unique tracers that label dopamine D2 or histamine H1 receptors. With other available ligands for the muscarinic cholinergic receptors and [18F] fluorodopa, we started clinical investigations to document the state of neurotransmission in patients with epilepsy, Parkinson's disease and dementia. Using [11C] doxepin we observed an increase of H1 receptors in the epileptic foci that showed decreased glucose metabolic rate at the interictal phase. This phenomenon is compatible with reported increase of mu opiate receptors in the brains of epileptic patients. Brain uptake of FDOPA (Ki), calculated by the graphical plot was found relatively stable with age both in the normal population and dementia patients. However, the striatal Ki of FDOPA of severely demented patients significantly reduced, compared with the normal aged subjects. The correlation analysis between FDOPA Ki and severity of dementia as assessed by mini-mental state examination revealed a significant reduction of Ki associated with the disease progression. Increase in D2 receptor density as assessed by the uptake of YM 09151-2 was observed in cases with reduced FDOPA uptake, which may correspond to the state of supersensitivity of the D2 receptors.

To elucidate the synaptic transmission in the neural system, we have been developing fundamental studies for intracellular signaling. For clinical application of carbon-11 labeled diacylglycerol (1-[1-11C]butyryl-2-palmitoyl-rac-glycerol: 11C-DAG) using positron emission computed tomography (PET), we evaluated the quality and the safety of 11C-DAG as the solution for injection. As a result, 11C-DAG was synthesized within 50 minutes, including the preparation step for injection. The half life time and energy spectrum of 11C-DAG were the same as the physical character of carbon-11, and other radioisotopes were not detected. In the quality control, 11C-DAG solution was negative in the examination of bacterial contamination and the pyrogen test in three successive synthesis procedures. In the acute toxicity test by administration of 11C-DAG and 100 mumol/kg of non-radioactive DAG to the rat intravenously, the systemic condition of the rat was not changed and no abnormalities were found in any organ 24 hours after administration. These findings indicated the safety of 11C-DAG solution. Clinical application of 11C-DAG using positron emission tomography may be useful to elucidate the dysfunction of intracellular signaling in disorders of higher cortical function such as Alzheimer disease.

Carbon-11 labeled diacylglycerol (11C-DAG) has been developed as a signal transduction imaging agent for the CNS, and it can visualize the second messenger. For clinical application by positron CT (PET), the 11C-DAG solution must be prepared for intravenous injection. However, the 11C-DAG does not dissolve in water because of its lipophilicity and requires a solubilizer such as human serum albumin (HSA) and Tween 80 (TW-80). We examined the influence of these solubilizers on the tissue distribution of 11C-DAG, and estimated the radiation dosimetry. In the brain, uptake of 11C-DAG dissolved with HSA was 1.3-1.8 times higher than that of dissolved with TW-80. On the other hand, the lung and spleen showed a higher uptake of 11C-DAG using TW-80 than when using HSA. Especially, the lungs showed 20-40 times higher uptake than when using HSA. Also, the washout of radioactivity from tissue was slower, and the dose of radiation exposure was estimated to be higher, with TW-80 than with HSA. Therefore, between TW-80 and HSA with different solubilizing mechanisms, the later was suggested to be a better solubilizer of 11C-DAG.

18F-fluorodeoxygalactose (18FDGal) is a tracer for the evaluation of galactose metabolism in the tissue. PET with 18FDGal was performed in a hepatoma (HCC) patient with lumbar bone metastasis. The image at 45 min after i.v. injection of 18FDGal demonstrated very high uptake by the bone metastasis with tumor-to-surrounding normal tissue ratio of 36. The tumor uptake expressed by differential absorption ratio was much higher than that in the cirrhotic liver and kidney. The result indicated that the HCC maintained high activity of galactose metabolism and rises the potential of this tracer for detecting extrahepatic metastases of HCC using PET.

To demonstrate the distribution of 2-deoxy-2-18F-fluoro-D-glucose (FDG) within the tumor in vivo, C3H/He mice transplanted with FM3A tumors were studied one hour after intravenous injection of FDG using whole-body, macro- and micro-autoradiography. The whole-body autoradiograph showed that the tumor mass as well as the brain, heart, bone marrows, and the diaphragm and crus diaphragm were clearly visualized. The macro-autoradiograph showed the heterogeneous distribution of FDG in the tumor mass. Markedly dense areas surrounding the tumor and the necrotic area were observed. Micro-autoradiograph showed the high grain densities in the macrophages between the necrosis and viable tumor cells, and in the young granulation tissues demarcating between the tumor and surrounding intact host tissues. Our results showed that the FDG uptake in the tumors may reflect not only the uptake by the tumor cells but also that by the inflammatory reaction elements.

A system was developed for producing short-lived radioactive substances (11CO, 11CO2, 13NN, 13NH3, 18F-, 62Zn2+, 123I-, etc.) on a scale enough for clinical use, which could also be used for analyzing them rapidly and for investigating their production methods, with less received dose by workers. The system enabled us to produce remotely several tens mCi of of short-lived radioactive susbtances readily usable for clinical diagnosis, continuosly for radioactive gases, 11CO, 11CO2 and 13NN, or repeatedly at short intervals for radioactive aqueous solutions of 13NH3, 18F-, etc. Employing this system, the average received dose per month was reduced considerably.

A simple method has been developed for the production of 13NN and 15OO by proton irradiation of aqueous solutions. 90 mCi of 13NN was obtained in a 200 ml. of He by using 1.0M NH4CI solution at pH 11 as the target with 10 min irradiation of 15 MeV, 10 microamperemeter protons. 80 mCi/min of 15OO was continuously obtained in a 200 ml of O2 by using pure water as the target with 40 MeV, 2 microamperemeter protons. The radiochemical purity of these short-lived radioactive gases obtained by this method was greater than 99.9% by passing through a single absorber.

Computerized digital image analysis of the optic nerve heads of 17 eyes with various sizes of optic disc cupping was performed using two kinds of three dimensional image analyzers, the IMAGEnet and the Optic Nerve Head Analyzer (ONHA). Intraphotographic error variances of measurements with both instruments were evaluated by measuring each image of the optic discs twice. The mean coefficient of variation (CV) with the IMAGEnet for the vertical cup/disc ratio, the horizontal cup/disc ratio, the cup volume, the rim area, and the rim area/disc area ratio were 3.75%, 3.03%, 7.89%, 2.55% and 1.36%, respectively. With the ONHA, the mean CV for the total cup/disc ratio, the cup volume, the rim area, and the rim area/disc area ratio were 0.82%, 0.21%, 2.39%, and 1.56%, respectively. The value of the cup/disc ratio and the cup volume obtained by the IMAGEnet was smaller than those by the ONHA (p greater than 0.1). Conversely, the rim area and rim area/disc area ratio measured by the IMAGEnet were statistically significantly larger than those by the ONHA (p = 0.01). Statistically significantly positive correlation was demonstrated for measurements made by both instruments in all disc parameters (p less than 0.01). These results seem to indicate the high reliability of the two instruments, however, further investigation is needed for the evaluation of the accuracy of measurements.

Although adrenal scintigraphy with 131I-6 beta-iodomethyl-19-norcholesterol (NCL-6-131I) was used for the first noninvasive imaging of the adrenal glands, it has the disadvantages. These are: (i) relatively high radiation dose to patients, (ii) the long time required for completion of the scan. To solve these problems, 123I-labeled 6 beta-iodomethyl-19-norcholesterol (NCL-6-123I) was synthesized and was used for adrenal scintigraphy in 6 cases. Successful images were obtained with 185 MBq (5 mCi)-260 MBq (7 mCi) of NCL-6-123I, and optimal time required for the satisfactory scan was 2-3 days after the administration. The estimate radiation dose was reduced by using 185 MBq (5 mCi) of NCL-6-123I instead of 18.5 MBq (0.5 mCi) of NCL-6-131I. From the result of this clinical study, NCL-6-123I was preferred for the adrenal scintigraphy.

A fully automated apparatus for repeated production of 13NH3 from proton-bombarded water has been developed. Its operation sequence consists of the introduction of NaOH, the bombarded water containing 13NO3- and TiCl3 into a reaction vessel, the distillation of 13NH3 formed by the reduction of the 13NO3-, and the washing of the vessel for the next sequence. The NaOH and TiCl3 are added as 4 ml of saturated solution and 4 ml of 10% aqueous solution, respectively, and halogen lamps are used as the heat source for the distillation. By this apparatus, 13NH3 can be produced automatically and repeatedly in a radiochemical yield of 80-90% within 10 min from the EOB.

Ischemia causes disturbances of the ionic equilibrium, i.e., Na+ and water influx and K+ efflux. When the ischemic tissue keeps contact with cerebral blood flow, brain tissue equilibrates with systemic circulation and consequently shifts of electrolytes and water are induced. Therefore, brain edema should initiate in the peripheral area of focal cerebral ischemia. To test this hypothesis, we performed the following experiments. Focal ischemia was induced by occlusion of the right common carotid artery in gerbils and by embolization with microspheres in rats. Water and electrolyte content was determined using punched out samples and regional K+ and Ca2+ distribution was visualized by histochemical K+ staining and 45Ca-autoradiography, respectively. Cerebral blood flow and glucose metabolism were evaluated by 14C-iodoantipyrine or 18F-fluoroantipyrine and 14C-deoxyglucose autoradiographies, respectively. Two hours of ischemia in gerbils with definite hemiparesis caused K+ depletion in the ischemic area, often most pronounced in the periphery of the lesion. Water content of cerebral cortex was 79.0 +/- 0.9, 82.0 +/- 1.0, 80.7 +/- 0.9 (%; mean +/- SD) for nonischemic, periphery and center of ischemia, respectively (significantly different with each other). Na+ content was increased and K+ content was decreased most prominently in the periphery of ischemia. Exogenous Ca2+ was also accumulated in the periphery. In the embolized stroke in rats, K+ depletion and Ca2+ accumulation obviously rimmed the ischemic focus. Furthermore the infarcted area was only part of the disturbed area of acute-phase glucose metabolism. Thus water and ionic disturbances were different between in the periphery and in the center of focal cerebral ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Caffeine, ephedrine and methylephedrine were labeled with carbon-11 by the action of methyliodide-11C on theophylline, norephedrine and ephedrine, respectively. Caffeine-11C was prepared in 44 min with a radiochemical yield of 40%, ephedrine-11C in 45 min with a 11% radiochemical yield and methylephedrine-11C in 36 min with a 43% radiochemical yield. When injected in mice intravenously, these products show a high uptake in the liver, the kidney and the blood for caffeine-11C and in the liver and the kidney for ephedrine-11C and methylephedrine-11C. The brain uptake for these products was found to be 2.4 to 3.9% of the injected dose per gram at 5 min after injection. These studies in mice have demonstrated that these products are potentially useful agents for the dynamic studies of the brain.

The technique of freezing whole body autoradiography using positron emitting nuclides has been developed in the present study. Because of rapid decay of positron emitters, a frozen section to contact with a X-ray film must be prepared within a few hours. All the procedures to obtain autoradiograms of rats using 18F-2-deoxy-2-fluoro-D-glucose (18F-FDG) or 11C-glucose-fructose mixture (11C-glucose) were described in detail. In the present technique, exposure must be performed at -20 degrees C to keep a section frozen. Density of X-ray films after exposure at 20 degrees C or -20 degrees C was examined using various radioactive sections. The reduction of the density exposed at -20 degrees C was observed. But the density exposed at -20 degrees C was proportional to the radioactivity. Freezing whole body autoradiography of rats bearing subcutaneous AH109A tumors was performed using 18F-FDG (half life of 109.7 min) and 11C-glucose (half life of 20 min). Density of tumors and other organs on the autoradiogram was comparable with tissue distribution studies of 18F-FDG and 11C-glucose. Freezing whole body autoradiography can be feasible for the analysis of tissue distribution on positron emitting radiopharmaceuticals.

We investigated glucose and amino acid metabolism in tumors and other organs using whole body autoradiography with a short-lived positron emitter and a long-lived beta emitter. The radioactive compounds used were 2-deoxy-2-[18F]-fluoro-D-glucose (18F-FDG) with a half life of 109.8 min and L-[methyl-14C]-methionine (14C-MET) with a half life of 5,730 years. A Donryu rat weighing about 150 g was subcutaneously inoculated at the back with experimental tumors of AH109A and AH272. 74 MBq (2 mCi) of 18F-FDG and 740 kBq (20 microCi) of 14C-MET was administered and after 30 min, the rat was sacrificed. Whole body frozen sections were obtained using autocryotome. For the 18F-FDG autoradiogram, the frozen sections were exposed to an X-ray film for 6 h. After seven days, these frozen sections were again exposed to 14C-MET for a week. Cross-contamination was minimized by adjusting the exposure time, the interval of exposures and the administered dose. The accumulation of the tracers was represented as the optical density ratio of the tissue of interest to the muscle. The tumor ratios were 12.5 for 18F-FDG and 8.6 for 14C-MET showing the highest accumulation in the whole body autoradiogram. In contrast the inflammatory tissue ratios were 1.27 for 18F-FDG and 0.77 for 14C-MET showing very low amino acid metabolism. With the present double tracer whole body autoradiogram, 18F-FDG accumulation was seen in the brain and the heart but not to the liver as against 14C-MET accumulation which was seen to the liver but not to the brain and the heart.

A fully automated synthesis system of 11C-glucose by the photosynthesis method has been developed for clinical use. This system has been designed to be as convenient as possible for routine use, and the full automation of the whole procedure from the target gas recovery to collection of the final 11C-glucose/fructose mixture has been accomplished by microcomputer control. A mixture of 11C-glucose/fructose (1:1) was obtained with 20 approximately 35% of radiochemical yield within 60 min.