Biomedical subjects
T J Ruth
Publications and source records attributed to T J Ruth.
Altered metabolism of [18F]-6-fluorodopa in the hooded rat following inhibition of catechol-O-methyltransferase with U-0521.
[18F]-6-Fluoro-L-DOPA ([18F]DOPA), a tracer for cerebral dopamine in studies utilizing positron emission tomography (PET), is rapidly metabolized by catechol-O-methyltransferase (COMT) in the periphery following intravenous injection to carbidopa-pretreated humans and rats. Experiments were performed to determine the effect of pretreatment with 3',4'-dihydroxy-2-methyl-propiophenone (U-0521), a competitive inhibitor of COMT, on [18F]DOPA metabolism in the carbidopa-pretreated hooded rat. U-0521 (25 mg/kg, i.p.), administered 10 min prior to the [18F]DOPA, served to increase the persistence of [18F]DOPA in plasma over a 2-hr period by decreasing the rate of formation of the peripheral metabolite 3-O-methyl-6-fluorotyrosine (Me[18F]DOPA). This compound passes readily into brain and was the sole [18F]DOPA metabolite observed in cortex and cerebellum. U-0521 produced a short-lasting decrease in Me[18F]DOPA levels in these two tissues. In striatum, decreases in Me[18F]DOPA were found to last at least 90 min. Associated with the elevated availability of [18F]DOPA in plasma produced by U-0521 were 50% increases in striatal [18F]dopamine ([18F]DA) levels and 40% increases in the levels of [18F]dihydroxyphenylacetic acid ([18F]DOPAC) at times between 30 and 90 min following [18F]DOPA injection. Increased decarboxylation of [18F]DOPA in the striatum of U-0521-treated rats resulted in heightened radiocontrast between striatum and other cerebral tissues.
Lesions of the putamen: their relevance to dystonia.
Two patients with acquired dystonia were studied by computed imaging techniques and found to have lesions predominantly involving the putamen. The implications of these findings are discussed, and it is concluded that, for the genesis of dystonia, a relative increase of other inputs to the pallidum may be important, such as those from the caudate and subthalamic nuclei.
Positron emission tomography in Parkinson's disease: glucose and DOPA metabolism.
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Routine synthesis of carbon-11-carboxyl-labeled L-dopa.
Carbon-11-carboxyl-labeled L-dopa has been synthesized by the modified Bucherer-Strecker method. The reaction mixture was first purified by chiral HPLC followed by deprotection using hydriodic acid. The entire procedure was performed in a remotely operated system which gave the product in 28% radiochemical yield (decay corrected) in an overall synthesis time of 55-60 min.
Synthesis and murine tissue uptake of sodium [18F]fluoroacetate.
Fluoroacetate (FAc) is well known as the rodenticide "1080" and for its potent biochemical properties, but much less is known about its behavior in vivo. In order to study this behavior, the compound was labeled with 18F. The synthesis was accomplished in good yields (30%) from carrier-added radiofluorine gas by its conversion to [18F]tetrabutylammonium fluoride, followed by a heat-assisted halogen exchange with ethylbromoacetate. The isolated ester was rapidly and quantitatively hydrolysed with base to form [18F]FAc. preliminary studies in mice revealed relatively little soft tissue retention over the 4 h study period. However, substantial bone accumulation, indicative of defluorination, occurred to a significant degree.
PET studies of cerebral glucose metabolism in idiopathic torticollis.
Regional cerebral glucose metabolism was studied in 16 patients with idiopathic torticollis, using positron emission tomography. Analysis of subcortical regions revealed no consistent focal abnormality of cerebral metabolic rate for glucose, but there was a bilateral breakdown of the normal relationships between the thalamus and basal ganglia. The findings suggest disruption of the pallidothalamic projections in this focal dystonia and may imply a disturbance of GABA.
Routine synthesis of L-[18F]6-fluorodopa with fluorine-18 acetyl hypofluorite.
The synthesis of L-[18F]6-fluorodopa (2.4-10.6 mCi) was done by passing gaseous [18F]acetyl hypofluorite through a solution of L-methyl-N- acetyl-[beta-(3-methoxy-4-acetoxyphenyl)]alaninate in acetic acid at room temperature followed by the hydrolysis of the intermediate products with concentrated hydriodic acid. The desired fluorodopa isomer was isolated in 8% EOB radiochemical yield by high performance liquid chromatography in an overall synthesis time of 100 min.
The in vitro radiobiology of astatine-211 decay.
Chinese hamster V79 cells in culture were exposed to astatine-211, an alpha-particle-emitting radiohalogen. The dose-log survival response was linear with no detectable shoulder. Cells in monolayers had a D0 of 1.0 microCi/ml. Suspended cells had a D0 of 0.60 microCi/ml with a cellular uptake of 2.5 fCi/cell; this is equal to approximately 1.5 alpha-particle traversals per cell nucleus. The frequencies of chromosome and chromatid breaks were linear with dose, but the number declined rapidly with time. These data are discussed in relation to published alpha-particle beam studies and the potential use of 211At in radionuclide therapy.
The use of C-18 SEP PAK cartridges to simplify routine production of 2-deoxy-2-[18F]fluoro-D-glucose.
The synthesis of 2-deoxy-2[18F]fluoro-D-glucose has been simplified by the use of C-18 SEP PAK cartridges. The fluorinated sugar produced from the reaction of acetyl hypofluorite and tri-acetyl glucal (TAG) was extracted from the neutralized reaction mixture with C-18 SEP PAK cartridges. The product was washed off the cartridge with diethyl ether and hydrolyzed by HCl. After hydrolysis the product was purified by passage through ion retardation resin, alumina and another C-18 cartridge. The radiochemical purity was 98% and the radiochemical yield was 28%, decay corrected to EOB, with a total synthesis time of 50 min from EOB.
Cerebral glucose metabolism in Parkinson's disease.
Local cerebral glucose utilization was measured in patients with predominantly unilateral Parkinson's disease using 18F-2-fluoro-deoxyglucose and positron emission tomography. Preliminary results indicate the presence of asymmetric metabolic rates in the inferior basal ganglia. The structure comprising the largest portion of basal ganglia at this level is globus pallidus. These findings are consistent with metabolic studies on animals with unilateral nigrostriatal lesions in which pallidal hypermetabolism on the lesioned side has been demonstrated. Increased pallidal activity is likely secondary to a loss of inhibitory dopaminergic input to the striatum from substantia nigra.
Astatine-211--tellurium radiocolloid cures experimental malignant ascites.
An investigation of the efficacy of astatine-211--tellurium colloid for the treatment of experimental malignant ascites in mice reveals that this alpha-emitting radiocolloid can be curative without causing undue toxicity to normal tissue. By comparison, negatron-emitting phosphorus-32 as colloidal chromic phosphate had no antineoplastic activity. The most compelling explanation for this striking difference is the dense ionization and short range of action associated with alpha-emission. These results have important implications for the development and use of alpha-emitters as radiocolloid therapy for the treatment of human tumors.
A shielded synthesis system for production of 2-deoxy-2-[18F]fluoro-D-glucose.
A remotely operated, shielded synthesis system for the production of 2-deoxy-2-[18F]fluoro-D-glucose (18FDG) for clinical studies has been developed. Using this system, 25 mCi of 18FDG are produced a the end of a 60-min synthesis from approximately 300 mCi of F-18 (total F-18 recovered from the target at the end of bombardment). The fractional distribution of F-18 among various components of the synthesis system has been measured. This yield of 18FDG (25 mCi) is ample for two consecutive human studies in house or for shipment to collaborating institutions within a 3-hr (door to door) radius.
The effect of target-gas purity on the chemical form of F-18 during 18F-F2 production using the neon/fluorine target.
Irradiation of gas mixtures of F2/Ne (20Ne leads to d,alpha 18F) which contained percent levels ( > 0.1%) of N2, CO2, CO2, or CF4 resulted in the production of unacceptable levels of F-18-labeled NF3 and CF4 at the expense of 18F-F2. Analycical gas chromatographic methods have been devised to determine contaminant levels in the target gas as well as in the products arising from them. Commercial mixtures of 1T F2/Ne, pur F2, and neon have been analyzed for contaminants (N2, O2, CO, CO2, and CF4) and found to vary widely in the levels of these impurities from batch to batch. The N2 levels in the 1% F2/Ne mixtures varied from 0.039 to 0.49%, and the CO2 levels from 0o.018 to 0.13%. No detectable impurities were found in the neon (Research Purity), but F2 was found to contain approximately 11% CF4. Reproducibly high yields of 18F-F2 are obtained if the levels of N2, CO2, and CF4 in the final target gas mixture are < 0.01% and carrier F2 is approximately 0.1%. Hydrocarbons and CO were not detected in our gas mixtures, but would also be expected to decrease yields of 18F-F2.
Anhydrous F-18 labeled eslemental flurine for radiopharmaceutical preparation.
Interest in fluorine- 18 as a label in radiopharmaceutical studies has led to the development of a method for the production of decicuries of anhydrous 18F-F2 using the 20Ne(d, alpha) 18F reaction. The amount of anhydrous 18F-F2 that can be removed from the target is a function of target pressure and carrier cokncentration increasing with rising target pressure and decreasing with decreasing carrier concentration. At a target pressure of 24 atmospheres and a carrier concentration of 0.1% F2, nearly 95% of the theoretical yield of fluorine- 18 produced can be removed and up to 85% delivered through a 10o-m stainless steel tube to the reaction chamber. Other functions affecting yield--including target design, target-gas handling and purity--have been addressed. Thick target yields for 14.0- and 9.4-MeV deuterons on target were measured to be 82 and 67 mCl/microA at saturation. With the BNL 60-in. cyclotron, production okf 600-800 mCl of 18F-F2 with a specific activity of approximately 10 mCi/mumole has been in effect since 1976.
Krypton-81m: a better radiopharmaceutical for assessment of regional lung function in children.
Krypton-81m, an inert, radioactive gas with a physical half-life of 13 seconds was used to evaluate regional lung ventilation in 25 pediatric patients. The results suggest that Kr-81m has several advantages over previous methods employing xenon-133. These include: more favorable physical characteristics for imaging with present scintillation cameras; ease of performance of the examinations; improved resolution and multiple views with better detection and localization of abnormalities; and a much lower dose to the patient.
Positron emission tomography after MPTP: observations relating to the cause of Parkinson's disease.
The dopa analogue 6-fluorodopa (6-FD) used with positron emission tomography (PET) allows in vivo visualization of dopamine and its metabolites in nigrostriatal nerve endings. We have now found abnormal 6-FD scans in four subjects exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). None had parkinsonism. The results suggest subclinical damage to the nigrostriatal pathway. This is the first direct evidence that dopaminergic impairment can exist without clinical deficits. Here we discuss this finding in the context of the hypothesis that Parkinson's disease may stem from clinically silent damage to the substantia nigra, followed by slow attrition of neurones in this region because of its particular vulnerability to cell loss as a normal consequence of ageing.
Basal ganglia studies with 3D acquisition and 2D reconstruction on a retractable septa PET scanner.
OBJECTIVE: We have tested the feasibility of applying an approximate three-dimensional (3D) reconstruction algorithm, the single slice rebinning method followed by standard 2D filtered back-projection (SSRB), to human basal ganglia studies. Such an approximate algorithm solves the problem of long reconstruction times and large dataset size associated with mathematically correct 3D reconstruction algorithms. MATERIALS AND METHODS: First, recovery achieved when images were reconstructed with the SSRB method was compared with that achieved when a mathematically correct 3D reconstruction algorithm (3D method) was used with a series of spherical phantom studies. The SSRB method was then applied to 14 human receptor studies and the images compared with those obtained with the 3D method. The striatum/background contrast dependence of the SSRB method performance was tested by extending the comparison of the two reconstruction methods to single frames of two dynamic scanning sequences. RESULTS: There was no significant visual difference in the human images obtained with the two methods and a quantitative striatal/cortical activity ratio analysis showed a contrast decrease of approximately 3% for the SSRB method. The analysis of the dynamic sequence did not show any contrast dependence of the SSRB method performance. CONCLUSION: The SSRB method was found adequate for processing data related to human striatal imaging for this particular tomograph geometry.