Alvin P. Callahan

Processing of reactor-produced 188W for fabrication of clinical scale alumina-based 188W/188Re generators

Abstract The traditional technique for processing of reactor-irradiated 186 W-enriched tungsten oxide (WO 3 ) targets involves formation of 188 W-sodium tungstate solutions by target dissolution in 0.1 M NaOH. Following long irradiations (> 21 days) in the ORNL High Flux Isotope Reactor (HFIR) the 186 WO 3 targets contain a NaOH-insoluble 188 W-labeled black solid (approx. 30–50% of total activity) which decreases the yield and specific activity of the processed 188 W (e.g. 5–6 mCi/mg 186 W for a 79-day irradiation). The black material is postulated to represent a “tungsten blue” insoluble polymeric form of tungsten oxide, which we have now found to dissolve in 0.1 M NaOH containing 5% sodium hypochlorite solution. Complete dissolution results in a significant increase in the yield and specific activity of sodium 188 W-tungstate. As an alternative approach, irradiated 186 W-enriched metal targets dissolve in sodium hydroxide solution by cautious addition of 188 W-tungstate solutions prepared from processing of such metal targets show no evidence of residual black insoluble material. Specific activity values for completely dissolved HFIR-irradiated 186 W targets have increased to 10 mCi/mg (43.5 days) and 12.9 mCi/mg (49.2 days). Large clinical scale (> 1 Ci) generators prepared from hypochlorite-processed 186 W oxide or peroxide-processed 186 W metal targets exhibit the expected 188 Re high yield and low 188 W breakthrough.

Preparation and preliminary tissue studies of optically active 11C-d- and l-phenylalanine

Abstract A rapid method for the preparation of l -phenylalanine-1-11C and d -phenylalanine-1-11C is described. dl -Phenylalanine-1-11C (375 mCi) was synthesized from 11C-cyanide (2.4 Ci) by a modified Bucherer- Strecker reaction with a chemical yield of 65% in 40 min (including purification). The resolution of the d - and l -isomers was accomplished in 35 min (including purification) by oxidative deamination using immobilized l - and d -amino acid oxidase, respectively; the yields for d - and l -phenylalanine-1-11C were 19 mCi and 27 mCi. Preliminary tissue distribution studies of these labeled isomers in the rat showed that the pancreas-to-liver ratio for the l -isomer increased throughout the first hour of observation following i.v. administration while that of the d -isomer decreased after 30 min. Whole body retention data revealed that the loss of radioactivity from dl - or d -phenylalanine-1-11C was less than 2% during the first hour of observation after i.v. administration.

Design, synthesis, and evaluation of omega-iodovinyl- and omega-iodoalkyl-substituted methyl-branched long-chain fatty acids.

The synthesis of a new methyl-branched fatty acid, (E)-19-iodo-3(RS)-methyl-18-nonadecenoic acid (19), is described. Methyl branching has been introduced at the 3-position to inhibit beta-oxidation and radioiodide has been attached as a trans-vinyl iodide. Preparation of 19 involved a 15-step sequence of reactions climaxing with formation of the methyl ester 18 by iododestannylation of methyl (E)-19-(tri-n-butylstannyl)-3(RS)-methyl-18-nonadecenoate (17) resulting from the reaction of n-Bu3SnH with methyl 3(RS)-methyl-18-nonadecynoate (16). Methyl branching was introduced at an early stage by Friedel-Crafts acylation of thiophene with 3(RS)-methyl-4-carbomethoxybutanoyl chloride (3) generated from 3-methylglutaric anhydride. The new agent, [125I]-19, showed high myocardial uptake (5 min, 4.89% dose/g; 30 min, 3.32% dose/g), good heart/blood (H/B) ratios (5 min, 5.4/1; 30 min, 4.3/1), and significantly greater myocardial retention in fasted rats than the corresponding straight-chain analogue 19-[125I]-iodo-18-nonadecenoic acid (5 min, 3.52% dose/g, H/B = 4.8/1; 30 min, 1.19% dose/g, H/B = 1.6/1). Excellent myocardial images were obtained in rats after administration of [123I]-19 and confirmed the slow myocardial washout over a 60-min period. These data suggest that 19 is a good candidate for evaluation of heart disease involving aberrations in fatty acid metabolism by use of imaging techniques such as single photon emission computerized tomography (SPECT) where redistribution or washout should be minimized.

Ascorbic acid/saline eluant increases 188Re yields after “wet” storage of 188W/188Re generators

Abstract We have evaluated several factors in an attempt to minimize the reduced yields observed after “wet” storage of 188 W/ 188 Re generators, which include the dispersion of 188 W-tungstic acid in the alumina column bed by pre-mixing with silica gel, incorporation of cupric ion as an antioxidant in the adsorbent, and elution of the alumina columns with saline solution containing ascorbic acid. The results demonstrate that dispersion of the 188 W-tungstic acid in a silicaalumina bed and the use of cupric ion do not significantly increase 188 Re yields after weekend “wet” storage. In contrast, addition of ascorbic acid at concentrations as low as 0.01% in the saline eluant was found to be an effective method of maintaining good 188 Re yields after “wet” weekend storage, resulting in Monday elution yields greater than 70%. Use of low concentrations of ascorbic acid is thus an effective alternative to drying the generator columns before storage.

The use of alumina “SepPaks®” as a simple method for the removal and determination of tungsten-188 breakthrough from tungsten-188/rhenium-188 generators

Abstract A simple method using an alumina SepPak ® has been developed to determine the breakthrough levels of 188 W from 188 W/ 188 Re generator systems. Detection of low levels of 188 W in the presence of high levels of 188 Re (155 keV, 15%) by traditional counting techniques is not possible because the 188 W parent emits gamma photons of only very low intensity at 227 keV (0.22%) and 290 keV (0.40%). In order to remove and quantitate levels of 188 W in “real time” without having to wait several days for decay of the 188 Re caughter, the use of an alumina SepPak ® in tandem with the alumina generator is an effective technique to trap the 188 W breakthrough. The efficiency of this technique was demonstrated by doping 2 mCi of 188 Re with 2 μCi of 188 W. This doped sample provided a control which would correspond to a very high breakthrough value (0.1%), which is 10 3 times greater than the usual breakthrough of the alumina system ( −4 %). Even these very high levels of 188 W could not be detected by gamma-ray spectroscopy in the presence of the 188 Re. When the eluant was subsequently passed through an acid-washed alumina SepPak ® followed by thorough washing (20 mL) with 0.9% NaCl, however, the 227 and 290 keV gamma lines were clearly detected, which facilitated quantification of the 188 W breakthrough levels. Breakthrough levels 1000 times lower could still be detected by this method, making it a useful quality control tool in assessing 188 W/ 188 Re generator performance.

Production of tungsten-188 and osmium-194 in a nuclear reactor for new clinical generators

Rhenium-188 and iridium-194 are potential candidates for radioimmunotherapy with monoclonal antibodies directed against tumor-associated antigens. Both nuclei are short-lived and decay by high energy β- emission. In addition, both nuclei emit γ-rays with energy suitable for imaging. An important characteristic is availability of 188Re and 194Ir from decay of reactor-produced parents (188W and 194Os, respectively) in convenient generator systems. The 188W and 194Os are produced by double neutron capture of 186W and 192Os, respectively. The large scale production yields of 188W in several nuclear reactors will be presented. We also report a new measurement for the cross-section of 193Os(n,γ)194Os reaction and discuss the feasibility of producing sufficient quantities of 194Os.

Effects of fasting on the myocardial subcellular distribution and lipid distribution of terminal p-iodophenyl-substituted fatty acids in rats.

The myocardial lipid pool distribution and subcellular distribution of radiolabeled methyl-branched fatty acids in rats was evaluated under conditions of fasting (24 h) and feeding. With the unbranched iodophenyl fatty acid, fasting resulted in increased myocardial extraction and clearance time with a decrease in the incorporation into triglycerides and greater radioactivity in the mitochondrial fraction. With the monomethyl-branched analogue, the effects of fasting on lipid and subcellular distribution were minor except for a decrease in triglyceride incorporation. Like the unbranched analogue, the dimethyl-branched iodophenyl fatty acid showed increased myocardial extraction with fasting, however, this structurally-modified fatty acid showed increased rather than decreased incorporation into triglycerides.

Reactor production and purification of osmium-191 for use in a new 191Os/191mIr radionuclide generator system

Abstract The production of osmium-191 by thermal neutron irradiation of enriched osmium-190 has been evaluated at neutron flux values from 4 × 10 14 to 2.5 × 10 15 neutron cm −2 s −1 in the Oak Ridge High Flux Isotope Reactor (HFIR), the High Flux Brookhaven Reactor (HFBR), and the BR2 reactor in Mol, Belgium. The production route has been analyzed and the cross section values evaluated. The existence of a secondary reaction 191 Os(n, γ) 192 Os with a cross section value of 740 barn has been demonstrated. In order to obtain 191 Os with a specific activity of 250 mCi/mg 190 Os, irradiation periods at neutron flux values lower than 2.5 × 10 15 neutron cm −2 s −1 have to be extended up to 2–4 weeks. This results in significantly increased levels of the undesirable 192 Ir. The 192 Ir is produced by capture of a neutron by 191 Ir, which is formed by decay of the short-lived 4.96 s 191m Ir daughter produced by β-decay of 191 Os. Elution of even small levels of 192 Ir from the 191 Os/ 191m Ir generator results in a large proportion of the total absorbed radiation dose from the generator eluate. Purification of 191 Os by conversion to osmium tetroxide and isolation by both distillation and solvent extraction methods has been developed for the efficient removal of 192 Ir.

The large-scale production of carrier-free 206Bi for medical application

Abstract An enriched 207Pb cyclotron target design has been developed for the large-scale proton production of 206Bi (∼ 185 mCi/hr) with

Evaluation of pancreatic lipase activity by simple urine analysis after oral administration of a new iodine-131-labeled triglyceride

A new iodine-131-labeled triglyceride analogue called “MIPAG” [1,2-dipalmitoyl-3-[(15-p-iodophenyl) pentadecan-1-oyl]rac-glycerol] has been prepared in which 15-(p-iodophenyl)pentadecanoic acid (IPPA) is attached to position-3. MIPAG has been developed for the evaluation of pancreatic exocrine function by simple urine analysis and has been evaluated in rats and humans. After oral administration, IPPA is released from the triglyceride by the action of pancreatic lipases followed by intestinal absorption and the principal IPPA metabolite (p-iodobenzoic acid, IBA) is primarily excreted in the urine. Excretion in the urine and feces was evaluated in rats, as well as the biodistribution in various organs over 21 days. Twenty patients without pancreatic disease (normals) and four patients with pancreatic insufficiency were also investigated. Following oral administration of 30 μCi of MIPAG, urine was collected for two successive 24-h periods. Blood samples were drawn and thin-layer chromatographic (TLC) analysis was performed on the serum lipid extracts. Urine from normals contained 44.9%±7.7% and 61.8%±8.4% of the administered activity after 24 and 48 h, respectively. The patients with pancreatic insufficiency excreted 13.1%±5.6% and 18.9%±6.2%, respectively, which was significantly decreased (P<0.001) compared with normals. The TLC profiles showed an increasing proportion of IBA with time. Urine analysis after oral administration of MIPAG thus appears to be an attractive new technique for the evaluation of pancreatic lipase activity by a simple urine analysis.