Applied Radiation and Isotopes 57 (2002) 641–646 Development of a titanium tungstate-based 188W/188Re gel generator using tungsten of natural isotopic abundance M.S Dadachova,b, Le Van Soa,c, R.M Lambrechta,{, E Dadachovaa,* a Australian Nuclear Science and Technology Organization, PMB 1, Menai, NSW 2234, Australia b Stevens Institute of Technology, Hoboken, NJ, USA c Nuclear Research Institute, Dalat, Viet Nam Received 23 November 2001; received in revised form 25 February 2002; accepted 12 June 2002 Abstract The feasibility of developing titanium tungstate-based 188W/188Re gel generator using tungsten of natural isotopic abundance irradiated in a moderate flux reactor has been investigated Influence of temperature, pH and eluent concentration on generator performance was studied It was found that ‘‘post-formed’’ approach allows to construct gel generators with elution performance and 188Re elution yields very close to those of conventional alumina 188W/188Re generator Curie-level 185W radionuclidic impurity presents a challenge during the processing of target material and subsequent elution of the generator In the future use of semi-enriched with 186W target material (50–60% enrichment) would be beneficial in the development of titanium tungstate-based 188W/188Re gel generators r 2002 Elsevier Science Ltd All rights reserved Introduction Rhenium-188 (188Re) has recently emerged as a useful therapeutic radioisotope in a variety of clinical trials such as cancer radioimmunotherapy, palliation of skeletal bone pain, endovascular brachytherapy to prevent restenosis after angioplasty (Knapp, 1998; Hoher et al., 2000; Seitz et al., 1999; Murray et al., 2001) as well as in the pre-clinical development of novel radiopharmaceuticals (Dadachova and Chapman, 1998; Emfietzoglou et al., 2001; Arteaga de Murphy et al., 2001) Rhenium is a chemical analogue of technetium and exhibits practically identical chemical and biodistribution properties (Deutsch et al., 1986) Emission characteristics and physical properties of 188Re (16.7 h half-life) make it suitable for application in radionuclide therapy—its high energy beta particles *Corresponding author Department of Nuclear Medicine, Albert Einstein College of Medicine of Yeshiva University, 1695A Eastchester Rd., Bronx, NY 10461, USA Tel.: +1-718405-8485; fax: +1-718-824-1369 E-mail address: edadacho@aecom.yu.edu (E Dadachova) { Deceased (Eaverage ¼ 0:764 MeV) are effective over a several mm range, sufficient to eradicate medium or large tumors by a ‘‘cross-fire’’ effect (O’Donoghue et al., 1995), while its low energy and low abundance gamma photons (155 keV, 15% abundance) are suitable for imaging (Saha, 1997) Carrier-free 188Re is obtained from the 188W/188Re generators in a similar fashion to 99mTc The parent radionuclide 188W (69 days half-life) is produced in a nuclear reactor via 186W(2n,g)188W nuclear reaction Much work has been carried out on development of 188 W/188Re generator systems In 188W/188Re generators available from the US from Oak Ridge National Laboratory the irradiated tungsten is absorbed on the alumina column in 188W-tungstate form, and 188Reperrhenate is eluted from the column with saline (Mikheev et al., 1972; Knapp et al., 1994; Kamioki et al., 1994) Availability of high specific activity 188W (B5 mCi/mg) is crucial for production of inorganic adsorbent-based 188Re/188W generators as only very limited amount of tungsten can be absorbed onto conventional inorganic adsorbents such as alumina (Ehrhardt et al., 1987; Kamioki et al., 1994) Production of high specific activity 188W requires irradiation of 0969-8043/02/$ - see front matter r 2002 Elsevier Science Ltd All rights reserved PII: S 9 - ( ) 0 - 642 M.S Dadachov et al / Applied Radiation and Isotopes 57 (2002) 641–646 expensive 186W-enriched targets (96% enrichment in 186 W also helps to reduce 185W in the final product) for several months in a high flux reactor (with neutron flux of at least  1014 n cmÀ2 sÀ1) as the yields in double neutron capture nuclear reactions are proportional to the square of neutron flux As an alternative 188W/188Re gel generator system which utilizes zirconium or other metal [188W]Wtungstate gel has been developed (Ehrhardt et al., 1992; Vanderheyden et al., 1992; Dadachov and Lambrecht, 1995) Gel generators permit use of low specific activity 188W, thus making it possible to irradiate semi-enriched W (50–50% enrichment in 186 W) or, theoretically, even W targets of natural isotopic abundance (28.6% abundance for 186W) in the reactors with low or moderate neutron flux Here we describe our experience in developing titanium tungstate-based 188W/188Re gel generator utilizing W targets with natural isotopic abundance irradiated in a moderate flux reactor Experimental 2.1 Materials and reagents WO3 of ‘‘SpecPure’’ grade and TiCl4 of ‘‘Pure’’ grade were supplied by B.D.H All other chemicals used for experiments were of ‘‘Reagent’’ grade 2.2 Reactor activation of W targets and radioactivity measurements 3.5 g WO3 of natural isotopic abundance or 0.5 g samples of titanium tungstate gel (further referred in the text as TiW) were placed in metallic titanium container and irradiated in HIFAR (ANSTO, Australia) nuclear reactor in thermal neutron flux of  1013 n cmÀ2 sÀ1 for 192 days After irradiation the targets were allowed to ‘‘cool’’ for one month before chemical processing (in case of tungsten oxide) or column packing (in case of TiW gel samples) Irradiated targets were processed in a hot cell The gross radioactivity of 188W and 188Re samples was measured in a calibrated ionization chamber The gamma-spectrometry of 188W, 188W/188Re at decaygrowth equilibrium (291 and 155 keV photo peaks, respectively) as well as determination of radioactive impurities in generator eluate was performed in Ge(Li) detector coupled with multichannel analyser (EG & G Ortec) 2.3 Preparation of titanium tungstate gels Two techniques were employed for the preparation of TiW gel generators When ‘‘post-formed’’ technique was used, the gel generator was synthesized through several steps from radioactive reactor-irradiated WO3 of natural isotope abundance Conversely, ‘‘pre-formed’’ TiW gel was prepared from inactive WO3, irradiated in the reactor and used directly for generator column packing 2.3.1 ‘‘Post-formed’’ TiW gel preparation Neutron-irradiated 3.5 g WO3 target was dissolved in 52.5 ml of M NaOH solution To facilitate the dissolution of the target 10 ml 30% H2O2 solution was added and the mixture was stirred at 801C until clear solution of sodium tungstate was formed 39 ml 10 M HCl was added to sodium tungstate to adjust its pH to 4.5 Following filtration through a fine filter paper, the solution of sodium tungstate was diluted to 100 ml with distilled water The tungstate concentration of this solution was 0.15 M To precipitate TiW gel, 100 ml 0.15 M TiCl4 solution, pH=1.0, was added to tungstate solution under stirring at 601C White TiW gel formed in this step was filtered, washed and dried at 801C for h forming a final product with particle size o1 mm The gel precipitation yield (percentage of W complexed in the gel) was 96% For preparation of 188Re/188W generator 4.8 g TiW gel was packed into a 12 mmdiameter glass column fitted with sintered glass bottom The column which contained 25 mCi 188W and B3.5 Ci 185 W was washed extensively with water, and 188Re was eluted with normal saline 2.3.2 ‘‘Pre-formed’’ TiW gel preparation In the ‘‘pre-formed’’ approach TiW gel of natural isotopic abundance was prepared in the same manner as in ‘‘post-formed’’ approach except that it was irradiated in the reactor after the preparation Following 192 days irradiation and month cooling 0.5 g TiW gel containing 3.8 mCi 188W and 0.51 Ci 185W was packed into generator column, and 188Re elution with saline was performed directly or after treating the generator with 0.1 M K2CrO4 2.4 Structural characteristics of TiW gel The crystallinity of TiW was determined by X-ray powder diffraction using a CuKa radiation 2.5 Investigation of the elution performance of TiW gel generators The effects of different drying temperatures, pH and NaCl concentration of the eluent on 188Re elution yields and W breakthrough were investigated To evaluate 188 Re elution profile 1-ml portions of the generator eluate were collected and counted in an ionization chamber For evaluation of 185,188W breakthrough the eluate portions were combined, left to decay for weeks and 188W contents determined by gamma spectrometry M.S Dadachov et al / Applied Radiation and Isotopes 57 (2002) 641–646 500 450 400 350 Intensity from the intensity of the 155 keV g-ray of 188Re Direct detection of 185W in the presence of 188Re is difficult, as 125 keV peak emitted by 185W has only 0.019% abundance, thus making it hard to observe it under the Compton background of 188Re 155 keV peak with an abundance of 15% Fortunately, the ratio of 188W/185W activities in the target or generator which in our study was 0.0076 at EOB can be calculated at any moment of time using 185W and 188W half-lives As chemical properties of 185W and 188W isotopes are identical, 185 W breakthrough was calculated from 188W breakthrough and the ratio of 188W/185W activities In some experiments the generators were connected to a small 1.5 g alumina column for the purpose of purification/concentration of generator eluate 643 300 250 200 150 100 50 10 20 30 theta 40 50 Fig X-ray diffraction pattern of TiW gel 100 Results and discussion 3.1 Titanium tungstate gel formation and characteristics The reaction between TiCl4 and Na2WO4 (1:1 molar ratio) resulted in formation of TiW gel in 96% yield The X-ray diffraction pattern (Fig 1) of dried TiW gel revealed its amorphous nature Our later EXAFS study of the local structure of tungstate-based gel generators ( born (Dadachov et al., 1999) proved that Re7+ (0.56 A) 6+ ( is in the same place as its parent isotope W (0.65 A) located in the highly distorted octahedral oxygen coordination, and being too small to be stable in this 188 Re elution yield,% 80 The gel generator approach makes it possible to manufacture 99mTc/99Mo and 188Re/188W generators using low specific activity 99Mo and 188W obtainable from a variety of low to medium flux nuclear reactors In addition, the possibility of using W of natural isotopic abundance in place of expensive 186W-enriched targets would further decrease the price of 188Re/188W generators Previously, we reported the results of the development of 99mTc/99Mo and 188Re/188W gel generators based on multivalent metal molybdate or tungstate gels, respectively (Dadachov and Lambrecht, 1995; Le Van So and Lambrecht, 1994) Of these, Ti is of particular interest for gel generator development because of its low cost, non-toxicity and low solubility of its compounds For construction of generators we utilized both traditional ‘‘post-formed’’ technique when the gel generator was synthesized through several steps from radioactive reactor-irradiated WO3, and ‘‘pre-formed’’ technique when TiW gel was prepared from inactive WO3, irradiated in the reactor and used directly for generator column packing Use of ‘‘pre-formed’’ columns eliminated several radiochemical processing steps preceding generator elution 60 40 20 30 50 70 90 110 130 Temperature oC Fig Effect of drying temperature on ‘‘post-formed’’ TiW gel generator 188 Re elution yields of environment, can be easily removed by even slightly polar solvents in the form of perrhenate 188ReOÀ Fig demonstrates the dependence of 188Re elution yields on the drying temperature of the gel Practically linear drop in yields was observed in the interval of 80–1051C We have recently shown with the help of EXAFS spectroscopy (Dadachov et al., 1999) that in gel generators tungsten atoms are coordinated by six oxygen ligands and are too loose to fit octahedral hole The structure of the generator can be easily destabilized by thermal dehydration, which removes oxygen atoms belonging to OH groups and H2O and lowers coordination number of tungsten atoms At >1201C drying temperatures 188Re elution yields dropped dramatically This drop in yields of TiW generator can be attributed to the collapse of the gel structure caused by the loss of most of the structural water Fig displays the effect of pH and NaCl concentration of the eluent on 188Re elution yield and 188W breakthrough Both 188Re elution yield and 188W breakthrough increase with the increasing eluent pH M.S Dadachov et al / Applied Radiation and Isotopes 57 (2002) 641–646 644 NaCl concentration of eluent, [mol/L] 0.1 0.2 0.3 0.4 0.5 40 0.1 20 188 Re elution yields and Acidity of 0.9% NaCl solution, pH Re elution yield, [%] 60 188 0.2 Fig Dependence of pH of the eluent 100 80 188 W breakthrough, [%] 0.3 0 188 W breakthrough of ‘‘post-formed’’ TiW gel generator on NaCl concentration and and molar concentration which can be explained by swelling of TiW gel structure resulting in easier 188Re elution and higher dissolution of tungstate 3.2 Elution performance of ‘‘post-formed’’ gel generator The elution performance data and elution profile of ‘‘post-formed’’ TiW gel column are shown in Table and Fig 4, respectively It is evident that both elution performance and elution profile of the gel column were quite similar to those of the conventional alumina-based generator (Kamioki et al., 1994) The use of additional 1.5 g alumina clean-up column (so-called ‘‘tandem’’ generator design) not only decreased W breakthrough below detection limits but also allowed to concentrate the eluate from 9–15 to 2–3 ml This was achieved by eluting gel generator with water onto the alumina clean-up column, which was later eluted with saline to obtain the purified and concentrated 188Re eluate As gel generators described in this paper were prepared from W targets of natural isotopic abundance, it was important to assess the radionuclidic impurities in the generator itself and in its eluate The main radionuclidic impurity in the generator was 185W This isotope (75.1 day half-life, b-emission 0.433 MeV) is a product of 184W (n,g)185W nuclear reaction, as 184W has 30.7% isotopic abundance Because of its high radioactivity and long half-life 185W, apparently, causes the biggest problem in the preparation of 188W/188Re generators from W of natural isotopic abundance as a reactor irradiation target As a consequence, rigorous separation is required to obtain 188Re eluate essentially free from not only 188W parent isotope but also from 185 W Our gamma-spectrometry measurements showed that out of B3.5 Ci 185W in the target material 3.2 Ci was converted into TiW gel, B2.5 mCi was trapped on alumina clean-up column per elution and none was detected in 188Re eluate Besides 185W other radionuclides were found in much smaller quantities in target material, such as 124Sb (B100 mCi) and 182Ta (B50 mCi) About 50 mCi 124Sb and 10 mCi 182Ta were converted into TiW gel; 10 mCi 124Sb and none of 182Ta was found on alumina column after 1st elution; and none of these isotopes were present in 188Re eluate The alumina column was changed after every elutions Also, other methods of concentrating 188Re eluate have been recently described (Blower, 1993; Guhlke et al., 2000) employing combinations of commercially available disposable ion exchange cartridges 3.3 Elution performance of ‘‘pre-formed’’ gel generator We investigated a possibility of preparing gel generator from the ‘‘cold’’ precursors then irradiating the ‘‘pre-formed’’ column in the reactor The use of ‘‘preformed’’ columns would eliminate several radiochemical processing steps during which an accidental loss of valuable target material could occur Irradiation of 0.5 g samples of TiW gel in the reactor for 192 days resulted in color change of the gel from white to dark brown Numerous radionuclidic impurities were detected in the target material such as 185W, 60Co, 46Sc, 124Sb, 59Fe and 182 Ta Attempts to elute 188Re with saline after packing 10À4, 188W/188Re, o0.1 mg W/ml Re, [cpm] 645 H2 O C 0.9%NaCl 0.9%NaCl 4.8g TiW 188 Radioactivity of 84.2 Not detected W Breakthrough (%) 188 Re yield (%) W breakthrough (%) Elution and Elution M.S Dadachov et al / Applied Radiation and Isotopes 57 (2002) 641–646 1.5g Al2 O A Waste B C A 82.5 10À4, o1.0 mg W/ml 83.2 Not detected 10 12 14 16 18 Re eluate volume, [ml] Fig 188Re elution profiles of ‘‘post-formed’’ TiW gel generator the irradiated gel into the generator column resulted in very low yields of B5% Soaking the generator for days in 0.1 M K2CrO4 oxidizing solution caused the change of generator color to light green 188Re elution yields also improved and varied within 30–32% range which was still significantly lower than the B80% elution yields of ‘‘post-formed’’ generator It is known that neutron irradiations result in significant increase in target temperature and in profound chemical changes in target material especially in oxyanions (McKay, 1971) The poor performance of ‘‘pre-formed’’ gel generator can be explained by partial gel structure collapse and reduction of W and Ti to lower oxidation states caused by prolonged exposure to high dose radiation and high temperatures during irradiation Conclusion A new alumina column was supplied a 0.03, 92.3 mg W/ml 84.5 Eluant volume: 9.0 ml for operation mode I plus 2.0 ml for operation mode II 188 82.2 Re yield (%) Re yield (%) 188 188 188 Re yield (%) W breakthrough (%) W breakthrough (%) Elution 5a and Elution Elution and Elution Elution and Elution W breakthrough (%) Re elution yield (%) 188 Operation mode II: Elution with 1.5 g alumina clean-up column Operation mode I: Elution without clean-up column TiW gel column Table Elution performance of ‘‘post-formed’’ TiW gel generator (eluant—0.9% NaCl) B We have investigated the feasibility of developing titanium tungstate-based 188W/188Re gel generator using tungsten of natural isotopic abundance irradiated in the moderate flux reactor While elution performance and 188 Re elution yields of ‘‘post-formed’’ generator were very close to those of conventional alumina 188W/188Re, Curie-level 185W radionuclidic impurity presented a challenge during processing of target material and subsequent elution of the generator In the future use of semi-enriched with 186W target material (50–60% enrichment) would be beneficial in the development of titanium tungstate-based 188W/188Re gel generators Acknowledgements The research was funded by the Commonwealth of Australia 646 M.S Dadachov et al / Applied Radiation and Isotopes 57 (2002) 641–646 References Arteaga de Murphy, C., Pedraza-Lopez, M., Ferro-Flores, G., et al., 2001 Uptake of 188-Re-beta-naphthyl-peptide in cervical carcinoma tumours in athymic mice Nucl Med Biol 28 (3), 319–326 Blower, P.J., 1993 Extending the life of a 99mTc generator: a simple and convenient method for concentrating generator eluate for clinical use Nucl Med Commun 14 (11), 995–997 Dadachov, M.S., Lambrecht, R.M., 1995 188W–188Re gel generator based on metal tungstates J Radioanal Nucl Chem Lett 200 (3), 211–221 Dadachov, M.S., Howe, R.F., Lambrecht, R.M., 1999 EXAFS study of the local structure of zirconium tungstate and molybdate biomedical gel generators Radiochim Acta 86 (1–2), 51–60 Dadachova, E., Chapman, J., 1998 188-Re(V)DMSA revisited—preparation and biodistribution of potential radiotherapeutic agent with the low kidney uptake Nucl Med Commun 19 (2), 173–181 Deutsch, E., Libson, K., Vanderheyden, J.L., et al., 1986 The chemistry of rhenium and technetium as related to the use of isotopes of these elements in therapeutic and diagnostic nuclear medicine Int J Rad Appl Instrum B 13 (4), 465–477 Ehrhardt, G.J., Ketring, A.R., Turpin, T.A., 1987 An improved W-188/Re-188 generator for radio-therapeutic applications J Nucl Med 28 (suppl), 656 Ehrhardt, G.J., Ketring, A.R., Liang, Q., 1992 Improved W188/Re-188 zirconium tungstate gel radioisotope generator chemistry 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(10), 1151–1165 Le Van So, Lambrecht, R.M., 1994 Development of alternative technologies for gel-type chromatographic Tc-99 m generator J Label Comp Radiopharm 35(4), 270–272 McKay, H.A.C., 1971 Principles of Radiochemistry Butterworths, London, pp 496–499 Mikheev, N.B., Popovich, V.B., Rumer, I.A., et al., 1972 Re188 Generator Isotopenpraxis 8, 248 Murray, A., Simms, M.S., Scholfield, D.P., et al., 2001 Production and characterization of 188-Re-c595 antibody for radioimmunotherapy of transitional cell bladder cancer J Nucl Med 42 (5), 726–732 O’Donoghue, J.A., Bardi"es, M., Wheldon, T.E., 1995 Relationship between tumor size and curability for uniformly targeted therapy with beta-emitting radionuclides J Nucl Med 36 (10), 1902–1909 Saha, G.P., 1997 Fundamentals of Nuclear Pharmacy Springer, New York, p 249 Seitz, U., Neumaier, B., Glatting, G., et al., 1999 Preparation and evaluation of the rhenium-188-labelled anti-NCA antigen monoclonal antibody BW 250/183 for radioimmunotherapy of leukemia Eur J Nucl Med 26 (10), 1265–1273 Vanderheyden, J.-L., Su, F.-M., Ehrhardt, G.J., 1992 Soluble irradiation targets and methods for the production of radiorhenium US Patent 5,145,636 ... chemicals used for experiments were of ‘‘Reagent’’ grade 2.2 Reactor activation of W targets and radioactivity measurements 3.5 g WO3 of natural isotopic abundance or 0.5 g samples of titanium tungstate. .. gel of natural isotopic abundance was prepared in the same manner as in ‘‘post-formed’’ approach except that it was irradiated in the reactor after the preparation Following 192 days irradiation... developing titanium tungstate- based 188W/188Re gel generator using tungsten of natural isotopic abundance irradiated in the moderate flux reactor While elution performance and 188 Re elution yields of