Pyridyl derivatives provide new pathways for labeling protein with fac-[<Superscript>188</Superscript>Re(CO)<Subscript>3</Subscript>(H<Subscript>2</Subscript>O)<Subscript>3</Subscript>]<Superscript>+</Superscript>

The purpose of this work was to indirect label IgG with fac-[¹⁸⁸Re(CO)₃(H₂O)₃]⁺ and to check the radiochemical behavior of the labeled product. The compound of (bis(2-pyridylmethyl)-amino)-acetic acid (L²H) was synthesized and labeled with fac-[¹⁸⁸Re(CO)₃(H₂O)₃]⁺. The labeling yield of ¹⁸⁸Re(CO)₃–L²H was more than 90%. The effects of protein concentration, reaction time, pH and reaction temperature of labeling of IgG with ¹⁸⁸Re(CO)₃–L²H were investigated. The conjugation conditions were optimized. The labeled product was analyzed by size exclusion HPLC and TLC. The stability of ¹⁸⁸Re(CO)₃–L²H–IgG in vitro was high. The results of this study may be useful for [¹⁸⁸Re(CO)₃(H₂O)₃]⁺ labeling of protein for radioimmunotherapy.     

Production of carrier free <Superscript>188</Superscript>Re radioisotope generator based on aluminum tungstate matrix

Improved radionuclide generator include a substantially insoluble salt of a radioactive parent which may be directly packed in column for subsequent elution of the daughter radionuclide. An improved ¹⁸⁸Re generator was prepared by reacting a radioactive tungsten (¹⁸⁸W) as parent radionuclide incorporated with aluminum chloride to obtain an insoluble radioactive aluminum tungstate matrix. The investigated matrix was characterized on the basis of the chemical composition, IR, thermal analysis and mechanical stabilities. The factors affecting the elution performance were studied such as influence of pH, molar ratio and drying temperature. From the obtained data, the molar ratio W:Al was 1.5:1 at pH = 4, the matrix dried at 105 °C for 2 h. Chromatographic and multichannel analysis has been currently used to investigate the radiochemical and radionuclidic purity respectively on eluted ¹⁸⁸Re. An elution yield more than 80%, with radiochemical purity <98% and radionuclidic purity <99% with a ¹⁸⁸W break through >10⁻⁴% of the column. The Al⁺³ and W contents value were about 2 and 3 μg/mL eluate. The obtained data approved the stability of the prepared generator and its suitability for medical application.     

Synthesis of a <Superscript>188</Superscript>Re–DTPMP complex using carrier-free <Superscript>188</Superscript>Re and study of its stability

Labeling of diethylenetriamine-N,N,N′,N″,N″-pentakis(methylenephosphonic) acid (DTPMP) with rhenium-188 using stannous chloride as a reducing agent has been investigated. Dependence of the yield of the ¹⁸⁸Re–DTPMP complex on the concentration of the reducing agent, pH, reaction time, temperature, ascorbic acid and amount of carrier added has been studied. Under optimum conditions, the labeling yield of ¹⁸⁸Re–DTPMP complex is 95% for the carrier-free ¹⁸⁸Re but with the carrier-added ¹⁸⁸Re the labeling yield is more than 97%. Furthermore, the stability of the ¹⁸⁸Re–DTPMP complex against pH change and dilution with saline has been also studied. It is found that the addition of carrier stabilizes the ¹⁸⁸Re–DTPMP complex against pH change and dilution.     

Synthesis of pyridyl derivatives for the future functionalization of biomolecules labeled with the fac-[<Superscript>188</Superscript>Re(CO)<Subscript>3</Subscript>(H<Subscript>2</Subscript>O)<Subscript>3</Subscript>]<Superscript>+</Superscript> precursor

In this paper, we investigated three ligand systems, symmetric and asymmetric pyridyl-containing tridentate ligands (L¹NH₂ = (bis(2-pyridylmethyl)-amino)-ethylamine, L²H = (bis(2-pyridylmethyl)-amino)-acetic acid, L³NH₂ = [(6-amino-hexyl)-pyridyl-2-methyl-amino]-acetic acid) as bifunctional chelating agents for labeling biomolecules. These ligands reacted with the precursor fac-[¹⁸⁸Re(CO)₃(H₂O)₃]⁺ and yielded the radioactive complexes fac-[¹⁸⁸Re(CO)₃L] (L = three ligands), which were identified by RP-HPLC. The corresponding stable rhenium tricarbonyl complexes (1–3) were allowed for macroscopic identification of the radiochemical compounds. ¹⁸⁸Re tricarbonyl complexes, with log P _o/w values ranging from −1.36 to −0.32, were obtained with yields of ≥90% using ligand concentrations within the 10⁻⁶−10⁻⁴M range. Challenge studies with cysteine and histidine revealed the high stability properties of these radioactive complexes, and biodistribution studies in normal mice indicated a fast rate of blood clearance and high rate of total radioactivity excretion, primarily through the renal-urinary pathway. In summary, these asymmetric and symmetric pyridyl-containing tridentate ligands are potent bifunctional chelators for the future biomolecules labeling of fac-[¹⁸⁸Re(CO)₃(H₂O)₃]⁺.     

2,5-Diamino-5,5-diphosphonovaleric Acid as a Ligand for an Osteotropic <Superscript>188</Superscript>Re Radiopharmaceutical

A modified method for the preparation of 2,5-diamino-5,5-diphosphonovaleric acid (DADP5) has been developed in the search for new synthetically available organic ligands to produce ¹⁸⁸Re radiopharmaceuticals with an increased accumulation in the bone tissue. Interaction of the obtained acid with ¹⁸⁸Re was studied by radio-TLC. An optimal system for separating unbound ¹⁸⁸Re and labeled complex in a yield of at least 95% was found. The biological distribution of ¹⁸⁸Re-DADP5 was studied based on direct radiometric data. The osteotropicity of ¹⁸⁸Re-DADP5 and its increased accumulation in bone fracture sites, which represent oncological pathology models, was detected at a level comparable to known radiopharmaceuticals.     

Separation of Clinical Grade 188Re from 188W Using Polymer Embedded Nanocrystalline Titania

Currently, ¹⁸⁸Re is obtained from ¹⁸⁸W/¹⁸⁸Re chromatographic generator containing alumina which has a limited capacity (~80 mg Wg^?1) for ¹⁸⁸W. This results in high bolus volumes of ¹⁸⁸Re, which often needs to be concentrated before radiolabeling. We have demonstrated the feasibility of using polymer embedded nano crystalline titania (TiP), a novel high capacity sorbent material (~300 mg Wg^?1), for developing a ¹⁸⁸W/¹⁸⁸Re chromatographic generator. A TiP based chromatographic ¹⁸⁸W/¹⁸⁸Re generator was developed in which ¹⁸⁸Re could be eluted with 0.9% saline solution. About 90% of the ¹⁸⁸Re could be recovered in the first 4–5 mL of total activity with more than 80% yield. The purity of ¹⁸⁸Re is adequate for clinical applications.     

Separation of Clinical Grade 188Re from 188W Using Polymer Embedded Nanocrystalline Titania

Currently, ¹⁸⁸Re is obtained from ¹⁸⁸W/¹⁸⁸Re chromatographic generator containing alumina which has a limited capacity (~80 mg Wg⁻¹) for ¹⁸⁸W. This results in high bolus volumes of ¹⁸⁸Re, which often needs to be concentrated before radiolabeling. We have demonstrated the feasibility of using polymer embedded nano crystalline titania (TiP), a novel high capacity sorbent material (~300 mg Wg⁻¹), for developing a ¹⁸⁸W/¹⁸⁸Re chromatographic generator. A TiP based chromatographic ¹⁸⁸W/¹⁸⁸Re generator was developed in which ¹⁸⁸Re could be eluted with 0.9% saline solution. About 90% of the ¹⁸⁸Re could be recovered in the first 4–5 mL of total activity with more than 80% yield. The purity of ¹⁸⁸Re is adequate for clinical applications.

     

The tungsten-188/rhenium-188 generator: Effective coordination of tungsten-188 production between the HFIR and BR2 reactors

The rapidly increasing therapeutic applications of ¹⁸⁸Re in nuclear medicine, oncology and interventional cardiology require routine production of large, multi-Curie levels of the ¹⁸⁸W parent. The capability and effective coordination of back-up production sites is important to insure that high level ¹⁸⁸W/¹⁸⁸Re generators are continually available. We have coordinated ¹⁸⁸W production at the High Flux Isotope Reactor (HFIR - Oak Ridge, US) with production at the BR2 Reactor (Mol, Belgium) characterized by peak thermal neutron fluxes of 2.51·0¹⁵ (HFIR) and 1·10¹⁵ (BR2) neutrons/cm²·sec, respectively. The long 69-day physical half-life permits receipt of ¹⁸⁸W from BR2 within 0.25 T _1/2's, even after the 12-day post irradiation cooling required for ¹⁸⁷W decay (T _1/2 = 24 hours). Since ¹⁸⁸W production by double neutron capture of enriched ¹⁸⁶W is a function of the square of the thermal neutron flux, HFIR production (4-5 Ci ¹⁸⁸W/g ¹⁸⁶W/cycle) is higher than at the BR2 (1.0-1.1 Ci/g ¹⁸⁶W/cycle). However, the specific activity (SA) of BR2-produced ¹⁸⁸W is still about 0.8-0.9 Ci/g after processing at ORNL following shipment from Belgium. This SA is sufficiently high to permit fabrication of 1 Ci generators suitable for clinical use, since simple post elution concentration of the saline bolus (30-50 ml) obtained from the generator can provide samples with high specific volume (1 ml volume). The time periods from reactor push in Mol and completion of processing, fabrication and shipment of generators from Oak Ridge have been 19-21 days. Six campaigns have been successfully completed since 1998, with processed levels of ¹⁸⁸W in Oak Ridge from 8-26 Curies/campaign. ¹⁸⁸W has been provided to MAP Medical technologies Oy (Tikkakoski, Finland) for fabrication and distribution of generators for use at IAEA-supported research projects in developing countries. We have thus established and demonstrated an effective collaboration between the Studiecentrum voor Kernenergie-Centre d'Etude de l'Energie Nucléaire (SCK·CEN) and ORNL for back-up production of ¹⁸⁸W. This collaboration continues to be especially helpful during periods when interruption of HFIR operation is necessary for maintenance and upgrades.     

Studies of gel metal-oxide composite samples as filling materials for W-188/Re-188 generator column

Studies of zirconium tungstate gels for production of ¹⁸⁸W/¹⁸⁸Re generators using tungsten of natural isotopic abundance irradiated in a moderate flux nuclear reactor have been carried out. Composites of WO₃–ZrO₂ have been synthesized by Complex Sol–Gel Process developed in INCT and other techniques. Different proportions of metal oxides and temperature were applied. Elution profiles of columns filled with gel samples irradiated in nuclear reactor have been studied using as an eluent 0.9% NaCl solution. Purity of ¹⁸⁸Re fraction and efficiency of elution were determined. Ageing effect on elution efficiency was also examined. It was found that the best elution performance showed zirconium tungstate gel prepared in 110 °C or 500 °C in which molar ratio of metal oxides was 1:2.     

An improved tungsten-188/rhenium-188 gel generator based on zirconium tungstate

An improved¹⁸⁸W-¹⁸⁸Re gel generator based on Zr tungstate is described. The influence of synthesis parameters and pre-treatment conditions on¹⁸⁸Re elution yields and the¹⁸⁸W breakthrough was studied with 0.15M aqueous solution of NaCl at pH 5.3 to 7.3 as well as with some organic solvents. An elution efficiency of 80% was achieved during 3 month of explotation with 0.15M NaCl at pH=6.3. The¹⁸⁸W breakthrough was 10^–4 to 10^–3%. The¹⁸⁸W breakthrough may be decreased to 10^–6% when converted into tandem generator with an alumina column. However,¹⁸⁸Re yields are reduced by 8–12% with a tandem generator.     

188W-188Re gel generators based on metal tungstates

Gel generators based on Zn, Co, Ni, Mn and Pb tungstates were prepared as potential supports for the development of¹⁸⁸Re radiopharmaceuticals. Factors which affected either the elution efficiency of¹⁸⁸Re or the breakthrough of¹⁸⁸W were examined.¹⁸⁸Re was produced as perrenate when the generators were eluted with saline (0.15M NaCl) and different organic solvents. The elution yield of¹⁸⁸Re decreased for the various gel supports as: Zn (75%), Co (60%), Ni (37%), Mn (24%), Pb (15%). When a tandem system comprised of a chromatographic alumina column was utilized in combination with the gel generator the¹⁸⁸W breakthrough was controlled to of the order of 10^–6%.     

<Superscript>103</Superscript>Ru/<Superscript>103m</Superscript>Rh generator

^103mRh is a very promising radionuclide for Auger electron therapy due to its very low photon/electron ratio. The goal of the present work was the elaboration a method for production of large quantities of ^103mRh for generator system. It was found that the combination of solvent extraction with evaporation of ¹⁰³RuO₄ followed by decomposition of H₅IO₆ makes it possible to produce ^103mRh of high radionuclidic and chemical purity.     

Production of carrier-free 188Re in the past ten years in Taiwan

Twenty clinical scale alumina-based ¹⁸⁸W/¹⁸⁸Re generators and carrier-free ¹⁸⁸Re has been produced at the Institute of Nuclear Energy Research (INER-Taiwan) for over ten years. 2845.6 GBq (76.9 Ci) of ¹⁸⁸Re-perrhenate solution has been eluted from generators during the past ten years. We have used the harvesting ¹⁸⁸Re solution for labeling radiopharmaceuticals, such as ¹⁸⁸Re-HEDP, ¹⁸⁸Re-MDP, ¹⁸⁸Re-microsphere, ¹⁸⁸Re-lipiodol, and ¹⁸⁸Re-sulfur colloid, etc. The average eluting yield of ¹⁸⁸Re is 78.6±5.8% that was investigated at 1115 harvesting times from 20 generators. Each generator can be used more than six months but the Millipore needs to be changed every two months for smooth harvesting and high yield of ¹⁸⁸Re solution.     

188Rhenium-EDTMP: A potential therapeutic bone agent

Bone seeking radiopharmaceuticals such as ethylenediaminetetramethylene phosphonate (EDTMP) complexes of ¹⁵³Sm and ¹⁶⁶Ho are receiving considerable attention for therapeutic treatment of bone metastases. Rhenium-188 has both beta-particle emissions for a therapeutic effect and gamma-emissions for imaging and it is available from an in-house generator system similar to the current ^99mTc generator, which makes it convenient for clinical use. The preparation of ¹⁸⁸Re-EDTMP is described using ¹⁸⁸Re, which was obtained from the alumina-based ¹⁸⁸W/¹⁸⁸Re generator. Dependence of the radiolabeling yield of ¹⁸⁸Re-EDTMP on reducing agent concentration, EDTMP concentration, incubation time, pH and addition of carrier was examined. In the case of optimum conditions, the radiolabeling yields of ¹⁸⁸Re-EDTMP were ~98% for carrier-free as well as carrier-added ¹⁸⁸Re. The addition of ascorbic acid plays an important role in the stability of carrier-free as well as carrier-added ¹⁸⁸Re-EDTMP preparations. The biodistribution of carrier-free and carrier-added ¹⁸⁸Re-EDTMP compounds in rats was also studied. The results show that ¹⁸⁸Re (carrier-added)-EDTMP is a potential bone pain palliation radiopharmaceutical due to its high skeletal uptake, rapid blood clearance and relatively low soft tissue absorption.     

Formulation of a freeze-dried kit for 188Re-MAG3 and its quality control

The synthesis of ¹⁸⁸Re-MAG₃ is described using ¹⁸⁸Re, which was obtained from the alumina based ¹⁸⁸W/¹⁸⁸Re generator. Dependence of the radiolabeling yields of ¹⁸⁸Re-MAG₃ on reducing agent concentration, Bz-MAG₃ concentration, pH, temperature and incubation time was examined. In the case of optimum conditions the yield of ¹⁸⁸Re-MAG₃ was 98%. TLC and HPLC techniques were employed to monitor the different species formed. Biodistribution study of ¹⁸⁸Re-MAG₃ was carried out in rats and compared with behavior of ^99mTc-MAG₃.     

An improved synthesis of S-benzoyl mercaptoacetyltriglycine as BFCA and the labeling of IgG with carrier-free 188Re

S-benzoyl mercaptoacetyltriglycine (S-Bz-MAG₃) was synthesized and labeled with carrier-free ¹⁸⁸Re. The overall yield of S-Bz-MAG₃ is higher than those published in the literature. Dependence of the labeling yield of ¹⁸⁸Re-MAG₃ upon concentration of reducing agent, pH, reaction time, and other parameters was examined and optimum conditions were obtained. The labeling yield of ¹⁸⁸Re-MAG₃ was more than 98%. The concentration procedure was succeeded with Sep-Pak C18 column to obtain highly concentrated ¹⁸⁸Re-MAG₃. The experimental conditions of labeling of IgG with carrier free ¹⁸⁸Re via S-Bz-MAG₃ as a bifunctional chelating agent (BFCA) by pre-radiolabeling of the chelate was studied. The conjugation conditions were optimized. The stability of ¹⁸⁸Re-MAG₃-IgG in vitro was high. The results of this studiy may be useful for ¹⁸⁸Re labeling of MAbs for radioimmunotherapy.     

Systematic radiochemical separation for the determination of <Superscript>99</Superscript>Tc, <Superscript>90</Superscript>Sr, <Superscript>94</Superscript>Nb, <Superscript>55</Superscript>Fe and <Superscript>59,63</Superscript>Ni in low and intermediate radioactive waste samples

A simple and rapid separation procedure was systemized for the determination of ⁹⁹Tc, ⁹⁰Sr, ⁹⁴Nb, ⁵⁵Fe and ^59,63Ni in low and intermediate level radioactive wastes. The integrated procedure involves precipitation, anion exchange and extraction chromatography for the separation and purification of individual radionuclide from sample matrix elements and from other radionuclides. After separating Re (as a surrogate of ⁹⁹Tc) on an anion change resin column, Sr, Nb, Fe and Ni were sequentially separated as follows; Sr was separated as Sr (Ca-oxalate) co-precipitates from Nb, Fe and Ni followed by purification using Sr-Spec extraction chromatographic resin. Nb was separated from Fe and Ni by anion exchange chromatography. Fe was separated from Ni by anion exchange chromatography. Ni was separated as Ni-dimethylglyoxime precipitates after the removal of ^134,137Cs and ^110mAg by Cs-phosphotungstate and AgCl precipitation, respectively. Finally, the radionuclide sources were prepared by precipitation for their radioactivity measurements. The reliability of the procedure was evaluated by measuring the recovery of chemical carriers added to a synthetic radioactive waste solution.     

Sequential separation of <Superscript>99</Superscript>Tc, <Superscript>94</Superscript>Nb, <Superscript>55</Superscript>Fe, <Superscript>90</Superscript>Sr and <Superscript>59/63</Superscript>Ni from radioactive wastes

A sequential separation procedure has been developed for the determination of ⁹⁹Tc, ⁹⁴Nb, ⁵⁵Fe, ⁹⁰Sr and ^59/63Ni in various radioactive wastes generated from nuclear power plants. Ion exchange and extraction chromatography were adopted for individual separation of the radionuclides. Precipitation was supplementarily utilized for both purification of the individual radionuclides and preparation of the radionuclide sources for use in a radioactivity measurement. The chromatographic separation behavior of the radionuclides both from the sample matrix metals and from one another was investigated using stable metals, Re (as a surrogate of ⁹⁹Tc), Nb, Fe, Sr and Ni. The validity of the procedure for reliability and applicability was evaluated by measuring the recovery of the metal carriers added to synthetic radioactive waste solutions. The recoveries by the chromatographic separation were in the range of 84.8 to 102.2% with 2s of less than 8.6%, the recoveries by the precipitation being in the range of 84.3 to 97.3% with 2s of less than 10.9%.     

188Rhenium-glucoheptonate: A radiopharmaceutical for intravascular radiation therapy

The preparation of ¹⁸⁸Re-glucoheptonate (GH) is described using ¹⁸⁸Re, which was obtained from an alumina based ¹⁸⁸W/¹⁸⁸Re generator. The dependence of the radiolabeling yields of ¹⁸⁸Re-GH on reducing agent concentration, GH concentration, pH, temperature and incubation time was examined. In the case of optimum conditions the yield of ¹⁸⁸Re-GH was ~99%. The ITLC technique was employed to monitor the different species formed. A biodistribution study of ¹⁸⁸Re-GH was carried out in rats and compared to the biological behavior of ^99mTc-GH.     

Separation of radioarsenic from irradiated germanium oxide targets for the production of <Superscript>71</Superscript>As and <Superscript>72</Superscript>As

A method for the separation of no-carrier-added arsenic radionuclides from the bulk amount of proton-irradiated GeO₂ targets as well as from coproduced radiogallium was developed. The radionuclides ⁶⁹Ge and ⁶⁷Ga produced during irradiation of GeO₂ were used as tracers for Ge and Ga in the experiments. After dissolution of the target the ratio of As(III) to As(V) was determined via thin layer chromatography (TLC). The extraction of radioarsenic by different organic solvents from acid solutions containing alkali iodide was studied and optimized. The influence of the concentration of various acids (HCl, HClO₄, HNO₃, HBr, H₂SO₄) as well as of KI was studied using cyclohexane. The optimum separation of radioarsenic was achieved using cyclohexane with 4.75 M HCl and 0.5 M KI and its back-extraction with a 0.1% H₂O₂ solution. The separation leads to high purity radioarsenic containing no radiogallium and <0.001% [⁶⁹Ge]Ge. The overall radiochemical yield is 93 ± 3%. The practical application of the optimized procedure in the production of ⁷¹As and ⁷²As is demonstrated and batch yields achieved were in the range of 75–84% of the theoretical values.