Chromatographic and electromigration analysis of rhenium compounds used in radiopharmacy

A large group of radiopharmaceuticals includes complex radionuclide-ligand compounds which are very sensitive to the preparation conditions, as for example pH of reaction mixture, incubation time, temperature, molar ratio of reagents, etc. It is necessary to find the optimum condition for the formation of the radionuclide-ligand complex and to select the convenient analytical methods to determine the purity of the product. The preparation of radiopharmaceuticals labeled by rhenium-186 or rhenium-188 requires the addition of a reducing agent (commonly stannous chloride) to the reaction mixture in order to reduce perrhenate to a lower oxidation state which is capable of complex formation. For rhenium concentration up to approximately 10^-5 mol/l, the molar excess of reduction agent over perrhenate is usually higher than 800 to reach the optimum yield of reduction and complexation (between 80-95%). Because of the potentially toxic effect of SnCl₂ the reduction of perrhenate by stannous chloride was studied in detail to find the way for decreasing the concentration of reducing agent in the reaction mixture without significant lowering of the yield of perrhenate reduction. The reduction of perrhenate was determined by electromigration methods, i.e., capillary electrophoresis (CZE) and isotachophoresis (ITP), and thin-layer chromatography (TLC) with radiometric detection. The highest degree of reduction of perrhenate was obtained at pH 2 at perrhenate concentration ranging from 10^-4 to 10^-3 mol/l. The stability of reduced rhenium against a pH change from 2 to 5.5 (which corresponds to the pH close to physiological values) was tested as well. The influence of the presence of ascorbic acid as an antioxidant in the reaction mixture on the stability of the preparation against the pH change was determined. The stability of reduced rhenium against dilution of rhenium in the reaction mixture to the concentration suitable for the application in radiotherapy was also found out. The data acquired by capillary electrophoresis, isotachophoresis and thin-layer chromatography are comparable. Results obtained in these experiments were applied for the study of rhenium complexes with hydroxyethylidenediphosphonic acid (HEDP).     

Chromatographic study of186Re complexes with various ligands

Thin-layer and paper chromatography have been used for the determination of radiochemical yields of¹⁸⁶Re complexation with three selected ligands methylenediphosphonic acid (MDP), ethylenediamminotetraacetic acid (EDTA), and citrate convenient for the radiopharmaceutical applications. The combination of selected two chromatographic systems has been chosen due to the satisfactory separation of free perrhenate, corresponding complex with¹⁸⁶Re and reduced hydrolyzed rhenium. Rhenium complexes with studied ligands were prepared by reduction of perrhenate at presence of suitable ligand. Stannous chloride together with ascorbic acid (antioxidant) was used for perrhenate reduction. The effect of pH of reaction mixture, reaction time and concentration of reducing agent on the radiochemical yield of complexation is described and the optimal conditions for synthesis of rhenium complexes with MDP, EDTA and citrate have been found. Under optimal condition the radiochemical yield of complexation¹⁸⁶Re-MDP,¹⁸⁶Re-EDTA and¹⁸⁶Re-citrate reached more than 90%, 80%, and 80%, respectively.     

The Study of Various Rhenium Compounds by Capillary Electrophoresis

The conditions for the synthesis of rhenium compounds (pH, reaction time, concentration of reducing agent) have been determined previously by thin-layer chromatography. A Britton-Robinson buffer solution has been selected as a carrier electrolyte due to its possible use in a wide interval of pH, mainly at optimal pH for the formation of the complexes studied. The same electrolyte has been previously applied also in case of the study of rhenium and technetium complexes by polarography. The electrophoretic experiments have been carried out under both standard and reverse polarities with direct UV detection at the wavelength 214 nm and 20 °C. The signal of perrhenate has been observed at the reverse polarity (outlet+, inlet–), of reduced rhenium [probably Re(IV)] under normal polarity. The formation of rhenium complexes with EDTA has been shown by lowering of the cationic rhenium signal due to the addition of the ligand. The rhenium complexes with EDTA are observable at reverse mode of CE. The formation of rhenium complexes with HEDP (hydroxyethylidenediphosphonic acid) has been studied in two different carrier electrolytes — 40 mM Britton-Robinson buffer solution and 50 mM phosphate buffer with 20 mM HEDP. The mechanism of perrhenate reduction by stannous chloride and of the formation of rhenium complexes with EDTA has been determined. The necessity of the presence of ascorbic acid as an antioxidant in the reaction mixture at different pH values has been described as well.     

Determination of Radiochemical Yield of 186Re-Labeled Complexes Using Thin-Layer Chromatography

The reaction conditions for synthesis of three rhenium complexes ¹⁸⁶Re-methylendiphosphonate (MDP), ¹⁸⁶Re-hydroxyethylidendiphosphonate (HEDP) and ¹⁸⁶Re-citrate were investigated. Radiochemical yield of complexation was determined by thin-layer chromatography and paper chromatography. The rhenium complexation with corresponding ligand was dependent on pH values of reaction mixture, concentration of the ligand studied (MDP, HEDP and sodium citrate) and concentration of the reducing agent. Stannous chloride with ascorbic acid (as antioxidant) was used for reduction of perrhenate. The labeling yield was about 90% for ¹⁸⁶Re-MDP, more than 80% for ¹⁸⁶Re-HEDP and more than 75% for ¹⁸⁶Re-citrate under optimum conditions. The possibility of application of porphyrines as organic ligands for complexation with rhenium isotopes was also examined.     

Electrochemical deposition and characterization of mixed-valent rhenium oxide films prepared from a perrhenate solution

Cathodic electrodeposition of mixed-valent rhenium oxides at indium tin oxide, gold, rhenium, and glassy carbon electrodes from acidic perrhenate solutions (pH = 1.5 +/- 0.1) prepared from hydrogen peroxide and zerovalent rhenium metal is described. Cyclic voltammetry, variable angle spectroscopic ellipsometry (VASE), X-ray photoelectron spectroscopy (XPS), UV-vis spectroelectrochemistry, and electrochemical quartz crystal microbalance (EQCM) data indicate that the chemical nature of the electrodeposited rhenium species depends mainly upon the potential and supporting electrolyte. The presence of SO4(2-) as a supporting electrolyte inhibits the adsorption of perrhenate, ReO4-, at non-hydrogen adsorbing electrode materials. However, in acidic perrhenate solutions containing only protons and ReO4- anions, strong adsorption of ReO4- at potentials preceding hydrogen evolution occurs. This leads to the formation of an unstable ReIII2O3 intermediate which catalytically disproportionates to form mixed-valent rhenium films consisting of 72% ReIVO2 and 28% Re0. During the hydrogen evolution reaction (HER), hydrogen polarization causes the principle deposit to be more reduced, consisting of roughly 64% ReIVO2 and 36% Re0. Conclusively, metallic rhenium can be deposited at potentials preceding the HER at non-hydrogen adsorbing electrode materials, especially in the absence of SO4(2-) anions.     

A new liquid membrane electrode for the selective determination of perrhenate

A new perrhenate ion-selective electrode has been developed, incorporating a nitrobenzene solution of nitron perrhenate as a liquid membrane. The electrode gives near-Nernstian response to 3 x 10(-5)-10(-2)M perrhenate over the pH range 3-8. Most common anions (except for periodate and perchlorate) give little interference. The electrode has been satisfactory for direct potentiometric determination of as little as 10 mu/ml rhenium. The average recovery and standard deviation were 99% and 2.1%, respectively. Measurements of the solubility products of some sparingly soluble perrhenates gave results that agreed closely with those recorded in the literature and obtained by other procedures.     

Reaction of [Pd(NH<Subscript>3</Subscript>)<Subscript>4</Subscript>]Cl<Subscript>2</Subscript> with NH<Subscript>4</Subscript>ReO<Subscript>4</Subscript> in alkaline water solution at 190°C (autoclave process)

A reaction of tetraammine palladium(II) chloride with ammonium perrhenate in aqueous alkaline solution in the autoclave conditions was studied. The possible routes of the palladium and rhenium reduction with ammonia were suggested.     

Extraction et dosage de traces de rhénium,en particulier dans les molybdénites

A simple solution to the difficult problem of the separation and determination of traces of rhenium contained in molybdenites is suggested. After the preliminary attack of the cres, rhenium is extracted quantitatively between, pH 8 and pH 9 by chloroform in the form of tetraphenylarsonium perrhenate. In this pH region the molybdenum remains in the aqueous phase.Calculation has allowed the determination of favourable conditions for the extraction of perrhenates by tetraphenylarsonium chloride and chloroform. Practical results are in satisfactory agreement with theory.The extracted rhenium, after conversion to the ions ReO₄^- in acid solution, is determined colorimetrically by reaction with thiocyanate and stannous chloride.By applying the method described it is possible to isolate and determine rhenium in molybdenites when the weight ratio rhenium/ore ecxeeds 10^-7.     

Gravimetric determination of rhenium as 2,4,6-triphenylpyrylium perrhenate

A gravimetric method for determination of rhenium is based on formation of sparingly soluble 2,4,6-triphenylpyrylium perrhenate. The conditional solubility product in O.1N sulphuric acid medium was found to be (3.72 +/- 0.08) x 10(-9). The interference of foreign anions (simple or complex) is eliminated by preliminary extraction of perrhenate with acetone from strongly alkaline medium. The method is applied to the determination of rhenium in perrhenates and rhenium alloys.     

Photoelectron Spectroscopy (XPS) and Thermogravimetry (TG) of Pure and Supported Rhenium Oxides. 2. Rhenium Oxides on Titanium Dioxide

Ammonium perrhenate supported on titanium dioxide has been investigated in order to elucidate the interaction between the carrier and the dispersed species. The samples, containing up to 14% by weight of rhenium, have been prepared by impregnation with an ammonium perrhenate solution. The study, performed using X-ray photoelectron spectroscopy and thermogravimetric techniques, demonstrates that a different situation is present depending on the starting rhenium content and gas environment. At low rhenium content (0–2.5%), rhenium is mainly atomically dispersed as per-rhenate-like surface compound; on heating in H₂ up to 500°C, the surface compound is reduced to metal which is still in a dispersed form. In the range 2.5–10% in addition to the perrhenate-like surface compound, small crystallites of NH₄ReO₄ are initially present on the surface. During the heat treatment in hydrogen these crystallites are reduced to ReO₂. The incorporation of Re(IV) in the TiO₂ structure preserves it from further reduction. At higher rhenium content large crystallites of ammonium perrhenate are present on the titanium dioxide surface. They show the reduction behaviour expected for this compound. The data also indicate that when metallic rhenium is heated in air, the heptoxide formed reacts with the free surface of the support and is not lost by volatilization.     

Electrochemical behavior of aqueous acid perrhenate-containing solutions on noble metals: critical review and new experimental evidence

The actual state of the art in the reduction of perrhenate ions on noble metals is reviewed and discussed. Also, with the aim of contributing to better knowledge of this process, results of several experiments are presented. For the first time, spectroscopic evidence on the nature of the deposited rhenium layer on Pt and Rh and the detection of an intermediate in the reduction pathway toward metallic rhenium is provided. The role of the substrate in the electroreduction of perrhenate ions in aqueous acid media is emphasized, because it is directly associated with the formation of different H-containing species as reducing agents. Thus, those metals capable of adsorbing H atoms are able to reduce ReO(4)(-) to ReO(2) by H(ad) at potentials more positive than that of the hydrogen evolution reaction. Moreover, H(ad) reacts with the ReO(2) layer previously deposited, resulting in the formation of Re(III)-soluble species, which subsequently undergo disproportionation to Re and ReO(2). For metals that are not capable of adsorbing H, i.e., Au, molecular hydrogen is the reducing agent, leading to the formation of metallic Re. In addition, ReO(4)(-) is chemically reduced to metallic Re by hydride.     

Optimizing the preparation of an alumina-supported rhenium catalyst for olefin metathesis

The processes involved in the formation of the alumina-supported rhenium catalyst for olefin metathesis, from the impregnation of the support (thermally activated alumina) with ammonium perrhenate to thermal activation, are studied. The monolayer coverage of the Al₂O₃ surface is observed at a rhenium content of 10 wt % (on Re₂O₇ basis), and the surplus rhenium is sublimed as heptoxide from the support upon thermal activation. In the metathesis of both linear α-olefins and methylenecyclobutanes, the optimum supported rhenium content of the catalyst is 10 wt % on Re₂O₇ basis.     

Reaction of [Pt(NH<Subscript>3</Subscript>)<Subscript>4</Subscript>]Cl<Subscript>2</Subscript>·H<Subscript>2</Subscript>O and NH<Subscript>4</Subscript>ReO<Subscript>4</Subscript> in alkaline aqueous solution at 190°C (under pressure)

Reactions of thermolysis under pressure of tetraammineplatinum(II) chloride and ammonium perrhenate in alkaline aqueous solution were studied. The products formed at the thermolysis in a pressure reactor were investigated. A model of platinum and rhenium ions reduction to metallic state by inner sphere ammonia from [Pt(NH₃)₄]Cl₂ is suggested.     

Rhenium bipyridine complexes for the recognition of glucose

Bipyridine ligands containing pendant methyl, amino, and amino-boronic acid groups were synthesized. Coordination complexes of these ligands with rhenium were prepared straightforwardly and in good yield. The fluorescence behavior of the Re complexes was studied as a function of pH and exposure to various concentrations of glucose. The methyl bipyridine complex showed no change in fluorescence with pH, the amino derivative showed a rapid decrease from low pH to neutral, and the amino-boronate derivative showed little change from pH 4 to 10. Fluorescence quenching was observed at high pH as expected on the basis of a photoinduced electron transfer (PET) signaling mechanism. This behavior can be explained on the basis of the first oxidation and reduction potentials of these complexes. Glucose testing showed a significant dependence on the solvent system used. In pure methanol, the rhenium boronate complex exhibited a 55% fluorescence intensity increase upon increasing glucose concentration from 0 to 400 mg/dL. However, in 50 vol % methanol/phosphate buffered saline, none of the complexes showed significant response in the glucose range of physiological interest.     

Neutron activation analysis of rhenium in rocks and sediments by extraction chromatography on a pyridine-Kel-F column

A simple method for the determination of rhenium in rocks and sediments has been established. After a neutron-irradiated sample was decomposed by NaOH−Na₂O₂ fusion, the alkaline solution was fed onto a column of the mixed solvent pyridine-benzene (7:3 v/v) supported on Kel-F powder. By passage through the column of 4, 5N NaOH solution which had been equilibrated with the solvent mixture, perrhenate ion remained on the column but other nuclides were eluted. Subsequently, the perrhenate ion on the column could be eluted with a small amount of distilled water, and precipitated as tetraphenylarsonium perrhenate for counting the γ-activity of¹⁸⁶Re. By the present method 0.1 ng of rhenium could be determined with a recovery of 90–95% and an error of ±10%. A part of this work was performed at the Research Reactor Institute, Kyoto University.     

Methylrhenium oxides

Reactions of the rhenium(VII) precursors Re₂O₇, acetyl perrhenate, trifluoroacetyl perrhenate, chlorotrioxorhenium and trimethylsilyl perrhenate are performed with various common tin free methylating agents. The yields of MTO and the products of partial reduction, bis[dimethyl(μ-oxo)oxo-rhenium(VI)] and (μ-oxo)bis[trimethyloxorhenium(VI)], are quantified by NMR spectroscopy. With aluminium- and copper-containing methylating agents none of the above mentioned compounds are formed, solely perrhenate and rhenium(VI) oxide are detected. The best result is achieved with trifluoroacetyl perrhenate and dimethylzinc, yielding >60% MTO.     

Mechanisms for CO production from CO2 using reduced rhenium tricarbonyl catalysts

The chemical conversion of CO(2) has been studied by numerous experimental groups. Particularly the use of rhenium tricarbonyl-based molecular catalysts has attracted interest owing to their ability to absorb light, store redox equivalents, and convert CO(2) into higher-energy products. The mechanism by which these catalysts mediate reduction, particularly to CO and HCOO(-), is poorly understood, and studies aimed at elucidating the reaction pathway have likely been hindered by the large number of species present in solution. Herein the mechanism for carbon monoxide production using rhenium tricarbonyl catalysts has been investigated using density functional theory. The investigation presented proceeds from the experimental work of Meyer's group (J. Chem. Soc., Chem. Commun.1985, 1414-1416) in DMSO and Fujita's group (J. Am. Chem. Soc.2003, 125, 11976-11987) in dry DMF. The latter work with a simplified reaction mixture, one that removes the photo-induced reduction step with a sacrificial donor, is used for validation of the proposed mechanism, which involves formation of a rhenium carboxylate dimer, [Re(dmb)(CO)(3)](2)(OCO), where dmb = 4,4'-dimethyl-2,2'-bipyridine. CO(2) insertion into this species, and subsequent rearrangement, is proposed to yield CO and the carbonate-bridged [Re(dmb)(CO)(3)](2)(OCO(2)). Structures and energies for the proposed reaction path are presented and compared to previously published experimental observations.     

Determination of rhenium in gold-containing ores by X-ray fluorescence spectrometry

A procedure is developed for determining rhenium in gold-containing ores by X-ray fluorescence spectrometry. The adsorption preconcentration of perrhenate ions on activated charcoal is studied. It is found that the pH of the solution, the time of exposing the adsorbent to the solution, UV irradiation, and the presence of associate elements (tungsten, gold, silver, and copper) affect the adsorption. The procedure is applied to the X-ray fluorescence determination of rhenium in gold-containing ores from different deposits.     

Field determination of rhenium in plants using catalytic test methods with dimethyldithiooxamide and Sulfonitrazo P

Methods for the field determination of rhenium in plants have been developed. The speciation of rhenium in solutions throughout the process of sample preparation has been investigated. It has been shown that, in the initial ethanol and water-salt extracts, rhenium occurs as perrhenate ions. Perrhenate ions have been established to be partially reduced in time to give Re(VI). Since test methods have been developed for determining rhenium as perrhenate-ions, their partial reduction in the process of sample preparation can lead to an low level of the results. The optimal conditions for preserving rhenium as perrhenate ions have been determined. Two procedures (in four versions) providing the determination of as low as 5 ng of rhenium in a 1-g sample with an error below 23% have been proposed. The developed procedures have been applied in the places of the collection of plant materials for the regional investigation of the occurrence of rhenium in the territories of different ore contents.     

Separation of rhenium by extraction with crown ethers and flow-injection extraction—spectrophotometric determination with Brilliant Green

The extraction behavior of perrhenate with crown ethers was studied and methods for the separation and determination of rhenium were developed. The distribution ratio of perrhenate with dicyclohexano-18-crown-6 (DC18C6) increases with increases in the dielectric constant of organic solvents and in the potassium ion concentration of aqueous solution. The molar ratios of crown ether to KReO₄ in the extracted species are probably 1:1 for DC18C6, dibenzo-18-crown-6 and 18-crown-6 and 2:1 for benzo-15-crown-5 and 15-crown-5. Microgram amounts of rhenium were satisfactorily separated from large amounts of molbdenum(VI) by extraction with DC18C6 in 1,2-dichloroethane from 2 M potassium hydroxide solution containing tartrate and by back-extraction with sodium phosphate buffer solution after the addition of a twofold volume of hexane to the organic phase. Rhenium was determined by the flow-injection extraction-photometric method with Brilliant Green. Rhenium was satisfactory determined in molybdenite and other ore samples.