Comparative study of different chromatographic methods for quality control of113mIn-radiopharmaceuticals

Paper chromatography and Gel Chromatography Column Scanning technique (GCS) have been applied for the separation of indium fractions in^113mIn-radiopharmaceuticals. By these techniques the percentage of ionic indium,^113mIn-colloid and^113mIn-compound have been determined. The resolution efficiency of the gels was found to be significantly influenced by the gel type media and the pH of the eluent. The results obtained from the GCS-profiles indicated that the Sephadex G-50 Fine was the best and can be routinely used in the radiochemical quality control of the^113mIn-phytate. Good separation of^113mIn-colloids,^113mIn-microaggregate and^113mIn-phytate from carrier-free^113mIn-eluate was performed using Whatman No. 3, previously washed with 0.04N HCl and developed either with 0.9% NaCl (for^113mIn-colloid), or 85% methanol (for^113mIn-phytate), or phosphate-methanol buffer (for^113mIn-microaggregate) as rapid and simple procedure for determination of the radiochemical quality control of indium compound in the forms of radiocolloids.     

Gel Chromatography Column Scanning (GCS) Method of Choice for Quality Control of 99mTc-Plasmin Preparations

Abstract

Gel chromatography column scanning (GCS) is useful for testing compounds labelled with gamma-emitting radionuclides. The elution volume used in this technique is so small that no components of the sample are eluted from the column. In the radioactivity distribution of the sealed column various species are recorded in characteristic zones of the column. Plasmin labelled with ^99mTc is used for scintigraphic detection of deep vein thrombosis. The quality of the ^99mTc-plasmin preparation has been tested by various methods. The GCS method employing small columns offers a very fast testing procedure and adequate resolution for quality control in routine radiopharmaceutical work.     

Combined determination of <Superscript>99</Superscript>Tc and <Superscript>108m</Superscript>Ag in L/ILW liquid wastes

The low- and intermediate-activity level liquid wastes produced by the Paks Nuclear Power Plant (NPP) contain routinely measureable gamma-emitting (e.g., ⁵⁴Mn, ⁶⁰Co, ^110mAg, and ¹³⁷Cs) as well as many so-called “difficult-to-measure” radionuclides. Despite of their low specific activity compared to the total, the reliable determination of these radionuclides is an important issue of nuclear waste management. The increasing amount of waste samples to be qualified yearly by our laboratory put a pressure on revising the existing procedure of ⁹⁹Tc separation applied. We have managed to halve the initial amount of the sample required to achieve the same level of detection of technetium. Furthermore, one of the new purifying steps introduced have proved to be able to separate ^108mAg (and ^110mAg) better than 99% keeping the ⁹⁹Tc content of the product almost intact. Means of separation of ⁹⁹Tc from ¹⁰⁶Ru and ^124+125Sb have also been successfully investigated. As intended, this new procedure has a major impact on the chemical reagent as well as the electricity requirement of the separation making it more cost-effective.     

Separation of no-carrier-added <Superscript>90</Superscript>Nb from proton induced natural zirconium target

Amongst various radionuclides of molybdenum, ⁹⁰Mo and ⁹⁹Mo have suitable β energy for clinical uses. In this paper we report separation of ⁹⁹Mo from ⁹⁹Mo-^99mTc equilibrium mixture. The liquid–liquid extraction technique has been employed using trioctylamine (TOA) diluted in cyclohexane as organic phase and HCl as aqueous phase. At 10⁻⁵ M HCl and 0.5 M TOA concentration ^99mTc quantitatively transferred to the organic phase leaving ⁹⁹Mo in the aqueous phase. The developed separation method is efficient and provides very high separation factor.     

113Sn-113mIn generator with a glass beads column

The adsorption characteristics of ¹¹³Sn(IV) and ^113mIn(III) on glass beads from NaCl solutions have been studied. On the basis of these studies, ¹¹³Sn-^113mIn generator has been prepared by adsorbing ¹¹³Sn on the glass beads column. ^113mIn has been eluted by the 0.16M NaCl solution with pH 3.0, remaining ¹¹³Sn adsorbed on the glass beads. The yield of ^113mIn has been about 73% in the first 6 ml of eluate, while the breakthrough of ¹¹³Sn has been about 0.042%.     

Intercomparison of phosphorus-32, technetium-99m and iodine-131 activity measurement in Pakistani nuclear medical centers and supplier

Technetium-99m and iodine-131 are the leading isotopes used in diagnosis and radiotherapy, respectively in Pakistani nuclear medical centers. Both radionuclides are regularly supplied by Isotope Production Division (IPD), PINSTECH to nuclear medical centers in Pakistan. The packages of ³²P, ⁹⁹Mo → ^99mTc generators, and ¹³¹I, are prepared at IPD and dispatched by air, rail or road according to the desired activity at reference day to nuclear medical centers. An accurate determination of the activity to be administered to the patient plays key role on the quality of the clinical result of a medical investigation. Activity meters are employed for quantification of radioactivity of radionuclides at supplier site as well as by the users. In order to investigate the performance on the quality of activity measurements and elution efficiency of PAKGEN ^99mTc generators, a pilot program of intercomparison was organized between the supplier and the users. The results of intercomparison of the activity measurements showed a maximum difference of ±13 % between supplier and nuclear medical centers.     

To Sandwich Technetium: Highly Functionalized Bis-Arene Complexes [99mTc(η6-arene)2]+ Directly from Water and [99mTcO4]−

The labeling of (bio)molecules with metallic radionuclides such as ^99mTc demands conjugated, multidentate chelators. However, this is not always necessary since phenyl rings can directly serve as integrated, organometallic ligands. Bis-arene sandwich complexes are generally prepared by the Fischer–Hafner reaction. In extension of this, we show that [^99mTc(η⁶-C₆R₆)₂]⁺-type complexes are directly accessible from water and [^99mTcO₄]⁻, even using arenes incompatible with Fischer–Hafner conditions. To unambiguously confirm the nature of these unprecedented ^99mTc complexes, their rhenium homologous have been prepared by substituting naphthalene ligands in [Re(η⁶-C₁₀H₈)₂]⁺ with the corresponding phenyl groups. The ease with which highly stable [^99mTc(η⁶-C₆R₆)₂]⁺ complexes are formed under standard labeling conditions enables a multitude of new potential imaging agents based on commercial pharmaceuticals or lead structures.     

Reaction of [TcNCl4]− with ethylenediamine-N,N'-diacetic acid ligand

The reaction of [^99mTcNCl₄]^– with ethylenediamine-N,N'-diacetic acid (ENDA) has been studied. Starting from [^99mTcNCl₄]^– prepared according to the method of Apparu et al.6, the exchange reaction with ENDA in the presence of stannous tartrate led to the formation of an anionic^99mTcN-ENDA complex. The labeling yield was about 90% at pH values of 10.5 and 6.5. In the absence of the reducing agent the formation of^99mTcO₄ ^– is reflected in the decrease of the complex yield. The exchange reaction of [⁹⁹TcNCl₄]^– with ENDA at pH 6.5 and in the absence of a reducing agent resulted in the formation of the anionic⁹⁹TcN-ENDA complex and⁹⁹TcO₄ ^–. The spectrophotometric characteristics (UV-vis. and IR) of the pure complex are similar to those of some tcN²⁺-complexes with amine ligands. The electrophoretic and chromatographic behaviors of^99mTcN- and⁹⁹TcN-ENDA anions are identical; this proves the formation of the same complex with both radionuclides.     

Determination of radionuclidic impurities in <Superscript>99m</Superscript>Tc eluate from <Superscript>99</Superscript>Mo/<Superscript>99m</Superscript>Tc generator for quality control

Technetium-99m is the principal radioisotope used in medical diagnostics; radionuclidic impurity is the major concern of its quality. This work presents a analytical method for sequential determination of all radionuclidic impurities listed in pharmacopoeia including gamma emitters, alpha emitters, ⁸⁹Sr and ⁹⁰Sr. Radioactive decay for removal of ^99mTc, ion exchange and extraction chromatography for removal of ⁹⁹Mo and ⁹⁹Tc are effective for separation of interferences. Gamma spectrometry, LSC with alpha/beta discrimination, and Cherenkov counting using LSC are sensitive methods for measurement of the impurity radionuclides. The detection limits of this method are well meet the requirement of the quality control according to the limitation of the pharmacopoeia.     

To Sandwich Technetium: Highly Functionalized Bis‐Arene Complexes [99mTc(η6‐arene)2]+ Directly from Water and [99mTcO4]−

The labeling of (bio)molecules with metallic radionuclides such as ^99mTc demands conjugated, multidentate chelators. However, this is not always necessary since phenyl rings can directly serve as integrated, organometallic ligands. Bis‐arene sandwich complexes are generally prepared by the Fischer–Hafner reaction. In extension of this, we show that [^99mTc(η⁶‐C₆R₆)₂]⁺‐type complexes are directly accessible from water and [^99mTcO₄]^?, even using arenes incompatible with Fischer–Hafner conditions. To unambiguously confirm the nature of these unprecedented ^99mTc complexes, their rhenium homologous have been prepared by substituting naphthalene ligands in [Re(η⁶‐C₁₀H₈)₂]⁺ with the corresponding phenyl groups. The ease with which highly stable [^99mTc(η⁶‐C₆R₆)₂]⁺ complexes are formed under standard labeling conditions enables a multitude of new potential imaging agents based on commercial pharmaceuticals or lead structures.     

Radionuclides used for therapy and suggestion for new candidates

Summary Targeted radiotherapy has the potential to provide radiation doses from a wide range of radionuclides, some of them suitable for killing single cells while others are more suitable for killing tumor cell clusters of various sizes. A list of 64 radionuclides, including 20 new potential candidates for therapy (⁷³Ga, ⁷⁵Se, ^87mSr, ⁹⁷Ru, ¹⁰³Ru, ¹¹³Sn, ^113mIn, ¹¹⁷Sb, ¹²³Sn, ¹³¹Cs, ¹³⁹Ce, ¹⁴¹Ce, ¹⁴⁹Eu, ¹⁶⁷Tm, ¹⁷⁰Tm, ¹⁷³Tm, ¹⁹⁵Au, ^195mPt, ¹⁹⁷Pt and ¹⁹⁷Hg) were analyzed in terms of the suitability of their energies for killing tumor cells which grow as single, small, intermediate and large clusters. In addition, their possible production routes were studied.     

Radiochemical solvent extraction of molybdenum/VI/ using99Mo tracer

A radiochemical solvent extraction method has been developed for the micro determination of Mo/VI/ using⁹⁹Mo tracer. It involves removal of^99mTc by ethyl methyl ketone /EMK/ and extraction of Mo with tri-n-butyl phosphate /TBP/ from 5M HCl. Different parameters affecting the extraction such as pH dependence, nature of solvent and interferences due to other radionuclides have been studied. The method can be used up to 2 g of Mo.     

Application of macroautoradiography and instantimage in radiopharmaceutical research

The evaluation of the pharmacokinetics of pure, beta radiopharmaceuticals is not possible with scintigraphy. Both whole-body autoradiography (WBAR) and Packard Instantimager, a device for rapid imaging, were used to study the whole body distribution of γ- and β-emitting radionuclides (^99mTc-MDP,^99mTc-sulfur colloid, or¹⁸⁸Re-HEDP), and results obtained from both methods were compared. The biodistribution of^99mTc-MDP and¹⁸⁸Re-HEDP were seen mainly in bones including skull, spine, and vertebrae of spine and cardiac and skeletal muscles. The^99mTc-sulfur colloid localized in liver, bone marrow, and spleen. The resolution of WBAR is superior than that of Packard Instantimager. However, the advantage of Packard Instantimager is that rapid imaging within few minutes is possible with it, while WBAR imaging requires several hours to days.     

Radiochemical studies on generator eluted113mIn chloride

^113mIn is milked out of a¹¹³Sn-^113mIn generator with dilute hydrochloric acid for use in nuclear medicine. The concentrations of the various impurities like Sn, Zr and their colloidal forms which may trap^113mIn activity have to be initially evaluated before releasing the generator for medicinal use. The authors have evaluated the purity of the^113mIn-chloride obtained from the generators in detail. The possibility of using a mixture of HCl and NaCl as an alternative eluent for^113mIn has also been investigated. It has been observed that this new eluent gives greater yields of^113mIn and renders the final manipulation of isotonicity of indium labelled compounds easy.     

Potential use of tungstocerate matrices on the separation of <Superscript>113m</Superscript>In from <Superscript>110m</Superscript>Ag relevant to the separation of the cyclotron-produced <Superscript>111</Superscript>In from its silver target

A procedure for separation of no-carrier-added ^113mIn(III) radioisotope from a bulk of ^110mAg has been developed. The sorption behavior of ^113mIn(III) and ^110mAg(I) ions in HNO₃ acid solutions on different tungstocerate matrices showed high affinity of ^110mAg(I) ions towards tungstocerate(IV) gel matrices compared with ^113mIn(III) ions. No-carrier-added ^113mIn radionuclide was separated from ^110mAg on 12-tungstocerate(IV) column matrix. 11 mL 0.3M HNO₃ acid solution was enough for eluting the ^113mIn from the column bed. ^110mAg was recovered from the column by eluting the column bed with 12 mL 2M HNO₃ acid solution.     

A certified reference material for radionuclides in the water sample from Irish Sea (IAEA-443)

A new certified reference material (CRM) for radionuclides in sea water from the Irish sea (IAEA-443) is described and the results of the certification process are presented. Ten radionuclides (³H, ⁴⁰K, ⁹⁰Sr, ¹³⁷Cs, ²³⁴U, ²³⁵U, ²³⁸U, ²³⁸Pu, ^239+240Pu and ²⁴¹Am) have been certified, and information values on massic activities with 95% confidence intervals are given for four radionuclides (²³⁰Th, ²³²Th, ²³⁹Pu and ²⁴⁰Pu). Results for less frequently reported radionuclides (⁹⁹Tc, ²²⁸Th, ²³⁷Np and ²⁴¹Pu) are also reported. The CRM can be used for quality assurance/quality control of the analysis of radionuclides in water samples, for the development and validation of analytical methods and for training purposes. The material is available in 5 L units from IAEA (http://nucleus.iaea.org/rpst/index.htm).     

A novel electrochemical <Superscript>99</Superscript>Mo/<Superscript>99m</Superscript>Tc generator

A novel electrochemical process to avail clinical grade ^99mTc from (n,γ)⁹⁹Mo has been demonstrated. The electrochemical parameters were optimized to maximize the ^99mTc yield with minimal ⁹⁹Mo contamination. ⁹⁹Mo/^99mTc generators containing up to 29.6 GBq (800 mCi) ⁹⁹Mo were developed and their performance were extensively evaluated for 10 days without changing the operating conditions. Very high radioactive concentration of ^99mTcO₄ ⁻ of acceptable quality, commensurate with hospital radiopharmacy requirements could be availed from the system with >90% yield. The compatibility of the product for the formulation of ^99mTc labeled radiopharmaceuticals such as ^99mTc-DMSA and ^99mTc-EC was found to be satisfactory in terms of high labeling yields. The proposed route represents an important step for enhancing the scope of accessing clinical grade ^99mTc from low specific activity (n, γ)⁹⁹Mo.     

Chemical and radiochemical evaluation of the purity of99mTc extracted by MEK

Solvent extraction separation of^99mTc from⁹⁹Mo using methyl ethyl ketone(MEK) has been found to be an effective method of obtaining^99mTc of medicinal purity from low specific activity⁹⁹Mo. The authors have investigated the effect of alkali and molybdenum concentration on the extraction of⁹⁹Mo and^99mTc into methyl ethyl ketone. The possibility of methyl ethyl ketone forming enol and condensation products and its effect on the final extraction efficiency and purity of^99mTc has been studied. Sodium molybdate has been found to have a good salting out effect on^99mTc pertechnetate and hence^99mTc extraction can be better accomplished from low specific activity⁹⁹Mo solutions. The ketone seems to form traces of condensation products in the extraction procedure. These have been found to be coextracted with^99mTc into MEK but did not affect the extractability of^99mTc. It was observed that neutral alumina column removes these condensation products from MEK containing^99mTc. Alternately these could be filtered off by acidification of the final aqueous^99mTc solution. The studies indicate that under optimum experimental conditions methyl ethyl ketone separates^99mTc from⁹⁹Mo with high efficiency and yields^99mTc of high purity suitable for use in nuclear medicine in the form of various labelled compounds.     

Detection of99Tc by accelerator mass spectrometry: Preliminary investigations

Accelerator mass spectrometry (AMS) is an established technique for the detection of long-lived radionuclides at environmental levels. At LLNL, planned facility upgrades and advances in detection techniques are allowing us to explore the applicability of AMS to isotopes not previously pursued. One such isotope is⁹⁹Tc. We have performed a number of preliminary tests to examine the technical feasibility of AMS for the detection of⁹⁹Tc. The questions addressed were negative ion production in the cesium sputter source, transport efficiency for the ions through the spectrometer, and detection efficiency for⁹⁹Tc ions after the spectrometer. Based on the positive results of these tests, we have begun to develo measurement protocol.     

Automated separation and measurement of radioxenon for the Comprehensive Test Ban Treaty

A fully automatic radioxenon sampler/analyzer (ARSA) has been developed and demonstrated for the collection and quantitative measurement of the four xenon radionuclides,^131mXe(11.9 d),^133mXe(2.2 d),¹³³Xe(5.2 d), and¹³⁵Xe(9.1 hr), in the atmosphere. These radionuclides are important signatures in monitoring for compliance to a Comprehensive Test Ban Treaty (CTBT). Activity ratios of these radionuclides permit source attribution. Xenon, continuously and automatically separated from the atmosphere, is automatically analyzed by electron-photon coincidence spectrometry providing a lower limit of detection of about 100 μBq/m³. The demonstrated detection limit is about 100 times better than achievable with reported laboratory-based procedures for the short-time collection intervals of interest.