Academic literature on the topic '68Ge/68Ga generators'

ABSTRACT 68Ga faces a renaissance initiated by the development of new 68Ge/68Ga radionuclide generators, sophisticated 68Ga radiopharmaceuticals, preclinical research and state-of-the-art clincial diagnoses via positron emission tomography/computed tomography (PET/CT). A new type of 68Ge/68Ga generator became commercially available in the first years of the 21st century, with eluates based on hydrochloric acid. These generators provided ‘cationic’ 68Ga instead of ‘inert’ 68Gacomplexes, and opened new pathways of MeIII radiopharmaceutical chemistry. The last decade has seen a 68Ga rush. Increasing interest in generator-based 68Ga radiopharmaceuticals in diagnostic applications has been accompanied by its potential use in the context of diease treatment planning, made possible by the inherent option expressed by theranostics. However, widespread acceptance and clinical application requires optimization of 68Ge/68Ga generators both from chemical and regulatory perspectives. How to cite this article Rösch F. 68Ge/68Ga Generators and 68Ga Radiopharmaceutical Chemistry on Their Way into a New Century. J Postgrad Med Edu Res 2013;47(1):18-25.

68Ga (T1 / 2 = 68 min) in complexes with peptides is used in positron emission tomography for diagnostics of neuroendocrine tumors. The most promising strategy for 68Ga production is usage of the radionuclide generator 68Ge → 68Ga. In this research, the sorption behavior of Ge(IV) and Ga (III) has been studied. The distribution coefficients (Kd) of Ge(IV) on the anion exchange (Dowex 1×8) and cation exchange (Dowex 50×8) resins in various ethanedioic and hydrochloric acid solutions were determined. For each ion exchange resin, four series of measurements were carried out, in which the concentration of oxalic acid was fixed (0.001 M, 0.003 M, 0.005 M, 0.01 M), and the concentrations of hydrochloric acid ranged from 0 to 3 M. Based on the distribution coefficients, the chemical scheme of the radionuclide generator 68Ge → 68Ga has been developed. The chemical system is based on the anion exchange resin Dowex 1×8 and mixture of 0.005 M C2H2O4 / 0.33 M HCl. Several types of the generators with direct and reverse mode of elution were tested and the optimal scheme was determined. Elution of the generators was performed once a day with 8 ml of 0.005 M C2H2O4 / 0.33 M HCl solution. The 68Ga yield and the 68Ge breakthrough are comparable for all the systems.

ABSTRACT The use of gallium-68 for molecular imaging is gaining momentum world-wide. While our understanding of 68Ga chemistry, generators, and associated synthesis modules appear to have advanced to a clinically-reliable stage, uncertainty in the supply of radiopharmaceutically-suitable parent is of significant concern. In this work, we examine the current supply of 68Ge in an effort to better understand the potential for expansion of manufacturing to meet an increasing demand for 68Ga. Although specific information on sales and demand of 68Ge is highly business sensitive and thus guarded, our examination finds no shortage in the current supply of 68Ge. On the other hand, increases in the use of 68Ge generators for clinical applications in the United States point to the need for continued support for production at DOE laboratories in the United States to ensure a reliable supply and suggests that new commercial facilities may be needed to meet the increasing demand. How to cite this article Schultz MK, Donahue P, Musgrave NI, Zhernosekov K, Naidoo C, Razbash A, Tworovska I, Dick DW, Watkins GL, Graham MM, Runde W, Clanton JA, Sunderland JJ. An Increasing Role for 68Ga PET Imaging: A Perspective on the Availability of Parent 68Ge Material for Generator Manufacturing in an Expanding Market. J Postgrad Med Edu Res 2013;47(1):26-30.

ABSTRACT Gallium-68, a positron emitter, is available via 68Ge/68Ga generators. The simple chemistry and easy availability has increased its application from the clinical diagnosis to personalized therapy and has lot more potential in future. How to cite this article Shukla J, Mittal BR. Ga-68: A Versatile PET Imaging Radionuclide. J Postgrad Med Edu Res 2013;47(1):74-76.

Over the past 20 years, 68Ga-labelled radiopharmaceuticals have become an important part in clinical routine. However, the worldwide supply with 68Ge/68Ga generators is limited as well as the number of patient doses per batch of 68Ga radiopharmaceutical. In the recent years, a new technique appeared, making use of the ease of aqueous labelling via chelators as with 68Ga but using 18F instead. This technique takes advantage of the strong coordinative bond between aluminium and fluoride, realized in the aqueous cation [Al18F]2+. Most applications to date make use of one-pot syntheses with free Al(III) ions in the system. In contrast, we investigated the labelling approach split into two steps: generating the Al-bearing precursor in pure form and using this Al compound as a precursor in the labelling step with aqueous [18F]fluoride. Hence, no free Al3+ ions are present in the labelling step. We investigated the impact of parameters: temperature, pH, addition of organic solvent, and reaction time using the model chelator NH2-MPAA-NODA. With optimized parameters we could stably achieve a 80% radiochemical yield exerting a 30-min reaction time at 100 °C. This technique has the potential to become an important approach in radiopharmaceutical syntheses.

During the preparation of [68Ga]Ga-NOTA-sdAb at high activity, degradation of the tracers was observed, impacting the radiochemical purity (RCP). Increasing starting activities in radiolabelings is often paired with increased degradation of the tracer due to the formation of free radical species, a process known as radiolysis. Radical scavengers and antioxidants can act as radioprotectant due to their fast interaction with formed radicals and can therefore reduce the degree of radiolysis. This study aims to optimize a formulation to prevent radiolysis during the labeling of NOTA derivatized single domain antibody (sdAbs) with 68Ga. Gentisic acid, ascorbic acid, ethanol and polyvinylpyrrolidone were tested individually or in combination to find an optimal mix able to prevent radiolysis without adversely influencing the radiochemical purity (RCP) or the functionality of the tracer. RCP and degree of radiolysis were assessed via thin layer chromatography and size exclusion chromatography for up to three hours after radiolabeling. Individually, the radioprotectants showed insufficient efficacy in reducing radiolysis when using high activities of 68Ga, while being limited in amount due to negative impact on radiolabeling of the tracer. A combination of 20% ethanol (VEtOH/VBuffer%) and 5 mg ascorbic acid proved successful in preventing radiolysis during labeling with starting activities up to 1–1.2 GBq of 68Ga, and is able to keep the tracer stable for up to at least 3 h after labeling at room temperature. The prevention of radiolysis by the combination of ethanol and ascorbic acid potentially allows radiolabeling compatibility of NOTA-sdAbs with all currently available 68Ge/68Ga generators. Additionally, a design is proposed to allow the incorporation of the radioprotectant in an ongoing diagnostic kit development for 68Ga labeling of NOTA-sdAbs.

>Magister Scientiae - MSc
68Ge/68Ga generators rely on metal oxide, inorganic and organic sorbents in order to prepare radionuclides useful for clinical applications. The requirements for 68Ge/68Ga generators are that the 68Ga obtained from the 68Ge loaded column should be optimally suited for the routine synthesis of 68Ga-labelled radiopharmaceuticals, that the separation of the 68Ga daughter from the 68Ge parent should happen easily, with a high yield of separation, a low specific volume of 68Ga and should not contain trace elements owing to the solubility of the metal oxide sorbent. Beginning with a metal oxide preparation and continuing through recent developments, several approaches for processing generator derived 68Ga have altered the production of 68Ge/68Ga generators. Still, the effects of sorbent modification on the properties of 68Ge/68Ga radionuclide generator systems are not necessarily optimally designed for direct application in a medical context. The objective of this research was to analyze and document characteristics of Titanium Oxide (TiO2) sorbents relevant to processing of a 68Ge/68Ga generator that is able to produce 68Ga eluates that are adequate for clinical requirements. Interest was shown in TiO2 based 68Ge/68Ga generators by a number of overseas companies for tumour imaging using 68Ga-labelled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated peptides. While a method involving production of the 68Ga radionuclide using TiO2 metal oxide had been published, problems with the production persisted. A method, using TiO2 metal oxide for ion exchange chromatography, was devised in this study to produce the 68Ga radionuclide, with the aim of being adopted for production purposes. The study focuses on the development of a dedicated procedure for the achievement of sufficient 68Ga yield along with low 68Ge breakthrough and low metallic impurities. Literature from 1970 to 2011 was reviewed to assess the radiochemical aspects of the 68Ga production and processing thereof. Various commercially available TiO2 metal oxides were characterized by subjecting the materials to x-ray diffraction (XRD), x-ray fluorescence (XRF) and scanning electron microscopy (SEM) for quantitative and qualitative analysis.

Há mais de 50 anos os geradores de 68Ge/68Ga vêm sendo desenvolvidos, obtendo o 68Ga sem a necessidade da instalação de um cíclotron próximo à radiofarmácia ou ao centro hospitalar que tenha um PET/CT. O 68Ga é um emissor de pósitron com baixa emissão de fóton (β+, 89%, 1077 keV) e meia vida de 67,7 minutos, compatível com a farmacocinética de moléculas de baixo peso molecular, como peptídeos e fragmentos de anticorpos. Além disso, a química do Ga permite a ligação estável com agentes quelantes acoplados com peptídeos, como o DOTA. Todas estas características do 68Ga aliado a tecnologia PET/CT permitiram avanços em imagem molecular, como no diagnóstico de doenças de origem neuroendócrina. Entretanto, o eluato de 68Ga proveniente dos geradores de 68Ge/68Ga comerciais, ainda contém altos níveis de contaminantes, como o 68Ge e outros metais que competem quimicamente com o 68Ga, como o Fe3+ e Zn2+ e, como consequência, há redução do rendimento de marcação com biomoléculas. Quanto menor a quantidade de impurezas no eluato, a competição entre o peptídeo radiomarcado e peptídeo não marcado será menor e a qualidade de imagem será melhor, por isso existe a necessidade de diminuir a quantidade destes metais. Portanto, os objetivos deste trabalho são avaliar os métodos de purificação do 68Ga para a marcação de biomoléculas, com ênfase no estudo das impurezas químicas presentes nos radioisótopos primários, e desenvolver um método de purificação inédito. Diversos métodos de purificação foram estudados. Na purificação em resina catiônica tradicional e comercial, em que o 68Ga é adsorvido em resina catiônica e eluído em uma solução de acetona/ácido, a resina utilizada não é disponível comercialmente. Várias resinas catiônicas foram testadas simulando o processo comercial, e o uso das menores partículas da resina catiônica AG50W-X4 (200-400 mesh) foi a que apresentou os melhores resultados. Um método inovador foi a cromatografia por extração, onde o éter diisopropílico é adsorvido em resina XAD 16 e o 68Ga eluído em água deionizada. Apesar dos resultados de recuperação do 68Ga e a separação entre o 68Ga e o 65Zn terem sido bons, não houve reprodutibilidade na purificação dos metais. O método mais promissor e inédito foi a purificação do 68Ga em resina catiônica em meio básico que apresentou bons resultados, principalmente em relação à redução do Zn (98 ± 2)%, o contaminante químico encontrado em maior abundância no eluato de 68Ga. A redução total de impurezas foi (95 ± 4)%. Os peptídeos DOTATOC/DOTATATO foram marcados com o 68Ga em três diferentes formas: purificado em meio básico, por extração por solventes e sem a purificação prévia, o melhor resultado de rendimento de marcação do 68Ga DOTATATO foi obtido após a purificação do 68Ga em meio básico, comprovando a eficiência do processo.
For more than fifty years, the long-lived 68Ge/68Ga generators have been in development, obtaining 68Ga without the need of having in house cyclotron, which is a considerable convenience for PET centers that have no nearby cyclotrons. 68Ga decays 89% by positron emission and low photon emission (1077 keV) and the physical half life of 67.7 minutes is compatible with the pharmacokinetics of low biomolecular weight substances like peptides and antibody fragments. Moreover, its established metallic chemistry allows it to be stably bound to the carrier peptide sequence via a suitable bifunctional chelator, such as DOTA. All these reasons together with the technology of PET/CT allowed advances in molecular imaging, in particular in the diagnosis of neuroendocrine diseases. However, the eluate from the commercial 68Ge/68Ga generators still contains high levels of long lived 68Ge, besides other metallic impurities, which competes with 68Ga with a consequent reduction of the labeling yield of biomolecules, such as Fe3+ and Zn2+. Thus, the lower the amount of impurities in the eluate, the competition between the radiolabeled and unlabeled peptide by the receptor will be smaller and the quality of imaging will be better, a subsequent purification step is needed after the generator elution. The aim of this work is to evaluate different purifications methods of 68Ga to label biomolecules, with emphasis on the study of the chemical impurities contained in the eluate and to develop a new purification method. Several purification methods were studied. Many cationic resin were tested simulating the commercial process. 68Ga is adsorbed in cationic resin, which is not commercial available and eluted in acid/acetone solution. The use of minor particles of cationic resin AG50W-X4 (200-400 mesh) showed the best results. An innovate method was the extraction chromatography, wich is based on the absorption of diisopropyl ether in XAD 16 and 68Ga recovery in deionized water. Although the results regarding to 68Ga recovery and the radiochemical separation between 68Ga and 65Zn were excellent, there was no reproducibility on the purification of metals. The most promising and innovative method was the 68Ga purification performed by cationic resin in basic media, which presented the best results, especially regarding the Zn reduction (98 ± 2)%, the chemical contaminant found in great abundance in 68Ga eluate. The total impurities reduction was (95 ± 4)%. The peptides DOTATOC/DOTATATE were labeled 68Ga in three different forms: purified 68Ga in basic solution, through solvent extraction and no purified 68Ga. The best result was achieved with DOTATATE labeling with purified 68Ga in basic media, proving the purification process efficiency.

The positron emitting radionuclide 68Ga (T1/2 = 68 min) might become of practical interest for clinical positron emission tomography (PET). The metallic cation, 68Ga(III), is suitable for complexation with chelators, either naked or conjugated with biological macromolecules. Such labelling procedures require pure and concentrated preparations of 68Ga(III), which cannot be sufficiently fulfilled by the presently available 68Ge/68Ga generator eluate. This thesis presents methods to increase the concentration and purity of 68Ga obtained from a commercial 68Ge/68Ga generator. The use of the preconcentrated and purified 68Ga eluate along with microwave heating allowed quantitative 68Ga-labelling of peptide conjugates within 15 min. The specific radioactivity of the radiolabelled peptides was improved considerably compared to previously applied techniques using non-treated generator eluate and conventional heating. A commercial 68Ge/68Ga generator in combination with the method for preconcentration/purification and microwave heated labelling might result in an automated device for 68Ga-based radiopharmaceutical kit production with quantitative incorporation of 68Ga(III). Macromolecules were labelled with 68Ga(III) either directly or via a chelator. The bifunctional chelator, DOTA, was conjugated in solution to peptides, an antibody and oligonucleotides. The peptides had varied pI values, constitution, and length ranging from 8 to 53 amino acid residues. The oligonucleotides were of various sequences and length with modifications in backbone, sugar moiety and both 3' and 5' ends with a molecular weight up to 9.8 kDa. The bioconjugates were labeled with 68Ga(III), and the resulting tracers were characterised chemically and biologically. The identity of the 68Ga-labelled bioconjugates was verified. The tracers were found to be stable and their biological activity maintained. Specific radioactivity was shown to be an important parameter influencing the feasibility of accurate imaging data quantification. Furthermore, 68Ga-labelled peptide imaging was shown to be a useful tool to study peptide adsorption to microstructures in a chemical analysis device.

Introduction: Targeted pharmaceuticals for labelling with radio-isotopes for very specific imaging (and possibly later for targeted therapy) play a major role in Theranostics which is currently an important topic in Nuclear Medicine as well as personalised medicine. There was a need for a very specific lung cancer radiopharmaceutical that would specifically be uptaken in integrin 3 expression cells to image patients using a Positron Emission Tomography- Computed Tomography (PET-CT) scanner. Background and problem statement: Cold kits of c (RGDyK)–SCN-Bz-NOTA were kindly donated by Seoul National University (SNU) to help meet Steve Biko Hospital’s need for this type of imaging. These cold kits showed great results internationally in labelling with a 0.1 M 68Ge/68Ga generator (t1/2 of 68Ge and 68Ga are 270.8 days and 67.6 min, respectively). However the same cold kits failed to show reproducible radiolabeling with the 0.6 M generator manufactured under cGMP conditions at iThemba LABS, Cape Town and distributed by IDB Holland, the Netherlands. Materials and methods: There was therefore a need for producing an in-house NOTA-RGD kit that would enable production of clinical 68Ga-NOTA-RGD in high yields from the IDB Holland/iThemba LABS generator. Quality control included ITLC in citric acid to observe labelling efficiency as well as in sodium carbonate to evaluate colloid formation. HPLC was also performed at iThemba LABS as well as Necsa (South African Nuclear Energy Corporation). RGD was obtained from Futurechem, Korea. Kit mass integrity was determined by testing labelling efficiency of 10, 30 and 60 μg of RGD per cold kit. The RGD was buffered with sodium acetate trihydrate. The original kits were dried in a desiccator and in later studies only freeze dried. Manual labelling was also tested. The radiolabelled in-house kit’s ex vivo biodistribution in healthy versus tumour mice were examined by obtaining xenografts. The normal biodistribution was investigated in three vervet monkeys by doing PET-CT scans on a Siemens Biograph TP 40 slice scanner. Results: Cold kit formulation radiolabeling and purification methods were established successfully and SOPs (standard operating procedures) created. HPLC results showed highest radiochemical purity in 60 μg cold kit vials. 68Ga-NOTA-RGD showed increased uptake in tumours of tumour bearing mouse. The cold kit also showed normal distribution according to literature with fast blood clearance and excretion through kidneys into urine, therefore making it a suitable radiopharmaceutical for clinical studies. Conclusion: The in-house prepared cold kit with a 4 month shelf-life was successfully tested in mice and monkeys.
MSc (Pharmaceutics), North-West University, Potchefstroom Campus, 2014

Gallium-68 was applied for positron emission tomography (PET) imaging already in the early beginnings of PET imaging. Today, with the introduction of PSMA-targeting tracers (e.g. PSMA-11, PSMA-617, and PSMA-I&T), the number of clinical applications of 68Ga-radiopharmaceuticals for diagnostic imaging has grown considerably. This development was initiated and supported already in the mid-2000s by the commercial availability of 68Ge/68Ga generators designed for clinical usage. This progression was accompanied by the development of several purification methods to generator eluate as well as sophisticated 68Ga-radiopharmaceuticals. Due to the 68Ga-rush, the need for implementation of gallium-68 (depending on production route) and its certain tracers into the pharmacopeia increased. Based on the specifications given by the pharmacopeia, interest focused on the development of automated synthesis systems, 99mTc-analog kits with regard to patient as well as operator safety.