EP1820197B1 - Method and device for isolating a chemically and radiochemically cleaned 68ga-radio nuclide and for marking a marking precursor with the 68ga-radio nuclide - Google Patents

Abstract

The invention relates to initial 68Ge/Ga-generator elute which is guided directly to a cation exchanger, whereon 68Ga is quantitatively absorbed and is cleaned simultaneously in a chemical and radio chemical manner. Subsequently, the 68Ga-radio nuclide is combined with a radio pharmaceutical substance by a marking precursor made of a ligand or a peptide or a protein which is cross-linked in a covalent manner to a ligand.

Description

The invention relates to a method and apparatus for isolating a ⁶⁸ Ga radionuclide from a ⁶⁸ Ge / Ga generator eluate and for labeling a label precursor with the ⁶⁸ Ga radionuclide to form a radiopharmaceutical.

The positron-emitting ⁶⁸ Ga radionuclide with T _½ = 68 min is of great practical importance for clinical positron emission tomography (PET). For the production of radionuclides known Radionuldidgeneratoren are used, wherein the obtained daughter Radionuldide generally have short half-times T _½ in comparison with their parent radionuclides.

Such radionuclide generators are based on a concept of effective radiochemical separation of decaying mother and daughter radionuldides in such a way that the daughter void should be obtained in radionuclidically and radiochemically as pure a form as possible.

Compared to in-house radionuclide production facilities such as accelerators or nuclear reactors, the availability of short-lived radionuclides from radionuclide generators offers a cheap and easy alternative.

The development of radionuclide generators over the last three decades has always been shaped by the growing spectrum of applications of radionuclides and labeled agents in medicine, particularly for nuclear medicine diagnostics and therapy. In addition, promising applications of generator-based therapeutic radionuclides in nuclear medicine, oncology and cardiology have been developed in recent years. This growing importance of radionuclide generators has stimulated a broad development of radionuclide production for radionuclide generators, for adequate radiochemical separations as well as for reliable engineering design of radionuclide generator systems. The first generator for life science applications was developed as early as 1920 and made available over ²²⁶ Ra (T _½ = 1.60 · 10 ³ a) for the production of radon seeds for radiotherapy the daughter) ²²² Rn (T _½ = 3,825 d) ,

Radionuldide generators, however, were of practical importance only in 1951 in the form of the ¹³² Te (T _½ = 3.26 d) / ¹³² I (T _½ = 1.39 h) generator, and to a much greater extent in 1957 by the groundbreaking development of the ⁹⁹ Mo / ^99m Tc generator (Stang et al., 1954, 1957). The potential of the daughter's technetium for medical uses soon became apparent, and in fact, the first clinical applications were described as early as 1961, which have since revolutionized radiopharmaceutical chemistry and nugary medicine.

The widespread use of the ⁹⁹ Mo / ⁹⁹ Tc generator system in nuclear medicine is a typical example of the importance of radionuclide generators for clinicians and radiopharmaceutical manufacturers for a wide range of diagnostic radiopharmaceuticals. More than 3 5 000 diagnostic studies using ^99m Tc are performed valued daily in the US alone, which is more than 12 million applications a year, estimated.

Radionuclide generator developments have often been systematized. Detailed reports have covered several aspects: parent-daughter half-lives, reactor-produced Nuldides, accelerator-produced Nuldide, generator mother nuclide cyclotron production, ultra-short-lived generator-produced radionuclides, generator-based positron-emitting radionuclides, clinical applications.

Meanwhile, various other generator systems have been developed and some of them have gained significant practical importance. At present, 68Ge (T _½ = 270.8 d) / ⁶⁸ Ga (T _½ = 68 min) generator systems determine the state of the art. Various types of separation, ⁶⁸ Ga yields and ⁶⁸ Ge contents are mixed below.

The initial generator systems separated ⁶⁸ Ga as an EDTA complex of ⁶⁸ Ge adsorbed on alumina or zirconia, with the resultant neutral [ ⁶⁸ Ga] EDTA solution serving to image tumors. According to an analogous concept, ⁶⁸ Ge was retained on antimony oxide Sb ₂ O ₅ and ⁶⁸ Ga was eluted with oxalate solutions. Anion exchange resins and dilute HF solutions as eluent allowed highly effective separations due to the significant Differences in the distribution coefficients of the elements. The breakthrough of ⁶⁸ Ge was below 10 ^-4 percent for up to 600 elutions; the ⁶⁸ Ga yield was greater than 90%.

In all these generator systems, further direct use of the generator eluates for ⁶⁸ Ga markers was not possible. Therefore, ⁶⁸ Ge / ⁶⁸ Ga generators were developed leading to ionic ⁶⁸ Ga ³⁺ eluates. In these cases, ⁶⁸ Ge was fixed on inorganic matrices such as alumina Al (OH) ₃ and Fe (OH) ₃ , on SnO ₂ , ZrO ₂ , TiO ₂ or CeO ₂ . Tin (IV) oxide SnO ₂ showed the best parameters for ⁶⁸ Ge breakthrough (10 ^-6 -10 ^-5 % by bolus) and ⁶⁸ Ga ³⁺ elution yield (70-80%) in 1 M HCl. Since Ge (IV) is known to form stable complexes with phenolic groups, ⁶⁸ Ge (VI) adsorption to 1,2,3-trihydroxybenzene (pyrogallol) -formaldehyde resins has also been exploited. Thus, for a 370 MBq (10 mCi) generator, ⁶⁸ Ga ³⁺ elution yields of greater than 50% and ⁶⁸ Ge breakthroughs of less than 0.01 ppm were described in the course of the first uses.

The ⁶⁸ Ge content defines the radiochemical purity of the separated ⁶⁸ Ga fraction. Even an initial contamination of about 10 ^-2 %, corresponding to, for example, 1 μCi ⁶⁸ Ge in a ⁶⁸ Ga fraction of a 10 mCi ⁶⁸ Ge / Ga generator system, already seems marginal with regard to a subsequent medical application.

⁶⁸ Ga eluate volume and chemical purity are further important data for the use of ⁶⁸ Ga for the synthesis of radiopharmaceuticals.

All currently commercially available ⁶⁸ Ge / Ga generator systems require elution volumes of several ml of different HCl solutions. In addition to the considerable volumes, the chemical purity of these ⁶⁸ Ga eluates is another critical aspect of ⁶⁸ Ge / Ga generator systems.

Highest chemical purities, especially a minimal content of various metallic cations, are required for efficient labeling reactions with high yields. This is especially true in cases where the labeling chemistry is designed via bifunctional chelating agents is. Already small contents of stable ⁶⁸ Zn as direct decay product of ⁶⁸ Ga, on titanium, in cases where the ⁶⁸ Ge / Ga generator system ion exchange column is formed of TiO ₂ , and especially iron, can prevent high labeling yields.

Currently available commercial ⁶⁸ Ge / Ga generator systems are limited to effective ⁶⁸ Ga elutions and do not include the modalities for volume minimization and purification of the generator eluates as well as markers of potential radiopharmaceuticals.

Initial volumes of the eluates range from a few ml up to 10 ml of HCl solutions of different concentrations. Both labeling reactions and filling of balloons usually require smaller volumes of about 0.5 ml to 0.1 ml. Therefore, chemical or technological strategies are required, which reduce the eluate volume immediately after the initial generator elution.

• dem Generatorsäulenmaterial (beispielsweise TiO₂);
• trivalentem Fe, das in Spuren allgegenwärtig ist und insbesondere mit diversen Elelctrolyten während der Generatorherstellung oder -benutzung eingeführt werden kann;
• ⁶⁸Zn als stabile metallische Verunreinigung, die systeminhärent kontinuierlich als Zerfallsprodukt des ⁶⁸Ga auf der Generatorsäule generiert wird;
• ⁶⁸Ge als Mutter-Radionuklid, wobei selbst geringe Kontaminationen von weniger als 0,01 % des ⁶⁸Ge im Eluat eine ähnliche Zahl von Atomen repräsentieren wie das ⁶⁸Ga selbst,
• und welche radiotoxisch und chemisch toxisch wirken können.

Second, the generator eluate may contain chemical and radiochemical contaminants that prevent efficient high yielding radiochemical labeling yields. These chemical contaminants can come from:

• the generator column material (eg, TiO ₂ );
• trivalent Fe, which is ubiquitous in trace amounts and, in particular, can be introduced with various eletrolytics during generator production or use;
• ⁶⁸ Zn as a stable metallic contaminant that is systemically inherently generated as a decay product of the ⁶⁸ Ga on the generator column;
• ⁶⁸ Ge as parent radionuclide, with even minor contaminations of less than 0.01% of the ⁶⁸ Ge in the eluate representing a similar number of atoms as the ⁶⁸ Ga itself,
• and which can be radiotoxic and chemically toxic.

In addition to the chemical impurity aspect of ⁶⁸ Ge in the generator eluate, this contamination is also radiochemically relevant, particularly with regard to potential medical applications. The post-elution procedure should therefore explicitly include a chemical strategy for further separation of the ⁶⁸ Ge.

Third, the ⁶⁸ Ga-labeling of potential radiophannaka plays a central role, for which the corresponding chemical reaction parameters have to be optimized.

The trivalent gallium already hydrolyzes above pH> 2 and has a pronounced tendency to adsorb on surfaces of glass and polymers at pH> 3, in particular in the state of low ⁶⁸ Ga concentrations ( no-carrier-added ), as they result from the generator system results. Finally, in the case of the labeling chemistry of targeting vectors via bifunctional chelators such as DOTA, special reaction conditions have to be chosen because of the complexing kinetics as well as because of the aqua-chemistry of the Ga (III) cation.

In addition to the metallic impurities associated with the operation of the generator system, which are eluted with the ⁶⁸ Ga, impurities contained therein may also interfere with high labeling yields, even in the buffer systems typically used in ⁶⁸ Ga tags.

Also, solvent evaporation processes to reduce the volumes of the generator eluates or the final solutions of the ⁶⁸ Ga radiopharmaceuticals can lead to loss of activity, both by the associated longer process time and by adsorption losses on the vessel walls.

Sporadic experimental designs have been developed to minimize the eluate volume for ^6g Ge / Ga generator systems. Some of these realizations (Meyer et al., 2004, Velikyan et al., 2004) minimize the initial eluate volume by mixing with a few ml of concentrated HCl, resulting in a total 6M HCl solution of increased volume of about 15 ml. This large volume is then transferred to an anion exchange column on which ⁶⁸ Ga is adsorbed. Thereafter, ⁶⁸ Ga is eluted with less than 1 ml of water. While this time-consuming procedure does reduce the volume of the ⁶⁸ Ga fraction, there is no obvious parallel strategy for separating chemical contaminants from the initial generator eluate.

This fraction is then added to 10-20 nmol of DOTATOC in a small volume of 1M HEPES or other aqueous buffer solution. Again, potential contamination by the concentrated buffer system can not be excluded.

These factors may be the reason why under standard heating protocols, labeling yields of ⁶⁸ Ga-DOTATOC and analogues of only 58 ± 20% are achieved (Meyer et al., 2004). Higher yields are described by microwave assisted heating (Velikyan et al., 2004).

Another method using an organic polymer as the adsorbent is in Nakayama et al., Applied Radiation and Isotopes 58 (2003) 9-14 disclosed. An example of an apparatus for isolating a ⁶⁸ Ga radionuclide from a ⁶⁸ Ge / Ga generator eluate is in US Pat WO 99/49935 disclosed.

None of the currently available commercial generator systems, on the whole, contain the appropriate chemical or technological strategies to solve the above problems altogether.

The object of the invention is to provide a method and an apparatus to provide the high purity ⁶⁸ Ga eluate, which is largely free of chemical and radiochemical impurities, with high yield and very low Eluatvolumen available. As part of this task, the chemical reaction parameters such as the pH of the ⁶⁸ Ga for the labeling of marker precursors to be optimized. Furthermore, a method for labeling potential radiopharmaceuticals for positron emission tomography is to be provided.

All process steps should meet the requirements of simple and routine use in a medical environment.

This object is achieved in accordance with the invention by a process in which the initial ⁶⁸ Ge / Ga generator eluate is fed directly to a cation exchanger and ⁶⁸ Ga is quantitatively adsorbed on the cation exchanger, simultaneously chemically and radiochemically purified and the ⁶⁸ Ga radionuclide with a marketed precursor from a ligand or a a peptide or protein covalently linked to a ligand is combined to form a radiopharmaceutical.

In a further development of the process, the cation exchanger from the group of strongly acidic cation exchanger polystyrene / divinylbenzene (DVB) resins is selected with a DVB content of 2 to 20%, based on the crosslinked polymers of the resins, and becomes the matrix of the cation exchanger with ⁶⁸ Ga loaded. The sulfonated polystyrene / divinylbenzene (DVB) resins have a gel-like structure and permanently have negatively charged sulfonic acid groups. Each of these active groups has a fixed electrical charge and is in equilibrium with a number of equivalent oppositely charged ions which are free to exchange with other ions of the same charge.

Already during the absorption of ⁶⁸ Ga on the cation exchanger, a chemical purification takes place in that the initially eluted ⁶⁸ Ge is not adsorbed and thus the radiochemical ⁶⁸ Ge contamination is reduced to a value less than 10 ^-8 percent.

In carrying out the process, further, the ⁶⁸ Ga fraction adsorbed on the cation exchanger is cleaned with acid solutions of the HCl / acetone or HCl / ethanol or analog systems type so that chemical impurities such as Fe (III) and Zn (II) elute from the cation exchanger become. During the elution ⁶⁸ Ga remains completely on the cation exchanger, and there is a substantial separation of initially eluted Ti (IV).

The chemically and radiochemically pure ⁶⁸ Ga radionuclide obtained by the elution can be used directly for the synthesis of radiopharmaceuticals.

The further embodiment of this method results from the features of the claims 6 to 16.

The apparatus for isolating a chemically and radiochemically purified ⁶⁸ Ga radionuclide from a ⁶⁸ Ge / Ga generator eluate and for labeling a label precursor with the ⁶⁸ Ga radionuclide, in an embodiment of the invention, includes a conveyor connected by a line to a ⁶⁸ Ge / Ga generator a number of conveyor means for purifying the ⁶⁸ Ga fraction adsorbed on a cation exchanger, a synthesis device, into which a line leads from the exit of the cation exchanger, and in which the ⁶⁸ Ga radionuclide and the labeling precursor are converted into a radiopharmaceutical, and for cleaning the radiopharmaceutical a cartridge, at the input conveyors are connected via lines and their output via a 3rd Way valve is connected to a line leading out of the synthesis device, a storage vessel and a product container for receiving the radiopharmaceutical.

• Fig. 1 schematisch die erfindungsgemäße Vorrichtung, und
• Fig. 2 das Ablaufschema der Arbeitsweise der Vorrichtung.

Based on FIGS. 1 and 2 describes the device and its operation for isolating a ⁶⁸ Ga fraction from a ⁶⁸ Ge / Ga generator, its purification and volume reduction to obtain the ⁶⁸ Ga radionuclide, and marking marker precursors with the purified ⁶⁸ Ga radionuclide. Show it:

• Fig. 1 schematically the device according to the invention, and
• Fig. 2 the flow chart of the operation of the device.

According to the relatively short half-life of 68 min of the ⁶⁸ Ga, the entire procedure of generator elution, purification, volume reduction, and labeling must be optimized: every 10 min, more than 10% of the ⁶⁸ Ga radioactivity decays. Many of the currently established generator systems with subsequent labeling reaction take up to one hour to complete the entire procedure. Alternative methods with, for example, half of this total time already signify a significant increase in the final radioactivity of the ⁶⁸ Ga-labeled radiopharmaceutical. This is particularly relevant because it can also result in a corresponding minimization of the initially required ⁶⁸ Ge activity of the generator system, which has the effect of a cost factor.

The device after Fig. 1 includes a ⁶⁸ Ge / Ga generator 1, which is preceded by a conveyor 2, for example in the form of a piston, a syringe or a peristaltic pump (peristaltic pump), via a line. The conveyor 2 is connected in a manner not shown with a liquid-filled storage or reservoir, if it is a Schlauchradpumpe. In the case of a piston or a syringe these are filled directly with a liquid. The output of the generator 1 is connected via a first 3-way valve 12 to the cation exchanger 14 on the input side. Furthermore, conveyors 3, 4, 5, 6, 7 are connected via lines to the 3-way valve 12. For these conveyors, as well as for conveyors described below, the statements made to the conveyor 2 also apply. Instead of a 3-way valve, a returnable valve can also be used. It is also possible to install in the individual lines control valves, open-close valves or taps that open the single line differently wide if necessary or fully open or completely shut off.

It is preferred, in a manner not shown, several ⁶⁸ Ge / Ga radionuclide generators simultaneously or sequentially eluted and the common initial eluates transferred to the cation exchanger 14. The ⁶⁸ Ge / Ga generators can still be operated or used even if their initial ⁶⁸ Ga eluate already contains an impermissibly high amount of ⁶⁸ Ge. This significantly extends the useful life of a ⁶⁸ Ge / Ga generator, especially for generators with 50 or more mCi ⁶⁸ Ge.

The cation exchanger 14 is connected on the output side to a second 3-way valve 15. A line 25 leads from the 3-way valve 15 to a waste container 19, a further line 23 leads from the 3-way valve 15 in a marking vessel 21, which is arranged in a synthesis device 20 of the device. The heatable synthesis device 20 is equipped with a heater 22 and is seated on a vertically movable table 27. By lowering the table 27 access to the marking vessel 21 is facilitated. The components of the device described so far are used to isolate the ⁶⁸ Ga eluate, its volume reduction and purification. Instead of a vertically movable table, a stable plate can accommodate the synthesis device 20, as well as a laterally movable on rails or rollers slide.

A line 24 leads from the marking vessel 21 to a third 3-way valve 13. The 3-way valve 13 is connected on the input side to a cartridge 11. From the 3-way valve 13 further leads a line 25 to a storage vessel 18 for the purified Markierungsagens. Another line 26 connects the storage vessel 18 with the product vessel 17. In this line 26, a filter 16 is arranged before entering the product vessel 17. In the product vessel 17, the radiopharmaceutical is provided for administration and may be withdrawn therefrom at any time.

The unit of filter 16, product vessel 17, line 26 is used for sterile filtration, which is an independent process step that can be performed in isolation. If necessary, therefore, the unit 16, 17 decoupled from the overall device and operated independently.

The operation of the device is based on the flowchart according to FIG. 2 described.

From the conveyor 2, pressure is applied to the eluent for the initial ⁶⁸ Ge / Ga generator elution from the ⁶⁸ Ge / Ga generator 1 in a manner not shown. The eluate passes via the first 3-way valve 12 to the cation exchanger 14 and further via the components 15 and 25 into the vessel 19th

The cation exchanger is a strongly acidic cation exchanger from the group polystyrene / divinylbenzene (DVB) resins with a DVB content of 2 to 20%, based on the crosslinked polymers of the resins. The sulfonated polystyrene / divinylbenzene (DVB) resins have a gel-like structure and permanently have negatively charged sulfonic acid groups. Each of these active groups has a fixed electrical charge and is in equilibrium with a number of equivalent oppositely charged ions which are free to exchange with other ions of the same charge.

On the cation exchanger 14, first ⁶⁸ Ga ^{3+ is} adsorbed, which is initially contaminated inter alia with Fe (III), Zn (II), Ti (IV) and ⁶⁸ Ge. At the same time, the elution of the entire volume of the initial generator eluate follows. At the same time, the proportion of ⁶⁸ Ge contained therein is removed.

This is followed by the elution of the fractions of Fe (III) and Zn (II), which were adsorbed on the cation exchanger together with ⁶⁸ Ga. For this purpose, an acidic solution of HCl / acetone or HCl / ethanol or analogous systems is forced through the first 3-way valve 12 into the cation exchanger 14 by the delivery devices 3 and Fe (III) and Zn (II) are flushed out and over the opened second 3-way valve 15 passed into the waste container 19.

Thereafter air is forced through the conduits by the conveyor 4 to purge them and remove any residue of Fe (III) and Zn (II).

In the subsequent step, this solution is fed through the 3-way valve 12 to the cation exchanger 14 through the conveyor 5, which is filled with a second acidic solution of HCl / acetone or HCl / ethanol or analog systems, and through this acidic solution ⁶⁸ Ga eluted from the cation exchanger and introduced via the 3-way valve 15 and line 23 into the marking vessel 21.

Thereafter, air is again forced through the lines via the conveying device 4 in order to rinse them and to detect possible residues of ⁶⁸ Ga and to introduce them into the marking vessel 21.

The processes described cause the initially eluted from generator Ti (IV) can not get together with the ⁶⁸ Ga fraction in the labeling vessel, which is given a further dry cleaning.

The remaining residues of Ti (IV) on the cation exchanger 14 are at first rinsed with HCl from the conveyors 6 at the appropriate time and sensed in the waste container 19; Subsequently, the cation exchanger is washed analogously with water from the conveyors 7, whereby the cation exchanger is finally ready for a new procedure.

• In dem Markierungsgefäß 21 erfolgt die Markierung des Markierungsvorläufers mit dem gereinigten ⁶⁸Ga-Radionuklid zu dem Radiopharmakon. Dieser Vorläufer besteht aus einem Liganden oder einem mit einem Liganden kovalent verknüpften Peptid oder Protein oder einer anderen Komponente, wobei das ⁶⁸Ga-Radionuklid von dem Liganden chemisch gebunden wird. Der Ligand wird u.a. aus der Gruppe linearer oder zyklischer Plyaminopolycarbonsäuren (DTPA, EDTA oder DOTA u.a) oder anderer, auch Phosphor und Schwefel als Donoratome enthaltenden Ligandenstrukturen ausgewählt, das Peptid aus der Gruppe Octreotid, Bombesin, Gastrin und v.a.m., wobei das jeweils gewählte Peptid eine möglichst hohe Affinität zu Tumorzellen bzw. Tumorzellmembran-ständigen Rezeptoren wie auch zu Rezeptoren an anderen Organen haben. Analog können modifizierte Proteine in Form von Antikörpern zur Bindung an Tumorantigene verwendet werden.

The labeling vessel can either be empty and then used to fill balloons with the now minimized ⁶⁸ Ga volume or for the synthesis of radiopharmaceuticals. The last case is described below:

• In the labeling vessel 21, the marker precursor is labeled with the purified ⁶⁸ Ga radionuclide to the radiopharmaceutical. This precursor consists of a ligand or ligand covalently linked to a peptide or protein or other component, wherein the ⁶⁸ Ga radionuclide is chemically bound by the ligand. The ligand is selected, inter alia, from the group of linear or cyclic plyaminopolycarboxylic acids (DTPA, EDTA or DOTA, etc.) or other, also phosphorus and sulfur donor atoms containing ligand structures, the peptide from the group octreotide, bombesin, gastrin and vam, wherein the respective selected peptide have the highest possible affinity for tumor cells or tumor cell membrane receptors as well as receptors on other organs. Analogously, modified proteins in the form of antibodies can be used for binding to tumor antigens.

For the reaction of the ⁶⁸ Ga radionuclide with the ligand of the label precursor, some kinetic energy is required, which is generated by heating the label precursor volume in the synthesizer 20 to an appropriate temperature. For DOTATOC, for example, the optimum temperature is equal / higher than 95 ° C.

The pH of the label precursor in the labeling vessel 21 is in the range of 2 to 5. For the radiopharmaceutical ⁶⁸ Ga-DOTATOC, a preferred pH is, for example, 2.3. The pH is adjusted by the volume of water and labeling precursor, preferably without a buffer solution, and the supplied HCl / acetone or HCl / ethanol solution or analogous systems. However, it is also possible to adjust the pH with the aid of a buffer solution or, for example, HEPES, which may result in a changed optimal pH.

The amount of the label precursor of a ligand or ligand covalently linked to a peptide or protein, such as DOTATOC, in the labeling vessel 21 is about 1 to 100 nmol, preferably 7 to 14 nmol, plus an appropriate volume of water or buffer or HEPES or analogous systems to adjust the pH.

After marking the marker precursor with the purified ⁶⁸ Ga fraction to the radiopharmaceutical, the liquid-containing conveyor 8 is operated with open 3-way valve 13 so that via the line 24 from the marker vessel 21, the radiopharmaceutical is applied to the cartridge 11 and is fixed. Thereafter, the 3-way valve 13 closes the line 24 and opens the line 25, which leads into the storage vessel 18 - or optionally in another, not shown storage vessel. By operating the conveyor 9, the cartridge 11 is washed with pure water or analogous solvents which elute free ⁶⁸ Ga or other unlabeled ⁶⁸ Ga species, and removed in a manner not shown, for example, back into the now no longer required 21 Markierungsgefaß.

Thereafter, by operating the conveyor 10 containing less than 0.5 ml of ethanol or analogous solvents, the elution of the radiopharmaceutical, for example ⁶⁸ Ga-DOTATOC, from the cartridge 11 and its introduction into the storage vessel 18 containing an isotonic saline solution , Alternatively, the specified fraction can also be eluted into an empty storage vessel 18, which in principle allows the removal of the ethanol or analogous solvent.

Thereafter, the 3-way valve 13 closes the line 25 and by means of a device, not shown, the radiopharmaceutical is drawn through the conduit 26 from the storage vessel 18 and introduced via a filter 16 into the product vessel 17. Through the filter 16 is a sterile filtering, so that thereafter the radiopharmaceutical is ready for use.

The binding of the ⁶⁸ Ga to the labeling precursor is more than 75%, based on the decay-corrected activity of the initial ⁶⁸ Ge / Ga generator eluate. For example, the reactivity of the label precursor at 10 mCi of the ⁶⁸ Ge / Ga generator elute is up to 80%, 90% and more than 95% after one, five and ten minutes.

The duration of the procedure from application of the initial generator eluate to the provision of the radiopharmaceutical is about 20 minutes.

The conveyors 2 to 10 and the lines connected to them can be subjected to negative pressure in order to transport the solutions through the lines.

Of course, the entire process of the device is fully automated and is controlled for example via a computer program.

Specifically for the imaging of neuroendocrine tumors with labeling reagents such as [ ⁶⁸ Ga] DOTA-DPhe ¹ -Tyr ³ octreotide ([ ⁶⁸ Ga] DOTATOC) and PET or analogous compounds with altered chelators or altered Peptidaminosäuresequenzen since about the year 2000 an excellent new application of the ⁶⁸ Ge / Ga generator eluates used as tumor targeting vectors. The octapeptide octreotide has a high affinity for the sstr2 subtype of human somatostatin receptor-expressing tumors, and the conjugated macrocyclic bifunctional chelator DOTA coordinately binds the trivalent ⁶⁸ Ga ³⁺ with high thermodynamic and kinetic stability also in vivo. Despite the relatively short half-life of ⁶⁸ Ga, this type of ⁶⁸ Ga-labeled compounds allows excellent visualization of tumors and small metastases. This ⁶⁸ Ga tumor targeting approach may potentially be extended to a variety of other tumors, using other peptides.

⁶⁸ Ga also finds applications in myocardial perfusion diagnostics in the form of the [ ⁶⁸ Ga] BAT-TECH complex as a perfusion tracer. This shows that, in principle, any type of ⁶⁸ Ga labeling via ligand structures can be used for nuclear medical diagnostics altogether or will be in the future.

The "kit" -like synthesis offers another advantage, as does the use of PET independent of in-house direct production from established positron emitters such as ^18F .

At the same time, there is currently a strong improvement in molecular imaging through the combination of PET and computed tomography, which also has application potential ⁶⁸ Ga-marked imaging tracer enlarged. For these reasons, the availability of optimized ⁶⁸ Ge / Ga generator systems becomes more and more significant. Effective production of the ⁶⁸ Ge is currently key among radiochemical and economic aspects.

An interesting and potentially significant application of ⁶⁸ Ga without labeling chemistry is in the area of the ⁶⁸ Ga-filled angioplasty containers for the inhibition of arterial restenosis following coronary angioplasty. This application of higher energy positron emitters follows the familiar ¹⁸⁸ Re and other medium and high energy β emitters applications. Since the liquid ⁶⁸ Ga eluates are used here, minimal volumes of the ⁶⁸ Ge / Ga generator eluates offer optimum conditions.

The device is also suitable for concentrating and purifying radiogallium solutions. It is also suitable for cleaning, volume reduction of gallium radioisotopes and labeling of marrow precursors with the ⁶⁶ Ga or ⁶⁷ Ga radioisotope.

Of course, the device is equally well suited for labeling ligands or ligand-covalently linked peptide or protein with radionuclides other than ⁶⁸ Ga. An example of this is ⁹⁰ Y, which requires purification of the eluate from other metals.

LIST OF REFERENCE NUMBERS

• 1 = ⁶⁸ Ge / Ga generator
• 2 = conveyor

• 3 =)
• 4 =) directions
• 5 =) (pump,
• 6 =) syringe,
• 7 =) piston)

• 8 =) conveyors,
• 9 =) (pump, syringe
• 10 =) piston)

• 11 = cartridge

• 12 =) 3 way
• 13 =) valves

• 14 = cation exchanger
• 15 = 3-way valve
• 16 = filter
• 17 = product vessel
• 18 = storage vessel
• 19 = waste container
• 20 = synthesis device
• 21 = marking vessel
• 22 = heating

• = 23)
• 24 =) lines
• 25 =)
• 26 =)

• 27 = table

Claims (29)

1. Method for extracting a ⁶⁸Ga radionuclide from a ⁶⁸Ge/Ga generator eluate which contains ⁶⁸Ga in ionic form, whereby the initial ⁶⁸Ge/Ga generator eluate is fed directly into an exchanger and ⁶⁸Ga is adsorbed quantitatively on the exchanger, and is simultaneously chemically and radiochemically purified and the ⁶⁸Ga radionuclide is combined with a labelling precursor from a ligand into a radiopharmaceutical, characterized in that, as an exchanger, a cation exchanger from the group of highly acidic cation exchangers polystyrene/divinylbenzene (DVB) resins, with a DVB concentration from 2 to over 20 % in reference to the cross-linked polymers of the resins, is selected, and the matrix of the cation exchanger is loaded with ⁶⁸Ga.
2. Method according to claim 1, characterized in that the ⁶⁸Ga radionuclide is combined with a labelling precursor from a peptide or protein cross-linked in a covalent manner with a ligand into a radiopharmaceutical.
3. Method according to claim 1, characterized in that several ⁶⁸Ge/Ga radionuclide generators are simultaneously or sequentially eluted and the common initial eluates are transferred to the cation exchanger.
4. Method according to claim 1, characterized in that the initially eluated ⁶⁸Ge is not adsorbed, a chemical purification of the ⁶⁸Ga takes place on the cation exchanger during which the radiochemical ⁶⁸Ge contamination is reduced to a value smaller 10^-8 percent.
5. Method according to claim 3, characterized in that ⁶⁸Ge/Ga generators remain in operating condition if their initial ⁶⁸Ga-eluate already contains 50 or more mCi ⁶⁸Ge.
6. Method according to claim 4, characterized in that with acidic solutions of the type HCl/acetone or HCl/ethanol or analogous systems the purification is such that chemical contaminations such as Fe(ITI) and Zn(II) are eluted from the cation exchanger.
7. Method according to claim 4, characterized in that during the elution processes of ⁶⁸Ga a substantial separation of initially eluted Ti(IV) occurs.
8. Method according to claim 1, characterized in that the purified and volume-reduced ⁶⁸Ga radionuclide is directly eluted into a labelling vessel in which the labelling precursors and pure water or buffer systems have been introduced.
9. Method according to claim 1, characterized in that the purified and volume-reduced ⁶⁸Ga radionuclide is directly eluted into a vessel from which the filling of balloons can occur.
10. Method according to claim 1, characterized in that the labelling precursor contains a ligand from the group of chelators with suitable thermodynamic and kinetic stability for the formation of the corresponding Ga ligand complexes DTPA, DOTA-, NOTA, DFO and many more others as well as their derivates.
11. Method according to claim 10, characterized in that the Ga ligand complexes from the group DTPA, DOTA-, NOTA, DFO and many more others as well as their derivates are selected.
12. Method according to claim 8, characterized in that the labelling precursor comprises a ligand or a peptide or protein covalently cross-linked with a ligand or other compounds in a quantity of roughly 1 to 100nmol, especially from 7 to 14 nmol, is introduced into the labelling vessel.
13. Method according to claims 8 to 10, characterized in that the bonding of the ⁶⁸Ga to the labelling precursor amounts to more than 75% in relation to the decay-corrected activity of the initial ⁶⁸Ge/Ga generator eluate.
14. Method according to claim 8, characterized in that the radiopharmaceutical from the labelling vessel is transferred to a cartridge onto which the radiopharmaceutical is fixed and the free ⁶⁸Ga and/or other ⁶⁸Ga species is eluated on the cartridge.
15. Method according to claim 14, characterized in that the cartridge is washed with a liquid, in particular with water or analogous systems and is purified of free ⁶⁸Ga and/or other ⁶⁸Ga species.
16. Method according to claim 14, characterized in that the radiopharmaceutical is eluated with less than 0.5 ml ethanol or analogous systems.
17. Method according to claim 14, that the radiopharmaceutical from the cartridge, eluated in an empty vessel for subsequent individual processes or in a vessel with a corresponding volume of isotonic physiological sodium chloride solution, is sterile filtered out of this and made available for use.
18. Method according to claim 8, characterized in that the pH value of the solutions for synthesizing the radiopharmaceutical in the labelling vessel is set to a value of 2.0 to 5.0, in particular to 2.3, and that at the same time either only water or also buffer systems or HEPES solutions, among others, are used.
19. Device for isolating a chemically and radiochemically purified ⁶⁸Ga radionuclide from a ⁶⁸Ge/Ga generator eluate, comprising a conveyance apparatus (2) connected by a conduit to a ⁶⁸Ge/Ga generator (1), a synthesis apparatus (20), into which a conduit (23) leads from the outlet of the exchanger (14) and in which the ⁶⁸Ga radionuclide is reacted into a radiopharmaceutical, a 3-way valve (13), that is connected by a conduit (24) to the synthesis apparatus (20) and leads out of the synthesis apparatus (20), a reservoir (18) and a product vessel (17), characterized in that the exchanger is a cation exchanger (14) and is connected to a number of conveyance facilities (3, 4, 5, 6, 7) for the purification of the ⁶⁸Ga fraction adsorbed on the cation exchanger (14), in the synthesis apparatus (20) a labelling precursor is labelled with a ⁶⁸Ga, ⁶⁶Ga, or ⁶⁷Ga radionuclide and is reacted into a radiopharmaceutical and that for the purification of the radiopharmaceutical a cartridge (11), at whose inlet conveyance facilities (8, 9, 10) are connected by means of conduits and whose outlet is connected via the 3-way valve (13) to the conduit (24) which leads out of the synthesis apparatus (20).
20. Device according to claim 19, characterized in that the conveyance facilities (2 to 10) are bidirectional acting pistons, syringes or peristaltic pumps.
21. Device according to claim 19, characterized in that by means of the conveyance facilities (2 to 19) the transport occurs by means of underpressure.
22. Device according to claim 19, characterized in that the synthesis apparatus (20) contains a labelling vessel (21) into which the conduit (23) penetrates which is connected to a 3-way valve (15) which is connected to the outlet of the cation exchanger (14) and a conduit to a waste vessel (19).
23. Device according to claim 19, characterized in that a conduit (25) leads from the 3-way valve (13) into the reservoir (18).
24. Device according to claim 19, characterized in that a conduit (26) connects the reservoir (18) via a filter (16) to the product vessel (17).
25. Device according to claim 19, characterized in that the outlets of the conveyance facilities (3, 4, 5, 6, 7) open into a common conduit which is connected to a 3-way valve (12) which is connected both to the ⁶⁸Ge/Ga generator (1) and to the cation exchanger (14).
26. Device according to one of the claims 19 to 25, characterized in that the overall process is automated.
27. Device according to claim 19, characterized in that the matrix of the cation exchanger (14) is selected from the group of polystyrene/divinylbenzene (DVB) resins.
28. Use of the device according to claim 19 for the concentration and purification of gallium isotope solutions.
29. Use of the device according to claim 19 for the purification, the volume reduction of gallium radioisotopes and labelling of labelling precursors with the ⁶⁶Ga or ⁶⁷Ga radioisotope.

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