The present invention relates to a method for obtaining a radionuclide, in which an absorption column containing the radionuclide is eluted by an eluent, and to a device for carrying out the method.
Methods and devices for obtaining selected radionuclides for radiopharmacological applications have been disclosed in the prior art (DE 10 2004 057 225 B4). Herein, a radioactive mother nuclide is initially provided, which is stored in a container that is referred to as radionuclide generator. Use is usually made of a mother nuclide with a half-life of a few days to a few thousand years. By contrast, a likewise radioactive daughter nuclide—with a very long-lived or stable decay product—formed in the case of radioactive decay of the mother nuclide has a relatively short half-life of a few minutes or hours up to a few days. As a result of its short half-life, the daughter nuclide is suitable for radiopharmaceutical applications because the daughter nuclide introduced into the body of a patient merely emits radioactive radiation for a short period of time and hence the radiation dose is correspondingly low.
In order to minimize the radiation exposure during the application of a radioactive daughter nuclide, the long-lived mother nuclide must be separated from the daughter nuclide to the greatest possible extent.
The device according to the invention enables an effective radiochemical separation of the mother nuclide, and so a daughter nuclide is obtained with a high radionuclidic and radiochemical purity. Since the daughter nuclide generally decays into a very long-lived or stable end product, the above-described systems, in which the daughter nuclide has a shorter half-life than the mother nuclide, are ideally suited to medical applications. The medical applications of such daughter nuclides lie in the field of radiopharmaceutical chemistry, molecular imaging and/or nuclear-medical diagnostics and endoradiotherapy. Here, the rare combination of radioactive mother nuclides with short-lived daughter nuclides opens up significant chemical, logistic and economic advantages.
The above-described mother and daughter nuclides can be handled and are available in laboratory-technical surroundings. For the applications of the daughter nuclides as such, or for the synthesis of radioactively marked tracer compounds, it is not necessary to maintain a complicated “in-house production” like in the case of the short-lived positron emitters 11C, 18F, etc., or to use expensive commercial initial products like in the case of typical SPECT nuclides, for example 123I, 111In or other important therapy nuclides.
As is well-known for the generator system 99Mo/99mTc, a longer half-life of the mother nuclide and the simple handling of mother/daughter nuclide systems simplify the radiopharmaceutical synthesis and use for the medical patient care in a very decisive manner.
Even if it is very complicated in some cases to produce or obtain the mother nuclide by means of a particle accelerator or reactor, or from natural resources or decay chains, the economic and medical advantages of the mother/daughter nuclide systems by far outweigh these disadvantages. Various clinical applications can be implemented by means of a device for separating mother/daughter nuclide systems. As a result of the broad applicability, the costs arising per patient batch are reduced significantly.
A host of factors need to be taken into account for the practical use of mother/daughter nuclide systems in radiopharmacology and/or for the synthesis of radioactively marked tracer compounds for very different relevant medical questions. One of the core questions is the chemical and technical concept of the mother/daughter nuclide systems themselves. This relates to the development of an optimum separation strategy (in general ion exchange or solid-state extraction) with high yields of the daughter nuclide with minimal penetration of the mother nuclide; the selection of solvents suitable in a chemical and radiopharmaceutical sense; the avoidance of radiolysis effects; the separation duration; the final chemical form and the volume of the daughter nuclide fraction, etc.
Mother/daughter nuclide systems are established, in particular, in nuclear-medical diagnostics by means of SPECT, for example using the 99Mo/99mTc system. In the case of endoradiotherapy, mother/daughter nuclide systems such as 90Sr/90Y and 188W/188Re have become indispensible. Moreover, in recent years, positron-emitting mother/daughter nuclide systems such as 82Sr/82Rb and 68Ge/68Ga are being increasingly used in clinical PET and PET/CT methods. In future, the mother/daughter nuclide system 44Ti/44Sc is also likely to obtain increased importance.
A mother/daughter nuclide system must satisfy various chemically and medically dependent demands and legal requirements. In particular, it is important to keep the therapeutic or diagnostic radiation exposure as low as possible by minimizing the content of the mother nuclide the so-called “breakthrough”—in the purified daughter nuclide. The allowed content of mother nuclide is regulated by pharmacological law and may not be exceeded during medical use.
The content of mother nuclide is substantially determined by the chemical concept of separation. The known chemical separation methods are based on liquid-liquid extraction or column chromatography. In the case of column chromatography, the daughter nuclide is partly or wholly deposited on a solid absorber and is washed out or eluted in a subsequent step by suitable, generally aqueous, eluents. Inorganic substances, such as oxides of the metals aluminum, silicon, tin, titanium, zirconium, etc., or organic anionic or cationic ion exchangers are preferably used as absorbers. Before the daughter nuclide is eluted, contaminants are optionally removed by means of secondary eluents, with the secondary eluents not reducing the content of the daughter nuclide in the absorber, or only reducing it to a small extent.
In the case of a given column material, the separation output is significantly influenced by the dimensions of the device, more particularly by the column volume and the column length. In general, the column volume and the column length should be designed to be that great that, firstly, the mother nuclide is completely absorbed and, secondly, the volume of eluent required for eluting the daughter nuclide is as low as possible.
In this case, it should be noted that there is a certain amount of co-elution of the mother nuclide as a result of chromatographic interactions between the absorber and the mother nuclide. Depending on column dimension, number of elutions or volume of the eluent, aging of the system, inter alia as a result of radiolytic processes, a zone of the absorber enriched with a mother nuclide expands or migrates in the direction of the eluent flow, as a result of which the breakthrough, i.e. the content of mother nuclide in the daughter nuclide eluate, increases.
Breakthrough is particularly critical if it relates to long-lived mother nuclides. Thus, in the mother/daughter nuclide system 82Sr/82Rb, which has recently become relevant for medical applications, the mother nuclide 82Sr has a half-life of more than 20 days (T1/2=25.6 d). Further examples of systems with long-lived mother nuclides are: 188W/188Re with T1/2(188W)=694 d; 68Ge/68Ga with T1/2(68Ge)=271 d and 44Ti/44Sc with T1/2(44Ti)≈60 y. This elucidates the substantial difference to the mother/daughter nuclide system 99Mo/99Tc previously most commonly used in medicine: the half-life of the mother nuclide 99Mo is only T1/2=66 h. In this case, the increase in the breakthrough accompanying repeated elution and long periods of use is negligible. By contrast, in the aforementioned systems with significantly longer half-lifes of the mother nuclides, this is a serious problem (
Accordingly, the object of the present invention is to provide a method in which the breakthrough of the mother nuclide absorbed on a column material is very low, even in the case of a high elution frequency, i.e. in the case of intensive use.
This object is achieved by a method for obtaining a radionuclide, comprising the following steps:
The method according to the invention more particularly comprises two embodiments, in which successive elutions are carried out with respectively opposite flow directions of the eluent (embodiment 1) or in which, after an initial elution, a subsequent “rinsing” of the absorption column is carried out in a flow direction that is opposite to the initial elution (embodiment 2).
What this achieves in the case of the absorptions of the mother nuclide based on equilibria of the ion exchange (in the case of organic ion exchangers) is that the component of the mother nuclide migrating in the flow direction is pushed back again in the direction of its initial absorption zone (
In the case of inorganic ion exchangers, the absorption of the mother nuclide is based on an equilibrium of the co-crystallization and is achieved by virtue of the fact that the component of the inorganic crystals of the column material containing the mother nuclide and migrating in the flow direction is pushed back again in the direction of the initial absorption zone (
The absorption column 14 has a first and second opening (14A, 14B), through which the various eluents are supplied or discharged. Furthermore, the absorption column 14 is connected to an adjustable fluid coupling (12A, 12B), which makes it possible to reverse the flow direction (16, 16′) of the eluents through the absorber column 14. In the position of the fluid coupling (12A, 12B) shown in
By way of example, the reversal of the flow direction (16, 16′) is implemented by virtue of the fluid coupling comprising a first and second channel plate (12A, 12B), with at least one of the channel plates 12A or 12B being rotatably mounted about an axis 12C and each of the channel plates having two ducts. The ducts of the channel plates (12A, 12B) are arranged such that, by rotation about the axis 12C, each of the two ducts of the channel plate 12A can simultaneously be made to coincide with each of the two ducts of the channel plate 12B such that two channels are available for passing a fluid through the fluid coupling (12A, 12B).
The two openings of the first channel plate 12A are connected to lines 10 and 11, with the line 10 connecting the absorption column 14 to the radionuclide generator or storage container 6 (optionally via the multi-port valve 9). The line 11 is used to transfer an eluent passed through the absorption column 14 into a collection vessel 18 or, via the multi-port valve 17 and the line 19, to a removal or synthesis station for the eluate enriched with the daughter nuclide.
According to the illustration in
In another expedient embodiment of the device according to the invention, provision is made for a commercially available multi-port valve with two direct and two crossed channels for reversing the flow direction (16, 16′) of the eluent in the absorption column 14. The use of such a multi-port valve renders it possible to configure a device such that neither the lines 10 and 11 nor the absorption column 14 are moveable.
A further cross valve 30 according to the invention is shown in
In the operating state, the valve body 40 is rotatably arranged in a cylindrical or conical bore 57 of the outer valve body 50. In the cylindrical embodiment of the cross valve 30, the bore 57 or the valve body 50 has an internal diameter Di, which is only insignificantly greater than the external diameter Da of the inner valve body 40. The difference between Di and Da, i.e. (Di-Da), is typically 0.5 to 10 μm, preferably 0.5 to 4 μm. Accordingly, the fit between the inner and outer valve body 40 and 50 is fluid-tight.
The outer valve body 50 has four ducts (51, 52, 53, 54) for supplying and discharging an eluate. The four ducts (51, 52, 53, 54) are labeled in a conventional mathematical sense, i.e. increasing in the case of circumnavigating the outer valve body 50 in an anticlockwise direction. The ducts (51, 52, 53, 54) are preferably embodied as cylindrical bores, the longitudinal axes of which are aligned perpendicular and radial with respect to the axis of symmetry of the bore 57. Here, the term “radial” denotes an arrangement in which the longitudinal axes of the ducts (51, 52, 53, 54) lie in a coplanar manner in a plane arranged with respect to the axis of symmetry of the bore 57 and intersect at the point where the axis of symmetry of the bore 57 passes through this plane. Here, the longitudinal axes of the ducts (51, 52, 53, 54) are preferably aligned like a cross, i.e. along two main axes rotated by 180 degrees with respect to one another. The above-described “cross-like” or “radial” arrangement of the ducts (51, 52, 53, 54) is expedient and advantageous from a manufacturing point of view. Nevertheless, arrangements deviating from this are also provided according to the invention, in which the longitudinal axes of the ducts (51, 52, 53, 54) are rotated by an angle between 0 and 90 degrees with respect to the radial direction, like the blades in a turbine. The essential features (i) and (ii) according to the invention for the function of the cross valve 30 are briefly listed below:
The above feature (ii) is represented in an illustrative manner in
a and 7b show two perspective sectional views of a cross valve 30, cut open along a transversal central plane, with the inner valve body 40 being arranged in two positions respectively rotated by 90 degrees with respect to one another. In the arrangement shown in
The reference signs 14, 16 and 16′ in
a and 7b make it clear that the flow direction of the eluate in the inlet flow 21 and in the discharge 23 (i.e. in lines 10 and 11) is constant, independently of the position of the inner valve body 40. By contrast, if the inner valve body is rotated by 90 degrees, the flow direction of the eluate through the absorption column 14 is reversed from 16′ to 16. Hence the cross valve 30 satisfies the same function as the fluid coupling 12A/12B in
The inner and outer valve body 40 and 50 are expediently manufactured from a metallic or polymer material, such as stainless steel or Teflon.
As mentioned above, embodiments are moreover provided according to the invention in which the inner valve body 40 and the bore 57 have a conical contour or the shape of a frustum.
The inner valve body is expediently coupled to an electrically driven actuator (not illustrated in
According to the prior art, the mother nuclide 68Ge as a tetravalent cation is placed on an absorber made of modified TiO2 such that the 68Ge remains in the upper quarter of the column (cf.
By contrast, according to the present invention, a volume of 3 to 10 ml 0.1 N HCl is passed through the absorption column directly after a daughter nuclide or 68Ga elution, in a flow direction opposing the initial elution and the 68Ga elution. The volume thus passed through the absorption column contains hardly any 68Ga activity and is discarded. Accordingly, this process is also referred to as “rinsing”. After rinsing, the absorption column is available for the next 68Ga elution. However, as a result of rinsing, the zone of the 68Ge distribution has again been shifted back in the direction of the initial absorbtion zone. As a result, the 68Ge content in the subsequent 68Ga elution is substantially reduced. In the case of 100 elutions according to the aforementioned method according to the invention, the breakthrough of 68Ge is only at approximately 2·10−3% instead of the approximately 1·10−2% expected otherwise.
According to the prior art, the mother nuclide 68Ge as a tetravalent cation is placed on an absorber made of modified TiO2 such that the 68Ge remains in the middle of the column (cf.
By contrast, according to the present invention, subsequent daughter nuclide or 68Ga elutions are respectively undertaken in opposing flow directions (cf.
In addition to regulating chromatographic processes, the vertical alignment shown in
Number | Date | Country | Kind |
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10 2009 049 108.2 | Oct 2009 | DE | national |
Filing Document | Filing Date | Country | Kind | 371c Date |
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PCT/EP2010/006209 | 10/12/2010 | WO | 00 | 6/25/2012 |