EP2439747B1 - 68 Ga generator - Google Patents

Description

The present invention relates to a generator for a ⁶⁸ Ga daughter nuclide according to the preamble of claim 1.

Radionuclides of the positron emitter type are used in so-called positron emission tomography. Positron emission tomography (PET), as a variant of emission computer tomography, is an imaging method of nuclear medicine that produces sectional images of living organisms by visualizing the distribution of a weakly radioactively labeled substance (radiopharmaceutical) in the organism and thus depicting biochemical and physiological functions , and thus belongs to the diagnostic department of so-called functional imaging. In such a PET examination on a patient, the distribution of a weakly radioactively labeled with a positron emitter substance is made visible in an organism by means of the radioactive decay of the positron emitter by means of usually several detectors.

In particular, based on the principle of scintigraphy, a radiopharmaceutical is administered intravenously to the patient at the beginning of a PET examination. PET uses radionuclides that emit positrons (β ⁺ radiation). In the interaction of a positron with an electron in the patient's body, two high-energy photons are emitted in exactly opposite directions, ie at an angle of 180 degrees to one another. In terms of nuclear physics, this is so-called destructive radiation. The PET device typically includes many detectors for the photons annularly disposed about the patient. The principle of the PET study is to record coincidences between any two opposing detectors. From the temporal and spatial distribution of these registered decay events is on the spatial distribution of the radiopharmaceutical in the interior of the body and especially in the for the respective studies of interest organs and / or pathological changes, such as space-occupying processes, closed. From the data obtained, a series of sectional images is calculated, as usual in computed tomography. PET is frequently used for metabolic issues in oncology, neurology and cardiology, but more and more fields of application have recently emerged.

The most commonly used nuclide in PET is the radioactive isotope ¹⁸ F. It is produced with the help of a cyclotron and, because of its relatively long half-life of about 110 minutes, can be transported from the cyclotron to a nuclear medicine unit of a hospital. For this reason, it is currently the most frequently used in PET examinations.

In addition to ¹⁸ F mainly ¹¹ C, ¹³ N, ¹⁵ O, ⁶⁸ Ga, ⁶⁴ Cu or ⁸² Rb are used.

The half-lives of these isotopes are shown in Tab. Tab. 1 nuclide Half-life ¹¹ C 20.3 minutes ¹³ N 10.1 minutes ¹⁵ o 2,03 minutes ¹⁸ F 110 minutes ⁶⁸ Ga 67.63 minutes ⁶⁴ Cu 12.7 hours ⁸² Rb 1.27 minutes

⁶⁸ Ga and ⁸² Rb are generator radioisotopes. The radioisotope arises here by decay of an unstable mother isotope in a nuclide generator in which it accumulates. All other mentioned PET nuclides are produced by means of a cyclotron.

Due to the half-lives and the production methods for the radionuclides shown in Table 1, the following consequences for PET investigations result: The use of ¹¹ C requires that a cyclotron be in relative proximity to the PET system. If the relatively short-lived ¹³ N or ¹⁵ O nuclides are used, the cyclotron must be in the immediate vicinity of the PET scanner. However, a cyclotron-based radiopharmaceutical manufacturing facility requires a double-digit million investment, which severely limits the use of cyclotron-produced nuclides for PET.

For this reason, among other things, generator radioisotopes and in particular the ⁶⁸ Ga are of particular interest for nuclear medicine and especially for the PET process.

In order to be able to carry out a PET, a radionuclide is coupled to a molecule (covalently bound or else in the form of a coordinative bond), which participates in the metabolism or in another way a biological and / or pharmacological effect, such as the binding to a specific receptor , having.

A typical molecule used in PET studies of the prior art is ¹⁸ F-fluorodeoxyglucose (FDG). Since FDG-6 phosphate is not further metabolized after phosphorylation in vivo, it is enriched ("metabolic trapping"), which is particularly beneficial for the early diagnosis of cancers, as well as finding FDG in the body tumors and metastases but also general conclusions about the glucose metabolism of tissues.

For the ⁶⁸ Ga PET, for example, a ⁶⁸ Ga DOTATOC chelate with the following structure is used:

By means of such a ⁶⁸ Ga-DOTATOC it is possible, for example, to detect and localize neuroendocrine tumors and their metastases by means of imaging methods such as PET. In particular, somatostatin-expressing tumors and their metastases can be detected by positron emission tomography. At the corresponding degenerated cells, the ⁶⁸ Ga-DOTATOC accumulates. These areas radiate much stronger than the normal tissue. The radiation is localized by means of detectors and processed by image processing into a three-dimensional representation.

After all, gallium-68 is a radionuclide that is of great interest to PET and new access sources are of great importance for clinical diagnostics and research.

⁶⁸ Ga can be obtained with a germanium-68 / gallium-68 radionuclide generator system, such as from the European patent application EP 2 216 789 A1 known.

The ⁶⁸ Ga decays with a half-life of 67.63 minutes while emitting a positron. As mentioned above, gallium-68 is very well suited for nuclear medicine examinations because of its physical and chemical properties.

From nuclear studies it is known that ⁶⁸ Ga can be generated by electron capture from the parent nuclide ⁶⁸ Ge, which decays with a half-life of 270.82 days.

Typically, in a ⁶⁸ Ga generator, the ⁶⁸ Ge is bound to an insoluble matrix of an inert support, with the continuous decay of the germanium constantly producing ⁶⁸ Ga, which can be extracted from the generator by elution with a solvent.

The production of radiopharmaceuticals requires high quality standards for the radionuclides used. In particular, the radionuclides produced must have a high degree of purity and be substantially free of metallic impurities since they can negatively influence the labeling of the radiopharmaceuticals by competing reactions and can reduce the production-technically achievable yield. In addition, metallic contaminants can disrupt sensitive biomedical measurement systems.

From the US 2007/0009409 A1 For example, radionuclide generators are known wherein the parent nuclide binds to an oxygen-containing functional group attached to an organic linker attached to an inorganically linked network. For example, ²¹² Bi or ²¹³ Bi generators are described wherein the parent nuclide may be ²²⁴ Ra, ²²⁵ Ra or ²²⁵ Ac. For example, the exchanger material may be formed from covalently linked inorganic oxides capable of forming oxygen-linked networks. The functional groups may include sulfato groups, especially -SO ₃ H, -SO ₃ Na, -SO ₃ K, -SO ₃ Li, -SO ₃ NH ₄ , or may be selected from -PO (OX) ₂ or -COOX, wherein X is selected from H, Na, K or NH ₄ or combinations thereof.

Furthermore, the describes GB 2 056 471 A an ion exchanger for separating gallium-68 from its parent nuclide germanium-68. The ion exchanger according to GB 2 056 471 A consists entirely or essentially of a condensation product obtained from a polyhydroxybenzene having not less than two adjacent ones Hydroxyl groups and formaldehyde in a molar excess of 5 to 15%, or contains such a condensation product which is incorporated therein, wherein the condensation product has a reversible water content of not less than 40 wt .-%. To elute the formed ⁶⁸ Ga from the ion exchanger, the ion exchange material must be treated with bound ⁶⁸ Ge with 2M to 5M HCl.

The high acid concentration on the one hand and the toxic effects of the formaldehyde used as a comonomer necessitate post-processing of the eluate prior to its use as a radiopharmaceutical.

In addition, the process for the synthesis of a di- or trihydroxyphenol-formaldehyde resin is technically complicated and expensive.

Compared to this prior art, the method of EP 2 216 789 A1 already a significant advance, since in this application a polyhydroxyphenol was attached to a hydrophobic moiety selected from the group comprising: an aromatic or heteroaromatic group; a fatty acid, saturated or unsaturated, containing more than three carbon atoms; a branched or unbranched alkyl chain having more than three C atoms such as octyl, decyl or octadecyl groups; and an organic carrier or inorganic carrier material such as resin and silica gel have been coated with this molecule without covalent bonding. From the thus-coated column material, small chromatographic columns were prepared which were charged with an aqueous solution of a ⁶⁸ Ge salt, quantitatively adsorbing the ⁶⁸ Ge to the columns.

The column materials were then eluted with 0.05 M HCl with the eluate containing essentially ⁶⁸ Ga and the mother nucleate breakthrough ranging from 1.0 x 10 ^-5 to 3 x 10 ^-3 %.

Although gallium-68 could be used directly and without further chemical post-processing to prepare injectable gallium-68 radiopharmaceuticals The hydrophobic compound to which the polyhydroxyphenol was coupled, over time and led to contamination of the desired ⁶⁸ Ga nuclide, so that before use as a radiopharmaceutical after a certain period of the support materials yet another purification step was required before the ⁶⁸ Ga fraction could be used for the production of a radiopharmaceutical.

Starting from the prior art of EP 2 216 789 A1 It is therefore an object of the present invention to provide a stable gallium-68 generator available which can be used repeatedly over a long period without having to further process the gallium-68 fraction prior to its use for the production of a radiopharmaceutical.

The solution of this object is achieved by a generator for a ⁶⁸ Ga daughter nuclide according to the features of claim 1.

In particular, the present invention relates to a ⁶⁸ Ga daughter nuclide generator in which its ⁶⁸ Ge parent nuclide is specifically immobilized on a support via a trihydroxyphenyl group or a dihydroxybenzene group and continuously decays to ⁶⁸ Ga with a half-life of 270.82d by electron capture the trihydroxyphenyl group (or dihydroxyphenyl group) is covalently bound to a support material via a linker, the linker being selected from the group consisting of: C ₂ to C ₂₀ esters, C ₂ to C ₂₀ alkylene, phenyl, thiourea, C ₂ C ₂₀ amines, melamine, maleimide, trihydroxyphenylalkoxysilanes, in particular 1,2,3-trihydroxyphenyltriethoxysilane, 1,2,3-trihydroxyphenyldiethoxysilane, 1,2,3-trihydroxyphenylethoxysilane, 1,2,3-trihydroxyphenyltripropoxysilane, 1,2,3- Trihydroxyphenylchlorosilane, epichlorohydrin, isothiocyanates, thiols.

A preferred embodiment of the present invention is a ⁶⁸ Ga generator, wherein the carrier material is selected from the group consisting of: inorganic inert oxide materials, in particular silica gel, SiO ₂ , TiO ₂ , SnO ₂ , Al ₂ O ₃ , ZnO, ZrO ₂ , HfO ₂ or organic inert polymers and copolymers, in particular styrene-divinylbenzene, polystyrene, styrene-acrylonitrile, styrene-acrylonitrile-methyl methacrylate, Acrylonitrile-methyl methacrylate, polyacrylonitrile, polyacrylates, acrylic or methacrylic esters, acrylonitrile-unsaturated dicarboxylic acid-styrene, vinylidene chloride-acrylonitrile.

It is preferred that the trihydroxyphenyl group is 1,2,3-trihydroxybenzene (pyrogallol), with preference being given to using silica gel as carrier material and 1,2,3-trihydroxyphenyltriethoxysilane as linker.

Typically, the silica gel has an average grain size of 10-150 μm and an average pore size of 6-50 nm.

As a preferred highly specific elution method, treatment of the ⁶⁸ Ge-loaded trihydroxyphenyl group of the support material to recover the ⁶⁸ Ga ions formed by radioactive decay of the parent nuclide with 0.05 to 0.5 M HCl has been found.

For the ⁶⁸ Ga generator of the present invention, preferably ⁶⁸ Ge salts in the form of a compound having the oxidation number IV are used to load the support material.

In particular, an aqueous solution of a ⁶⁸ Ge (IV) salt is used for the immobilization of ⁶⁸ Ge to the trihydroxyphenyl group, more preferably ⁶⁸ Ge are aquaions.

With the ⁶⁸ Ga generator according to the present invention, the generated Ga ^{68 has} a purity which permits immediate radiopharmaceutical use, the content of impurities, especially metallic impurities, in the range of 10 to 100 ppb (by weight), preferably between 1 and 10 ppb (by mass), and more preferably below 1 ppb (by mass).

Although basically covalent couplings such as silane or epichlorohydrin or isothiocyanate are couplings of organic molecules or biomolecules to one inert inorganic or organic carriers have long been known in the art, but the sensitivity to hydrolysis of such couplings using acids as eluents is also known. Through this acid hydrolysis of the carrier would irreversibly destroyed with prolonged use, which would also in turn lead to contamination of the ⁶⁸ Ga fraction.

However, in practical tests, in particular with silane couplers, it has surprisingly been found that they are acid-stable over a relatively long period of time and lead to highly pure ⁶⁸ Ga fractions, if the carrier materials loaded with ⁶⁸ Ge according to the present invention with 0.05 M to 0.5 M HCl elutes to wash out the ⁶⁸ Ga from the mother nuclide loaded substrate.

With the generator according to the invention for a ⁶⁸ Ga daughter nuclide, which is formed from a ⁶⁸ Ge mother nuclide, thus a long-term stable ⁶⁸ Ga generator is available for the first time, in which the obtained ⁶⁸ Ga fraction directly as a radiopharmaceutical, for example for PET , can be used.

Further advantages and features of the present invention will become apparent from the description of an embodiment.

example

A germanium-specific resin was prepared by treating an inert silica gel having a grain size of about 40 μm and a pore size of about 6 nm with 1,2,3-trihydroxyphenyltriethoxysilane. Silanation of the native silica gel resulted in covalently bonded 1,2,3-trihydroxybenzene functional groups on the inert support. Measurements of the weight distribution factors of Ge (IV) on the resin confirmed the high affinity of the material for germanium. The resin was used in the form of small chromatographic columns.

Aqueous solutions containing HCl or HNO ₃ or NaCl of radionuclide ⁶⁸ Ge with activities ranging from 100 to 1000 MBq were pumped through the columns. Due to the specific binding of the ⁶⁸ Ge this was quantitatively adsorbed or immobilized on the column materials.

These ⁶⁸ Ge-loaded columns were used to prepare the short-lived daughter nuclide ⁶⁸ Ga. While ⁶⁸ Ge is immobilized on the carrier, ⁶⁸ Ga is continuously formed, which can be repeatedly eluted. The highly specific elution of the ⁶⁸ Ga can be effectively carried out in weak hydrochloric acid solutions (0.05 to 0.5 M HCl) with small volumes up to 2.5 ml. The breakthrough of mother nuclide ⁶⁸ Ge was on the order of <10 ^-5 %.

The ⁶⁸ Ga thus obtained could be used immediately, ie, without any chemical post-processing, to produce injectable ⁶⁸ Ga radiopharmaceuticals.

In addition, the resin of the present invention can be used to remove any traces of germanium (both radioactive and stable isotopes) from aqueous solutions for analytical or pharmaceutical applications.

By a covalent coupling to the carrier material, the resin has an increased chemical and radiolytic stability over the prior art EP 2 216 789 A1 as well as improved chemical-mechanical properties such as lower hydrodynamic resistance.

Claims (9)

1. A generator for a ⁶⁸Ga daughter nuclide, wherein the ⁶⁸Ge parent nuclide thereof is specifically attached to a support through a trihydroxyphenyl group or a dihydroxyphenyl group and continuously disintegrates to ⁶⁸Ga by electron capture at a half-life of 270.82d,
   characterized in that
   the trihydroxyphenyl group or dihydroxyphenyl group is covalently bound via a linker to a supportmaterial, the linker being selected from the group consisting of: C₂ to C₂₀ esters; C₂ to C₂₀ alkyls, phenyl, thiourea, C₂-C₂₀ amines, melamine, maleimide, trihydroxyphenyl alkoxsilanes, in particular 1,2,3-trihydroxyphenyltriethoxysilane, 1,2,3-trihydroxyphenyldiethoxysilane, 1,2,3-trihydroxyphenylethoxysilane, 1,2,3-trihydroxyphenyltripropoxysilane, 1,2,3-trihydroxyphenylchlorosilane, epichlorohydrin, isothiocyanates, thiols.
2. The ⁶⁸Ga generator according to claim 1, characterized in that the support material is selected from the group consisting of: inorganic inert oxide materials, in particular silica gel, SiO₂, TiO₂, SnO₂, Al₂O₃, ZnO, ZrO₂, HfO₂, organic inert polymers and copolymers, in particular styrene-divinylbenzene, polystyrene, styrene-acrylonitrile, styrene-acrylonitrile-methylmethacrylate, acrylonitrile-methylmethacrylate, polyacrylonitrile, polyacrylates, acrylic or methacrylic esters, acrylonitrile-unsaturated dicarboxylic acid-styrene, vinylidene chloride-acrylonitrile.
3. The ⁶⁸Ga generator according to claim 1 or 2, characterized in that the trihydroxyphenyl group is 1,2,3-trihydroxybenzene (pyrogallol).
4. The ⁶⁸Ga generator according to one of the claims 1-3, characterized in that the support material is silica gel and the linker is 1,2,3-trihydroxyphenyltriethoxysilane.
5. The ⁶⁸Ga generator according to claim 4, characterized in that the silica gel has an average particle size of 10 - 150 µm and an average pore size of 6 - 50 nm.
6. The ⁶⁸Ga generator according to claim 4 or 5, characterized in that the ⁶⁸Ge-charged trihydroxyphenol group of the support material is treated with 0.05 to 0.5 M HCl for specifically eluting the ⁶⁸Ga ions formed by radioactive decay of the parent nuclide.
7. The ⁶⁸Ga generator according to one of the claims 1 to 6, characterized in that the parent nuclide ⁶⁸Ge is employed in the form of a compound having the oxidation value IV.
8. The ⁶⁸Ga generator according to claim 7, characterized in that an aqueous solution of a ⁶⁸Ge(IV) salt is employed for attaching ⁶⁸Ge to the trihydroxyphenol group, in particular ⁶⁸Ge-aqua ions.
9. The ⁶⁸Ga generator according to one of the preceding claims, characterized in that the ⁶⁸Ga produced possesses a purity permitting its direct radiopharmaceutical utilization, with the content of impurities, in particular metallic impurities, being in a range from 10 to 100 ppb (by mass), preferably between 1 and 10 ppb (by mass), preferably between 1 and 10 ppb (by mass), and in a particularly preferred manner less than 1 ppb (by mass).