EP2439747B1 - 68 Ga generator - Google Patents
68 Ga generator Download PDFInfo
- Publication number
- EP2439747B1 EP2439747B1 EP11176249.8A EP11176249A EP2439747B1 EP 2439747 B1 EP2439747 B1 EP 2439747B1 EP 11176249 A EP11176249 A EP 11176249A EP 2439747 B1 EP2439747 B1 EP 2439747B1
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- EP
- European Patent Office
- Prior art keywords
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- generator according
- acrylonitrile
- styrene
- ppb
- Prior art date
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- GYHNNYVSQQEPJS-YPZZEJLDSA-N Gallium-68 Chemical compound [68Ga] GYHNNYVSQQEPJS-YPZZEJLDSA-N 0.000 claims description 19
- 239000000463 material Substances 0.000 claims description 15
- 229940121896 radiopharmaceutical Drugs 0.000 claims description 15
- 239000012217 radiopharmaceutical Substances 0.000 claims description 15
- 230000002799 radiopharmaceutical effect Effects 0.000 claims description 15
- -1 trihydroxyphenyl group Chemical group 0.000 claims description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 11
- WQGWDDDVZFFDIG-UHFFFAOYSA-N pyrogallol Chemical compound OC1=CC=CC(O)=C1O WQGWDDDVZFFDIG-UHFFFAOYSA-N 0.000 claims description 9
- 229910002027 silica gel Inorganic materials 0.000 claims description 9
- 239000000741 silica gel Substances 0.000 claims description 9
- GNPVGFCGXDBREM-FTXFMUIASA-N Germanium-68 Chemical compound [68Ge] GNPVGFCGXDBREM-FTXFMUIASA-N 0.000 claims description 6
- FZJXMYVWAHJIPR-UHFFFAOYSA-N 1-triethoxysilylcyclohexa-3,5-diene-1,2,3-triol Chemical compound CCO[Si](OCC)(OCC)C1(O)C=CC=C(O)C1O FZJXMYVWAHJIPR-UHFFFAOYSA-N 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 239000012535 impurity Substances 0.000 claims description 5
- 150000002500 ions Chemical class 0.000 claims description 5
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 4
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 230000005264 electron capture Effects 0.000 claims description 3
- 150000002540 isothiocyanates Chemical class 0.000 claims description 3
- 239000011148 porous material Substances 0.000 claims description 3
- 230000005258 radioactive decay Effects 0.000 claims description 3
- QLUXVUVEVXYICG-UHFFFAOYSA-N 1,1-dichloroethene;prop-2-enenitrile Chemical compound C=CC#N.ClC(Cl)=C QLUXVUVEVXYICG-UHFFFAOYSA-N 0.000 claims description 2
- CHRJZRDFSQHIFI-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;styrene Chemical compound C=CC1=CC=CC=C1.C=CC1=CC=CC=C1C=C CHRJZRDFSQHIFI-UHFFFAOYSA-N 0.000 claims description 2
- AGHKCDIVQUYCEG-UHFFFAOYSA-N 1-(2-silyloxyethyl)cyclohexa-3,5-diene-1,2,3-triol Chemical compound OC1(C(C(=CC=C1)O)O)CCO[SiH3] AGHKCDIVQUYCEG-UHFFFAOYSA-N 0.000 claims description 2
- DHQACQLKHOJAGR-UHFFFAOYSA-N 1-chlorosilylcyclohexa-3,5-diene-1,2,3-triol Chemical compound OC1C(O)=CC=CC1(O)[SiH2]Cl DHQACQLKHOJAGR-UHFFFAOYSA-N 0.000 claims description 2
- LFGWURKIIWQKEI-UHFFFAOYSA-N 1-diethoxysilylcyclohexa-3,5-diene-1,2,3-triol Chemical compound CCO[SiH](OCC)C1(O)C=CC=C(O)C1O LFGWURKIIWQKEI-UHFFFAOYSA-N 0.000 claims description 2
- FYYBFTOLEHOARM-UHFFFAOYSA-N 1-tripropoxysilylcyclohexa-3,5-diene-1,2,3-triol Chemical compound CCCO[Si](OCCC)(OCCC)C1(O)C=CC=C(O)C1O FYYBFTOLEHOARM-UHFFFAOYSA-N 0.000 claims description 2
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 claims description 2
- 229920000877 Melamine resin Polymers 0.000 claims description 2
- 239000004793 Polystyrene Substances 0.000 claims description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 2
- 229920001577 copolymer Polymers 0.000 claims description 2
- JDSHMPZPIAZGSV-UHFFFAOYSA-N melamine Chemical compound NC1=NC(N)=NC(N)=N1 JDSHMPZPIAZGSV-UHFFFAOYSA-N 0.000 claims description 2
- 125000005395 methacrylic acid group Chemical group 0.000 claims description 2
- LGDNMDSHQLWPAK-UHFFFAOYSA-N methyl 2-methylprop-2-enoate;5-phenylpenta-2,4-dienenitrile Chemical compound COC(=O)C(C)=C.N#CC=CC=CC1=CC=CC=C1 LGDNMDSHQLWPAK-UHFFFAOYSA-N 0.000 claims description 2
- SMUVTFSHWISULV-UHFFFAOYSA-N methyl 2-methylprop-2-enoate;prop-2-enenitrile Chemical compound C=CC#N.COC(=O)C(C)=C SMUVTFSHWISULV-UHFFFAOYSA-N 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 229920000058 polyacrylate Polymers 0.000 claims description 2
- 229920002239 polyacrylonitrile Polymers 0.000 claims description 2
- 229920000642 polymer Polymers 0.000 claims description 2
- 229920002223 polystyrene Polymers 0.000 claims description 2
- SCUZVMOVTVSBLE-UHFFFAOYSA-N prop-2-enenitrile;styrene Chemical compound C=CC#N.C=CC1=CC=CC=C1 SCUZVMOVTVSBLE-UHFFFAOYSA-N 0.000 claims description 2
- 229940079877 pyrogallol Drugs 0.000 claims description 2
- 229920000638 styrene acrylonitrile Polymers 0.000 claims description 2
- 150000003573 thiols Chemical class 0.000 claims description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N zinc oxide Inorganic materials [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 claims description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims 2
- MCMNRKCIXSYSNV-UHFFFAOYSA-N Zirconium dioxide Chemical compound O=[Zr]=O MCMNRKCIXSYSNV-UHFFFAOYSA-N 0.000 claims 2
- VERMEZLHWFHDLK-UHFFFAOYSA-N benzene-1,2,3,4-tetrol Chemical group OC1=CC=C(O)C(O)=C1O VERMEZLHWFHDLK-UHFFFAOYSA-N 0.000 claims 2
- XOLBLPGZBRYERU-UHFFFAOYSA-N tin dioxide Chemical compound O=[Sn]=O XOLBLPGZBRYERU-UHFFFAOYSA-N 0.000 claims 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims 1
- 229910052681 coesite Inorganic materials 0.000 claims 1
- 229910052593 corundum Inorganic materials 0.000 claims 1
- 229910052906 cristobalite Inorganic materials 0.000 claims 1
- CJNBYAVZURUTKZ-UHFFFAOYSA-N hafnium(IV) oxide Inorganic materials O=[Hf]=O CJNBYAVZURUTKZ-UHFFFAOYSA-N 0.000 claims 1
- 239000002245 particle Substances 0.000 claims 1
- 239000000377 silicon dioxide Substances 0.000 claims 1
- 229910052682 stishovite Inorganic materials 0.000 claims 1
- 229910052905 tridymite Inorganic materials 0.000 claims 1
- 229910001845 yogo sapphire Inorganic materials 0.000 claims 1
- 238000002600 positron emission tomography Methods 0.000 description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 229920005989 resin Polymers 0.000 description 7
- 239000011347 resin Substances 0.000 description 7
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000012876 carrier material Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 229910052732 germanium Inorganic materials 0.000 description 4
- GNPVGFCGXDBREM-UHFFFAOYSA-N germanium atom Chemical compound [Ge] GNPVGFCGXDBREM-UHFFFAOYSA-N 0.000 description 4
- 125000005647 linker group Chemical group 0.000 description 4
- 238000009206 nuclear medicine Methods 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 206010027476 Metastases Diseases 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 239000007859 condensation product Substances 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 238000003384 imaging method Methods 0.000 description 3
- 238000012805 post-processing Methods 0.000 description 3
- 230000005855 radiation Effects 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000002591 computed tomography Methods 0.000 description 2
- 238000011109 contamination Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 150000008442 polyphenolic compounds Polymers 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 229910000077 silane Inorganic materials 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- RZHKDBRREKOZEW-AAXZNHDCSA-N 2-[4-[2-[[(2r)-1-[[(4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-4-[[(2r,3r)-1,3-dihydroxybutan-2-yl]carbamoyl]-7-[(1r)-1-hydroxyethyl]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicos-19-yl] Chemical compound C([C@H](C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)NC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1)C1=CC=CC=C1 RZHKDBRREKOZEW-AAXZNHDCSA-N 0.000 description 1
- ZCXUVYAZINUVJD-AHXZWLDOSA-N 2-deoxy-2-((18)F)fluoro-alpha-D-glucose Chemical group OC[C@H]1O[C@H](O)[C@H]([18F])[C@@H](O)[C@@H]1O ZCXUVYAZINUVJD-AHXZWLDOSA-N 0.000 description 1
- 229910018072 Al 2 O 3 Inorganic materials 0.000 description 1
- 108700038672 Edotreotide Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229910004298 SiO 2 Inorganic materials 0.000 description 1
- 229910006404 SnO 2 Inorganic materials 0.000 description 1
- 102000005157 Somatostatin Human genes 0.000 description 1
- 108010056088 Somatostatin Proteins 0.000 description 1
- 229910010413 TiO 2 Inorganic materials 0.000 description 1
- GEIAQOFPUVMAGM-UHFFFAOYSA-N ZrO Inorganic materials [Zr]=O GEIAQOFPUVMAGM-UHFFFAOYSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical group OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000001066 destructive effect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000013399 early diagnosis Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229910052809 inorganic oxide Inorganic materials 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 201000011519 neuroendocrine tumor Diseases 0.000 description 1
- 230000005658 nuclear physics Effects 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000009751 slip forming Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 description 1
- 229960000553 somatostatin Drugs 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 231100000331 toxic Toxicity 0.000 description 1
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- G—PHYSICS
- G21—NUCLEAR PHYSICS; NUCLEAR ENGINEERING
- G21G—CONVERSION OF CHEMICAL ELEMENTS; RADIOACTIVE SOURCES
- G21G1/00—Arrangements for converting chemical elements by electromagnetic radiation, corpuscular radiation or particle bombardment, e.g. producing radioactive isotopes
- G21G1/0005—Isotope delivery systems
-
- G—PHYSICS
- G21—NUCLEAR PHYSICS; NUCLEAR ENGINEERING
- G21G—CONVERSION OF CHEMICAL ELEMENTS; RADIOACTIVE SOURCES
- G21G1/00—Arrangements for converting chemical elements by electromagnetic radiation, corpuscular radiation or particle bombardment, e.g. producing radioactive isotopes
- G21G1/001—Recovery of specific isotopes from irradiated targets
-
- G—PHYSICS
- G21—NUCLEAR PHYSICS; NUCLEAR ENGINEERING
- G21G—CONVERSION OF CHEMICAL ELEMENTS; RADIOACTIVE SOURCES
- G21G1/00—Arrangements for converting chemical elements by electromagnetic radiation, corpuscular radiation or particle bombardment, e.g. producing radioactive isotopes
- G21G1/001—Recovery of specific isotopes from irradiated targets
- G21G2001/0021—Gallium
Definitions
- 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
- PET 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.
- 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.
- a radiopharmaceutical is administered intravenously to the patient at the beginning of a PET examination.
- PET uses radionuclides that emit positrons ( ⁇ + radiation).
- positrons ⁇ + radiation
- 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.
- 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.
- 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.
- generator radioisotopes and in particular the 68 Ga are of particular interest for nuclear medicine and especially for the PET process.
- 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.
- 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.
- 68 Ga PET for example, a 68 Ga DOTATOC chelate with the following structure is used:
- 68 Ga-DOTATOC 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.
- imaging methods such as PET.
- somatostatin-expressing tumors and their metastases can be detected by positron emission tomography.
- 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.
- 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.
- gallium-68 decays with a half-life of 67.63 minutes while emitting a positron.
- gallium-68 is very well suited for nuclear medicine examinations because of its physical and chemical properties.
- 68 Ga can be generated by electron capture from the parent nuclide 68 Ge, which decays with a half-life of 270.82 days.
- 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.
- radiopharmaceuticals require high quality standards for the radionuclides used.
- 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.
- metallic contaminants can disrupt sensitive biomedical measurement systems.
- 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.
- the parent nuclide may be 224 Ra, 225 Ra or 225 Ac.
- 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.
- 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 .-%.
- the ion exchange material must be treated with bound 68 Ge with 2M to 5M HCl.
- 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 %.
- 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.
- 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- Trihydroxyphenyl
- 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.
- inorganic inert oxide materials in particular silica gel, SiO 2 , TiO 2 , SnO 2 , Al 2 O 3 , Z
- 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.
- the silica gel has an average grain size of 10-150 ⁇ m and an average pore size of 6-50 nm.
- 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.
- 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.
- 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).
- a germanium-specific resin was prepared by treating an inert silica gel having a grain size of about 40 ⁇ m 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.
- the 68 Ga thus obtained could be used immediately, ie, without any chemical post-processing, to produce injectable 68 Ga radiopharmaceuticals.
- 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.
- the resin 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.
Description
Die vorliegende Erfindung betrifft einen Generator für ein 68Ga-Tochternuklid gemäß dem Oberbegriff des Anspruchs 1.The present invention relates to a generator for a 68 Ga daughter nuclide according to the preamble of claim 1.
Radionuklide vom Typ der Positronen-Emitter finden bei der sogenannten Positronen-Emissions-Tomografie Verwendung. Die Positronen-Emissions-Tomographie (PET) ist als Variante der Emissionscomputertomographie ein bildgebendes Verfahren der Nuklearmedizin, das Schnittbilder von lebenden Organismen erzeugt, indem es die Verteilung einer schwach radioaktiv markierten Substanz (Radiopharmakon) im Organismus sichtbar macht und damit biochemische und physiologische Funktionen abbildet, und gehört somit in die diagnostische Abteilung der sogenannten funktionellen Bildgebung. Bei einer derartigen PET-Untersuchung an einem Patienten wird die Verteilung einer schwach radioaktiv mit einem Positronen-Emitter markierten Substanz in einem Organismus mit Hilfe des radioaktiven Zerfalls des Positronen-Emitters mittels in der Regel mehrerer Detektoren sichtbar gemacht.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.
Insbesondere wird dem Patienten, basierend auf dem Prinzip der Szintigrafie, zu Beginn einer PET-Untersuchung ein Radiopharmakon intravenös verabreicht. Die PET verwendet Radionuklide, die Positronen emittieren (β+ -Strahlung). Bei der Wechselwirkung eines Positrons mit einem Elektron im Körper des Patienten werden zwei hochenergetische Photonen in genau entgegengesetzte Richtungen, also mit einem Winkel von 180 Grad zueinander, ausgesandt. Hierbei handelt es sich kernphysikalisch betrachtet um die sogenannte Vernichtungsstrahlung. Das PET-Gerät enthält typischerweise viele ringförmig um den Patienten angeordnete Detektoren für die Photonen. Das Prinzip der PET-Untersuchung besteht darin, Koinzidenzen zwischen je zwei gegenüberliegenden Detektoren aufzuzeichnen. Aus der zeitlichen und räumlichen Verteilung dieser registrierten Zerfallsereignisse wird auf die räumliche Verteilung des Radiopharmakons im Körperinneren und insbesondere in den für die jeweiligen Untersuchungen interessierenden Organen und/oder pathologischen Veränderungen, wie raumfordernden Prozessen, geschlossen. Aus den erhaltenen Daten wird ― wie bei der Computertomographie üblich - eine Serie von Schnittbildern errechnet. Häufige Anwendung findet die PET bei stoffwechselbezogenen Fragestellungen in der Onkologie, Neurologie sowie Kardiologie, jedoch ergeben sich in jüngerer Zeit immer weitere Anwendungsfelder.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.
Das bislang meist verwendete Nuklid in der PET ist das radioaktive Isotop 18F. Es wird mit Hilfe eines Zyklotrons hergestellt und kann aufgrund seiner relativ langen Halbwertszeit von etwa 110 Minuten über etwas weitere Strecken vom Zyklotron zu einer nuklearmedizinischen Einheit eines Krankenhauses transportiert werden. Es kommt aus diesem Grund derzeit noch am häufigsten bei PET-Untersuchungen zum Einsatz.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.
Neben 18F werden hauptsächlich 11C, 13N, 15O, 68Ga, 64Cu oder 82Rb eingesetzt.In addition to 18 F mainly 11 C, 13 N, 15 O, 68 Ga, 64 Cu or 82 Rb are used.
Die Halbwertszeiten dieser Isotope sind in Tab. 1 gezeigt.
68Ga und 82Rb sind Generator-Radioisotope. Das Radioisotop entsteht hier durch Zerfall eines instabilen Mutterisotops in einem Nuklidgenerator, in dem es sich anreichert. Alle anderen genannten PET-Nuklide werden mit Hilfe eines Zyklotrons hergestellt. 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.
Aufgrund der in Tab. 1 angegebenen Halbwertszeiten und der Herstellungsmethoden für die Radionuklide ergeben sich folgende Konsequenzen für PET-Untersuchungen: Die Verwendung von 11C erfordert, dass sich ein Zyklotron in relativer Nähe des PET-Systems befindet. Werden die relativ kurzlebigen 13N oder 15O Nuklide eingesetzt, muss sich das Zyklotron in unmittelbarer Nähe des PET-Scanners befinden. Ein radiopharmazeutischer Produktionsbetrieb mit Zyklotron erfordert jedoch eine Investition im zweistelligen Millionenbereich, was die Nutzung der im Zyklotron produzierten Nuklide für die PET wirtschaftlich stark einschränkt.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.
Unter anderem aus diesem Grunde sind Generator-Radioisotope und insbesondere das 68Ga von besonderem Interesse für die Nuklearmedizin und speziell für das PET-Verfahren.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.
Um eine PET durchführen zu können, wird ein Radionuklid an ein Molekül gekoppelt (kovalent gebunden oder auch in Form einer koordinativen Bindung), das am Stoffwechsel beteiligt ist oder in anderer Art eine biologische und/oder pharmakologische Wirkung, etwa die Bindung an einen speziellen Rezeptor, aufweist.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.
Ein typisches, bei PET-Untersuchungen des Standes der Technik verwendetes Molekül ist 18F-Fluordesoxyglucose (FDG). Da FDG-6-Phosphat nach der Phosphorylierung in vivo nicht weiter metabolisiert wird, findet eine Anreicherung statt (,,metabolic trapping"). Dies ist besonders für die frühe Diagnose von Krebserkrankungen von Vorteil. Die Verteilung von FDG im Körper erlaubt neben dem Auffinden von Tumoren und Metastasen aber auch generell Rückschlüsse auf den Glukosemetabolismus von Geweben.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.
Für die PET mit 68Ga wird beispielsweise ein 68Ga-DOTATOC-Chelat mit folgender Struktur eingesetzt:
Mittels eines solchen 68Ga-DOTATOC ist es beispielsweise möglich, mittels bildgebender Verfahren wie PET neuroendokrine Tumoren sowie ihre Metastasen nachzuweisen und zu lokalisieren. Insbesondere können Somatostatin-exprimierende Tumoren und deren Metastasen mit Hilfe der Positronen-Emissions-Tomographie nachgewiesen werden. An den entsprechend entarteten Zellen reichert sich das 68Ga-DOTATOC an. Diese Areale strahlen gegenüber dem normalen Gewebe deutlich stärker. Die Strahlung wird mittels Detektoren lokalisiert und über Bildverarbeitung zu einer dreidimensionalen Darstellung verarbeitet.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.
Nach alledem ist Gallium-68 ein für die PET hochinteressantes Radionuklid und neue Zugangsquellen sind für die klinische Diagnostik und Forschung von großer Bedeutung.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.
68Ga kann mit einem Germanium-68/Gallium-68-Radionuklidgeneratorsystem gewonnen werden, wie beispielsweise aus der europäischen Patentanmeldung
Das 68Ga zerfällt mit einer Halbwertszeit von 67,63 Minuten unter Aussendung eines Positrons. Wie oben erwähnt, eignet sich Gallium-68 aufgrund seiner physikalischen und chemischen Eigenschaften sehr gut für nuklearmedizinische Untersuchungen.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.
Aus kernphysikalischen Untersuchungen ist bekannt, dass 68Ga durch Elektroneneinfang aus dem Mutternuklid 68Ge erzeugt werden kann, das mit einer Halbwertszeit von 270,82 Tagen zerfällt.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.
Typischerweise ist in einem 68Ga-Generator das 68Ge an eine unlösliche Matrix eines inerten Trägers gebunden, wobei durch den kontinuierlichen Zerfall des Germaniums ständig 68Ga gebildet wird, das durch Eluieren mit einem Lösungsmittel aus dem Generator extrahiert werden kann.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.
Zur Herstellung von Radiopharmazeutika müssen hohe Qualitätsanforderungen an die verwendeten Radionuklide gestellt werden. Insbesondere müssen die erzeugten Radionuklide einen hohen Reinheitsgrad aufweisen und im Wesentlichen frei von metallischen Verunreinigungen sein, da diese die Markierung der Radiopharmazeutika durch Konkurrenzreaktionen negativ beeinflussen und die produktionstechnisch erzielbare Ausbeute mindern können. Darüber hinaus können metallische Verunreinigungen die empfindlichen biomedizinischen Messsysteme stören.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.
Aus der
Ferner beschreibt die
Die hohe Säurekonzentration einerseits sowie die toxischen Effekte des verwendeten Formaldehyds als Comonomer machen eine Nachbearbeitung des Eluats vor seiner Verwendung als Radiopharmazeutikum erforderlich.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.
Darüber hinaus ist das Verfahren zur Synthese eines Di- oder Trihydroxyphenol-Formaldehyd-Harzes technisch aufwendig und kostspielig.In addition, the process for the synthesis of a di- or trihydroxyphenol-formaldehyde resin is technically complicated and expensive.
Gegenüber diesem Stand der Technik war das Verfahren der
Die Säulenmaterialien wurden dann mit 0,05 M HCl eluiert, wobei das Eluat im Wesentlichen 68Ga enthielt und der Durchbruch des Mutternuklids im Bereich von 1,0 x 10-5 bis 3 x 10-3% lag.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 %.
Obwohl das Gallium-68 direkt und ohne weitere chemische Nachbereitung zur Zubereitung injizierbarer Gallium-68-Radiopharmaka verwendet werden konnte, löste sich die hydrophobe Verbindung, an welche das Polyhydroxyphenol gekoppelt war, im Laufe der Zeit ab und führte zu Verunreinigungen des gewünschten 68Ga-Nuklids, so dass vor Verwendung als Radiopharmazeutikum nach einer gewissen Laufzeit der Trägermaterialien doch noch ein weiterer Reinigungsschritt erforderlich war, bevor die 68Ga-Fraktion zur Herstellung eines Radiopharmazeutikums eingesetzt werden konnte.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.
Ausgehend vom Stand der Technik der
Die Lösung dieser Aufgabe erfolgt durch einen Generator für ein 68Ga-Tochternuklid gemäß den Merkmalen des Anspruchs 1.The solution of this object is achieved by a generator for a 68 Ga daughter nuclide according to the features of claim 1.
Insbesondere betrifft die vorliegende Erfindung einen Generator für ein 68Ga-Tochternuklid, bei welchem dessen 68Ge-Mutternuklid spezifisch an einem Träger über eine Trihydroxyphenylgruppe oder eine Dihydroxybenzengruppe immobilisiert ist und kontinuierlich mit einer Halbwertzeit von 270,82d durch Elektroneneinfang zu 68Ga zerfällt, wobei die Trihydroxyphenylgruppe (oder Dihydroxyphenylgruppe) kovalent über einen Linker an ein Trägermaterial gebunden ist, wobei der Linker ausgewählt wird aus der Gruppe bestehend aus: C2 bis C20 ― Estern, C2 bis C20 ― Alkylen, Phenyl, Thioharnstoff, C2-C20-Aminen, Melamin, Maleimid, Trihydroxyphenylalkoxsilanen, insbesondere 1,2,3-Trihydroxyphenyltriethoxysilan, 1,2,3-Trihydroxyphenyldiethoxysilan, 1,2,3-Trihydroxyphenylethoxysilan, 1,2,3-Trihydroxyphenyltripropoxysilan, 1,2,3-Trihydroxyphenylchlorsilan, Epichlorhydrin, Isothiocyanate, Thiole.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.
Eine bevorzugte Ausführungsform der vorliegenden Erfindung ist ein 68Ga-Generator, wobei das Trägermaterial ausgewählt ist aus der Gruppe bestehend aus: anorganischen inerten Oxidmaterialien, insbesondere Kieselgel, SiO2, TiO2, SnO2, Al2O3, ZnO, ZrO2, HfO2 oder organischen inerten Polymeren und Copolymeren, insbesondere Styrol-Divinylbenzol, Polystyrol, Styrol-Acrylnitril, Styrol-Acrylnitril-Methylmethacrylat, Acrylnitril-Methylmethacrylat, Polyacrylnitril, Polyacrylaten, Acryl- oder Methacrylestern, acrylnitrilungesättigte Dicarbonsäure-Styrol, Vinylidenchlorid-Acrylnitril.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.
Es ist bevorzugt, dass die Trihydroxyphenylgruppe 1,2,3-Trihydroxybenzol (Pyrogallol) ist, wobei bevorzugt als Trägermaterial Kieselgel und als Linker 1,2,3-Trihydroxyphenyltriethoxysilan eingesetzt werden kann.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.
Typischerweise weist das Kieselgel eine durchschnittliche Korngröße von 10 - 150 µm und eine durchschnittliche Porengröße von 6 - 50 nm auf.Typically, the silica gel has an average grain size of 10-150 μm and an average pore size of 6-50 nm.
Als bevorzugtes hochspezifisches Elutionsverfahren hat sich eine Behandlung der mit 68Ge beladenen Trihydroxyphenylgruppe des Trägermaterials zur Gewinnung der durch radioaktiven Zerfall des Mutternuklids gebildeten 68Ga-lonen mit 0,05 bis 0,5 M HCl herausgestellt.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.
Für den 68Ga-Generator der vorliegenden Erfindung werden zur Beladung des Trägermaterials vorzugsweise 68Ge-Salze in Form einer Verbindung mit der Oxidationszahl IV eingesetzt.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.
Insbesondere wird eine wässrige Lösung eines 68Ge(IV)-Salzes zur Immobilisierung von 68Ge an der Trihydroxyphenylgruppe eingesetzt, besonders bevorzugt sind 68Ge Aquaionen.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.
Mit dem 68Ga-Generator gemäß der vorliegenden Erfindung weist das erzeugte 68Ga eine solche Reinheit auf, die die unmittelbare radiopharmazeutische Verwendung gestattet, wobei der Gehalt an Verunreinigungen, insbesondere metallischen Verunreinigungen, im Bereich von 10 bis 100 ppb (massebezogen), vorzugsweise zwischen 1 und 10 ppb (massebezogen) und besonders bevorzugt unterhalb von 1 ppb (massebezogen), liegt.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).
Zwar sind grundsätzlich kovalente Kopplungen wie Silan oder Epichlorhydrin oder Isothiocyanat Kopplungen von organischen Molekülen oder Biomolekülen an einen inerten anorganischen oder organischen Träger seit langem im Stand der Technik bekannt, jedoch ist auch die Hydrolyseempfindlichkeit derartiger Kopplungen bei Verwendung von Säuren als Elutionsmittel ebenfalls bekannt. Durch diese Säurehydrolyse würde der Träger bei längerem Gebrauch irreversibel zerstört, was ebenfalls wiederum zu Kontaminationen der 68Ga-Fraktion führen würde.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.
Bei Praxistests insbesondere mit Silankopplern hat sich jedoch überraschend herausgestellt, dass diese über einen längeren Zeitraum säurestabil sind und zu hochreinen 68Ga-Fraktionen führen, wenn man die mit 68Ge beladenen Trägermaterialien gemäß der vorliegenden Erfindung mit 0,05 M bis 0,5 M HCl eluiert, um das 68Ga von dem mit dem Mutternuklid beladenen Trägermaterial herauszuwaschen.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.
Mit dem erfindungsgemäßen Generator für ein 68Ga-Tochternuklid, welches aus einem 68Ge-Mutternuklid gebildet wird, steht somit erstmals ein langzeitstabiler 68Ga-Generator zur Verfügung, bei dem die erhaltene 68Ga-Fraktion unmittelbar als Radiopharmazeutikum, zum Beispiel für die PET, verwendet werden kann.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.
Weitere Vorteile und Merkmale der vorliegenden Erfindung ergeben sich aufgrund der Beschreibung eines Ausführungsbeispiels.Further advantages and features of the present invention will become apparent from the description of an embodiment.
Ein Germanium-spezifisches Harz wurde hergestellt durch Behandeln eines inerten Kieselgels mit einer Korngröße von ca. 40 µm und einer Porengröße von ca. 6 nm mit 1,2,3-Trihydroxyphenyltriethoxysilan. Die Silanierung des nativen Kieselgels führte zu kovalent gebundenen 1,2,3-Trihydroxybenzol-funktionellen Gruppen auf dem inerten Träger. Messungen der Gewichtsverteilungsfaktoren von Ge(IV) auf dem Harz bestätigten die hohe Affinität des Materials zum Germanium. Das Harz wurde in Form kleiner Chromatografiesäulen verwendet.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.
Wässrige Lösungen mit HCl oder HNO3 oder NaCl des Radionuklids 68Ge mit Aktivitäten im Bereich von 100 bis 1000 MBq wurden durch die Säulen gepumpt. Aufgrund der spezifischen Bindung des 68Ge wurde dieses quantitativ auf den Säulenmaterialien adsorbiert bzw. immobilisiert.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.
Diese mit 68Ge beladenen Säulen wurden verwendet, um das kurzlebige Tochternuklid 68Ga herzustellen. Während 68Ge auf dem Träger immobilisiert ist, wird kontinuierlich 68Ga gebildet, welches wiederholt eluiert werden kann. Die hochspezifische Elution des 68Ga kann wirksam in schwachen salzsauren Lösungen (0,05 bis 0,5 M HCl) mit kleinen Volumina bis zu 2,5 ml durchgeführt werden. Der Durchbruch des Mutternuklids 68Ge lag in der Größenordnung von <10-5 %.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 %.
Das so erhaltene 68Ga konnte unmittelbar verwendet werden, d. h. ohne jegliche chemische Nachbearbeitung, um injizierbare 68Ga-Radiopharmazeutika herzustellen.The 68 Ga thus obtained could be used immediately, ie, without any chemical post-processing, to produce injectable 68 Ga radiopharmaceuticals.
Darüber hinaus kann das erfindungsgemäße Harz dazu verwendet werden, jegliche Germaniumspuren (sowohl radioaktive als auch stabile Isotope) aus wässrigen Lösungen für analytische oder pharmazeutische Anwendungen zu entfernen.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.
Durch eine kovalente Kopplung an das Trägermaterial weist das Harz eine erhöhte chemische und radiolytische Stabilität gegenüber dem Stand der Technik der
Claims (9)
- 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. - 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.
- The 68Ga generator according to claim 1 or 2, characterized in that the trihydroxyphenyl group is 1,2,3-trihydroxybenzene (pyrogallol).
- 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.
- 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.
- 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.
- 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.
- 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.
- 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).
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JP (1) | JP5335048B2 (en) |
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Cited By (2)
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EP3343570A1 (en) | 2016-12-27 | 2018-07-04 | ITM Isotopen Technologien München AG | 68ge/68ga generator |
EP3401283A1 (en) | 2017-05-10 | 2018-11-14 | ITM Isotopen Technologien München AG | Method for the manufacture of highly purified 68ge material for radiopharmaceutical purposes |
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MX2017009855A (en) * | 2015-01-30 | 2017-11-15 | Advanced Accelerator Applications Int S A | Process for the purification of ga-68 from eluate deriving from 68ge/ 68ga generators and chromatographic columns for use in said process. |
KR102218075B1 (en) * | 2018-06-04 | 2021-02-19 | 동국대학교 경주캠퍼스 산학협력단 | Chitosan immobilized metal oxide for the adsorption materials of radioisotope generator and method for fabricating the same and radioisotope generating method |
AU2019399674A1 (en) | 2018-12-11 | 2021-06-24 | Societe de Commercialisation des Produits de la Recherche Appliquée Socpra Sciences et Génie S.E.C. | Processes and systems for producing and/or purifying gallium-68 |
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AT334084B (en) * | 1975-02-25 | 1976-12-27 | Radiation Int Ag | PROCESS FOR THE PRODUCTION OF RESINS SUITABLE IN PARTICULAR FOR THE SELECTIVE SEPARATION OF VALUABLE METALS FROM Aqueous SOLUTIONS |
US4264468A (en) * | 1979-01-08 | 1981-04-28 | Massachusetts Institute Of Technology | Generator for gallium-68 and compositions obtained therefrom |
FR2455334A1 (en) * | 1979-04-24 | 1980-11-21 | Commissariat Energie Atomique | PROCESS FOR THE PREPARATION OF A GALLIUM 68 SOLUTION IN ION FORM |
DE2932948C2 (en) * | 1979-08-14 | 1982-11-18 | Stiftung Deutsches Krebsforschungszentrum, 6900 Heidelberg | Process for the production of an ion exchanger and its use |
AT383643B (en) * | 1984-10-19 | 1987-07-27 | Blum Gmbh Julius | HINGE |
US7011816B2 (en) * | 2001-12-26 | 2006-03-14 | Immunomedics, Inc. | Labeling targeting agents with gallium-68 and gallium-67 |
US7023000B2 (en) * | 2003-05-21 | 2006-04-04 | Triumf | Isotope generator |
DE102004057225B4 (en) * | 2004-11-26 | 2006-10-12 | Johannes-Gutenberg-Universität Mainz | A method and apparatus for isolating a chemically and radiochemically purified 68Ga radionuclide and labeling a label precursor with the 68Ga radionuclide |
US20070009409A1 (en) * | 2005-07-11 | 2007-01-11 | Hariprasad Gali | 212Bi or 213Bi Generator from supported parent isotope |
JP4509083B2 (en) | 2006-10-24 | 2010-07-21 | パナソニック株式会社 | Disk drive |
JP5005024B2 (en) * | 2007-03-02 | 2012-08-22 | 国立大学法人 長崎大学 | Ge adsorbent |
DE102009007799B4 (en) * | 2009-02-06 | 2010-10-14 | ITM Isotopen Technologien München AG | Molecule for the functionalization of a carrier, binding of a radionuclide to the carrier and radionuclide generator for the production of the radionuclide and production method |
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Cited By (4)
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EP3343570A1 (en) | 2016-12-27 | 2018-07-04 | ITM Isotopen Technologien München AG | 68ge/68ga generator |
WO2018122250A1 (en) | 2016-12-27 | 2018-07-05 | ITM Isotopen Technologien München AG | 68ge/68ga generator |
EP3401283A1 (en) | 2017-05-10 | 2018-11-14 | ITM Isotopen Technologien München AG | Method for the manufacture of highly purified 68ge material for radiopharmaceutical purposes |
WO2018206188A1 (en) | 2017-05-10 | 2018-11-15 | ITM Isotopen Technologien München AG | METHOD FOR THE MANUFACTURE OF HIGHLY PURIFIED 68Ge MATERIAL FOR RADIOPHARMACEUTICAL PURPOSES |
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CN102446570B (en) | 2014-12-03 |
US20120252981A1 (en) | 2012-10-04 |
US20140163211A1 (en) | 2014-06-12 |
CA2749505A1 (en) | 2012-04-05 |
AU2011211435A1 (en) | 2012-04-19 |
JP5335048B2 (en) | 2013-11-06 |
DK2439747T3 (en) | 2013-10-07 |
EP2439747A3 (en) | 2012-08-29 |
EP2439747A8 (en) | 2013-01-02 |
BRPI1103916B1 (en) | 2020-10-20 |
BRPI1103916A2 (en) | 2015-03-31 |
US8937166B2 (en) | 2015-01-20 |
CN102446570A (en) | 2012-05-09 |
EP2439747A2 (en) | 2012-04-11 |
PL2439747T3 (en) | 2014-02-28 |
JP2012078353A (en) | 2012-04-19 |
ES2439821T3 (en) | 2014-01-24 |
US8487047B2 (en) | 2013-07-16 |
DE102010037964B3 (en) | 2012-03-22 |
CA2749505C (en) | 2013-12-03 |
AU2011211435B2 (en) | 2012-11-08 |
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