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
- Authority
- 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
- 239000000758 substrate Substances 0.000 description 1
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- 230000002123 temporal effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 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.
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Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PL11176249T PL2439747T3 (pl) | 2010-10-05 | 2011-08-02 | Generator <sup>68</sup>GA |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102010037964A DE102010037964B3 (de) | 2010-10-05 | 2010-10-05 | 68Ga-Generator |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| EP2439747A2 EP2439747A2 (de) | 2012-04-11 |
| EP2439747A3 EP2439747A3 (de) | 2012-08-29 |
| EP2439747A8 EP2439747A8 (de) | 2013-01-02 |
| EP2439747B1 true EP2439747B1 (de) | 2013-09-18 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP11176249.8A Active EP2439747B1 (de) | 2010-10-05 | 2011-08-02 | 68 Ga-Generator |
Country Status (11)
| Country | Link |
|---|---|
| US (2) | US8487047B2 (pl) |
| EP (1) | EP2439747B1 (pl) |
| JP (1) | JP5335048B2 (pl) |
| CN (1) | CN102446570B (pl) |
| AU (1) | AU2011211435B2 (pl) |
| BR (1) | BRPI1103916B1 (pl) |
| CA (1) | CA2749505C (pl) |
| DE (1) | DE102010037964B3 (pl) |
| DK (1) | DK2439747T3 (pl) |
| ES (1) | ES2439821T3 (pl) |
| PL (1) | PL2439747T3 (pl) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10141079B2 (en) * | 2014-12-29 | 2018-11-27 | Terrapower, Llc | Targetry coupled separations |
| BR112017016492B1 (pt) * | 2015-01-30 | 2022-09-20 | Advanced Accelerator Applications International S.A.. | Processo para a purificação de ga-68 a partir de eluato que deriva de geradores de 68ge/ 68ga e colunas cromatográficas para uso no dito processo |
| KR102218075B1 (ko) * | 2018-06-04 | 2021-02-19 | 동국대학교 경주캠퍼스 산학협력단 | 방사성동위원소 발생장치용 키토산 코팅 금속산화물 흡착제, 그 제조방법 및 이를 이용한 방사성동위원소 발생방법 |
| WO2020118426A1 (en) | 2018-12-11 | 2020-06-18 | 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 |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT334084B (de) * | 1975-02-25 | 1976-12-27 | Radiation Int Ag | Verfahren zur herstellung von insbesondere fur die selektive abtrennung mehrwertiger metalle aus wasserigen losungen geeigneten harzen |
| US4264468A (en) * | 1979-01-08 | 1981-04-28 | Massachusetts Institute Of Technology | Generator for gallium-68 and compositions obtained therefrom |
| FR2455334A1 (fr) * | 1979-04-24 | 1980-11-21 | Commissariat Energie Atomique | Procede de preparation d'une solution de gallium 68 sous forme ionique |
| DE2932948C2 (de) * | 1979-08-14 | 1982-11-18 | Stiftung Deutsches Krebsforschungszentrum, 6900 Heidelberg | Verfahren zur Herstellung eines Ionenaustauschers und dessen Verwendung |
| AT383643B (de) * | 1984-10-19 | 1987-07-27 | Blum Gmbh Julius | Scharnier |
| 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 (de) * | 2004-11-26 | 2006-10-12 | Johannes-Gutenberg-Universität Mainz | Verfahren und Vorrichtung zur Isolierung eines chemisch und radiochemisch gereinigten 68Ga-Radionuklids und zum Markieren eines Markierungsvorläufers mit dem 68Ga-Radionuklid |
| US20070009409A1 (en) * | 2005-07-11 | 2007-01-11 | Hariprasad Gali | 212Bi or 213Bi Generator from supported parent isotope |
| JP4509083B2 (ja) | 2006-10-24 | 2010-07-21 | パナソニック株式会社 | ディスク駆動装置 |
| WO2008108311A1 (ja) * | 2007-03-02 | 2008-09-12 | Nagasaki University | Ｇｅ吸着剤 |
| DE102009007799B4 (de) * | 2009-02-06 | 2010-10-14 | ITM Isotopen Technologien München AG | Molekül zur Funktionalisierung eines Trägers, Bindung eines Radionuklids an den Träger und Radionuklidgenerator zur Herstellung des Radionuklids sowie Herstellungsverfahren |
-
2010
- 2010-10-05 DE DE102010037964A patent/DE102010037964B3/de not_active Expired - Fee Related
-
2011
- 2011-08-02 PL PL11176249T patent/PL2439747T3/pl unknown
- 2011-08-02 EP EP11176249.8A patent/EP2439747B1/de active Active
- 2011-08-02 DK DK11176249.8T patent/DK2439747T3/da active
- 2011-08-02 ES ES11176249.8T patent/ES2439821T3/es active Active
- 2011-08-15 AU AU2011211435A patent/AU2011211435B2/en active Active
- 2011-08-18 BR BRPI1103916-7A patent/BRPI1103916B1/pt active IP Right Grant
- 2011-08-18 CA CA2749505A patent/CA2749505C/en active Active
- 2011-08-25 CN CN201110275294.5A patent/CN102446570B/zh active Active
- 2011-09-20 JP JP2011204921A patent/JP5335048B2/ja active Active
- 2011-09-28 US US13/247,381 patent/US8487047B2/en active Active
-
2013
- 2013-06-27 US US13/929,374 patent/US8937166B2/en active Active
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2749505A1 (en) | 2012-04-05 |
| JP5335048B2 (ja) | 2013-11-06 |
| ES2439821T3 (es) | 2014-01-24 |
| CN102446570A (zh) | 2012-05-09 |
| DE102010037964B3 (de) | 2012-03-22 |
| EP2439747A8 (de) | 2013-01-02 |
| US20140163211A1 (en) | 2014-06-12 |
| US8937166B2 (en) | 2015-01-20 |
| AU2011211435A1 (en) | 2012-04-19 |
| US20120252981A1 (en) | 2012-10-04 |
| DK2439747T3 (da) | 2013-10-07 |
| BRPI1103916A2 (pt) | 2015-03-31 |
| EP2439747A2 (de) | 2012-04-11 |
| EP2439747A3 (de) | 2012-08-29 |
| US8487047B2 (en) | 2013-07-16 |
| CA2749505C (en) | 2013-12-03 |
| JP2012078353A (ja) | 2012-04-19 |
| PL2439747T3 (pl) | 2014-02-28 |
| CN102446570B (zh) | 2014-12-03 |
| BRPI1103916B1 (pt) | 2020-10-20 |
| AU2011211435B2 (en) | 2012-11-08 |
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