EP2439747B1 - 68 Ga-Generator - Google Patents

68 Ga-Generator Download PDF

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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
group
generator according
acrylonitrile
styrene
ppb
Prior art date
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EP11176249.8A
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German (de)
English (en)
French (fr)
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EP2439747A8 (de
EP2439747A2 (de
EP2439747A3 (de
Inventor
Konstantin Zhernosekov
Tuomo Nikula
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ITM Isotopen Technologien Muenchen AG
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ITM Isotopen Technologien Muenchen AG
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Priority to PL11176249T priority Critical patent/PL2439747T3/pl
Publication of EP2439747A2 publication Critical patent/EP2439747A2/de
Publication of EP2439747A3 publication Critical patent/EP2439747A3/de
Publication of EP2439747A8 publication Critical patent/EP2439747A8/de
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Classifications

    • GPHYSICS
    • G21NUCLEAR PHYSICS; NUCLEAR ENGINEERING
    • G21GCONVERSION OF CHEMICAL ELEMENTS; RADIOACTIVE SOURCES
    • G21G1/00Arrangements for converting chemical elements by electromagnetic radiation, corpuscular radiation or particle bombardment, e.g. producing radioactive isotopes
    • G21G1/0005Isotope delivery systems
    • GPHYSICS
    • G21NUCLEAR PHYSICS; NUCLEAR ENGINEERING
    • G21GCONVERSION OF CHEMICAL ELEMENTS; RADIOACTIVE SOURCES
    • G21G1/00Arrangements for converting chemical elements by electromagnetic radiation, corpuscular radiation or particle bombardment, e.g. producing radioactive isotopes
    • G21G1/001Recovery of specific isotopes from irradiated targets
    • GPHYSICS
    • G21NUCLEAR PHYSICS; NUCLEAR ENGINEERING
    • G21GCONVERSION OF CHEMICAL ELEMENTS; RADIOACTIVE SOURCES
    • G21G1/00Arrangements for converting chemical elements by electromagnetic radiation, corpuscular radiation or particle bombardment, e.g. producing radioactive isotopes
    • G21G1/001Recovery of specific isotopes from irradiated targets
    • G21G2001/0021Gallium

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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  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Physics & Mathematics (AREA)
  • Engineering & Computer Science (AREA)
  • General Engineering & Computer Science (AREA)
  • High Energy & Nuclear Physics (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nuclear Medicine (AREA)
  • Catalysts (AREA)
EP11176249.8A 2010-10-05 2011-08-02 68 Ga-Generator Active EP2439747B1 (de)

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

Family

ID=44645527

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)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
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)

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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

Cited By (4)

* Cited by examiner, † Cited by third party
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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