NO341638B1 - Framgangsmåte for å merke en vektor, nye forbindelser og bruk av disse i fremstilling av et radiofarmasøytikum, samt en radiofarmasøytisk sammensetning - Google Patents
Framgangsmåte for å merke en vektor, nye forbindelser og bruk av disse i fremstilling av et radiofarmasøytikum, samt en radiofarmasøytisk sammensetningInfo
- Publication number
- NO341638B1 NO341638B1 NO20073157A NO20073157A NO341638B1 NO 341638 B1 NO341638 B1 NO 341638B1 NO 20073157 A NO20073157 A NO 20073157A NO 20073157 A NO20073157 A NO 20073157A NO 341638 B1 NO341638 B1 NO 341638B1
- Authority
- NO
- Norway
- Prior art keywords
- radiopharmaceutical
- compound
- formula
- vector
- labeling
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title abstract 5
- 239000012217 radiopharmaceutical Substances 0.000 title abstract 3
- 229940121896 radiopharmaceutical Drugs 0.000 title abstract 3
- 230000002799 radiopharmaceutical effect Effects 0.000 title abstract 3
- 239000013598 vector Substances 0.000 title abstract 3
- 238000000034 method Methods 0.000 title abstract 2
- 238000002372 labelling Methods 0.000 title 1
- 238000002360 preparation method Methods 0.000 title 1
- 239000003054 catalyst Substances 0.000 abstract 1
- 239000003153 chemical reaction reagent Substances 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 238000002591 computed tomography Methods 0.000 abstract 1
- 239000000032 diagnostic agent Substances 0.000 abstract 1
- 229940039227 diagnostic agent Drugs 0.000 abstract 1
- 238000002600 positron emission tomography Methods 0.000 abstract 1
- 108090000765 processed proteins & peptides Proteins 0.000 abstract 1
- 230000003439 radiotherapeutic effect Effects 0.000 abstract 1
- 238000001959 radiotherapy Methods 0.000 abstract 1
- 238000002603 single-photon emission computed tomography Methods 0.000 abstract 1
- 238000003325 tomography Methods 0.000 abstract 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/082—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins the peptide being a RGD-containing peptide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
- A61K51/1045—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against animal or human tumor cells or tumor cell determinants
- A61K51/1051—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against animal or human tumor cells or tumor cell determinants the tumor cell being from breast, e.g. the antibody being herceptin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Optics & Photonics (AREA)
- Physics & Mathematics (AREA)
- Epidemiology (AREA)
- Oncology (AREA)
- Organic Chemistry (AREA)
- Cell Biology (AREA)
- Immunology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB0428012.9A GB0428012D0 (en) | 2004-12-22 | 2004-12-22 | Radiolabelling methods |
| PCT/GB2005/004729 WO2006067376A2 (en) | 2004-12-22 | 2005-12-09 | Radiolabelled conjugates of rgd-containing peptides and methods for their preparation via click-chemistry |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NO20073157L NO20073157L (no) | 2007-06-20 |
| NO341638B1 true NO341638B1 (no) | 2017-12-18 |
Family
ID=34112991
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO20073157A NO341638B1 (no) | 2004-12-22 | 2007-06-20 | Framgangsmåte for å merke en vektor, nye forbindelser og bruk av disse i fremstilling av et radiofarmasøytikum, samt en radiofarmasøytisk sammensetning |
Country Status (13)
| Country | Link |
|---|---|
| US (2) | US7972588B2 (enExample) |
| EP (4) | EP2275145A1 (enExample) |
| JP (2) | JP5743372B2 (enExample) |
| KR (1) | KR101314460B1 (enExample) |
| CN (2) | CN101084020A (enExample) |
| AU (1) | AU2005317903C1 (enExample) |
| BR (1) | BRPI0519317A2 (enExample) |
| CA (2) | CA2817636A1 (enExample) |
| GB (1) | GB0428012D0 (enExample) |
| MX (1) | MX2007007560A (enExample) |
| NO (1) | NO341638B1 (enExample) |
| RU (1) | RU2419627C2 (enExample) |
| WO (1) | WO2006067376A2 (enExample) |
Families Citing this family (49)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0428012D0 (en) * | 2004-12-22 | 2005-01-26 | Hammersmith Imanet Ltd | Radiolabelling methods |
| US8071718B2 (en) | 2004-12-22 | 2011-12-06 | General Electric Company | Selective radiolabeling of biomolecules |
| US8211403B2 (en) | 2006-06-21 | 2012-07-03 | Hammersmith Imanet Limited | Radiolabelling methods |
| US20100069609A1 (en) * | 2006-06-21 | 2010-03-18 | Erik Arstad | Chemical methods and apparatus |
| CN101528270A (zh) * | 2006-08-28 | 2009-09-09 | 通用电气健康护理有限公司 | 基于68Ga标记的肽的放射性药物 |
| WO2008025886A1 (en) * | 2006-09-01 | 2008-03-06 | Wallac Oy | Metal chelates and chelating agents containing triazolyl subunits |
| EP2155259A2 (en) * | 2007-05-10 | 2010-02-24 | The Trustees of Columbia University in the City of New York | Methods for diagnosing diseases and evaluating treatments therefor using pet |
| ES2662495T3 (es) | 2007-12-20 | 2018-04-06 | General Electric Company | Radiomarcación selectiva de biomoléculas |
| EP2147684A1 (en) * | 2008-07-22 | 2010-01-27 | Bracco Imaging S.p.A | Diagnostic Agents Selective Against Metalloproteases |
| GB0815831D0 (en) * | 2008-09-01 | 2008-10-08 | Imp Innovations Ltd | Compounds |
| CA2735970A1 (en) | 2008-09-05 | 2010-03-11 | Hammersmith Imanet Limited | Isatin derivatives for use as in vivo imaging agents |
| CN102177160B (zh) * | 2008-10-10 | 2014-11-26 | 默克及其合伙人公司 | 作为pet放射性示踪剂的18f-标记叶酸 |
| US20120165650A1 (en) | 2010-12-22 | 2012-06-28 | General Electric Company | Her2 binders |
| EP2210882A1 (en) * | 2009-01-16 | 2010-07-28 | Commissariat à l'Énergie Atomique et aux Énergies Alternatives | Synthesis of new protected azahistidine, their processes and their use in synthesises |
| US8435488B2 (en) * | 2009-02-27 | 2013-05-07 | Genentech, Inc. | Methods and compositions for protein labelling |
| US8722014B2 (en) * | 2009-05-01 | 2014-05-13 | Washington University | 1 H-[1, 2, 3] triazole substituted amino acids and uses thereof |
| GB0914543D0 (en) * | 2009-08-20 | 2009-09-30 | Ge Healthcare Ltd | Radioiodination method |
| EP2498826A1 (en) * | 2009-11-11 | 2012-09-19 | NeuroSearch AS | Labelled pyrrolyl-oxadiazolyl-diazabicyclononane derivatives and their use in diagnostic methods |
| GB0921573D0 (en) * | 2009-12-10 | 2010-01-27 | Ge Healthcare Ltd | Iodine radiolabelling method |
| GB0922304D0 (en) | 2009-12-22 | 2010-02-03 | Ge Healthcare Ltd | Radioiodinated compounds |
| US20120269725A1 (en) * | 2009-12-23 | 2012-10-25 | Janine Baranowska-Kortylewicz | Targeted radiolabeled compounds and their use for the treatment and diagnosis of cancer |
| US9517279B2 (en) * | 2010-04-14 | 2016-12-13 | The Mclean Hospital Corporation | 2-alkoxy-11-hydroxyaporphine derivatives and uses thereof |
| EP2575897A4 (en) * | 2010-06-01 | 2016-06-01 | Advanced Proteome Therapeutics Inc | CROSSLINKING OF PROTEINS AND OTHER ENTITIES THROUGH ALPHA-HALO-ACETOPHENONES CONJUGATES, BENZYL HALIDES, QUINONES |
| CN103221398B (zh) * | 2010-07-23 | 2016-03-23 | 特拉华大学 | 用于快速构建放射性核素标记探针的四嗪-反式环辛烯连接反应 |
| GB201014023D0 (en) * | 2010-08-20 | 2010-10-06 | Ucl Business Plc | Process for producing bioconjugates and products thereof |
| WO2012074840A2 (en) | 2010-11-22 | 2012-06-07 | The General Hospital Corporation | Compositions and methods for in vivo imaging |
| GB201019824D0 (en) | 2010-11-23 | 2011-01-05 | Ge Healthcare Ltd | Radioiodination method |
| GB201021369D0 (en) | 2010-12-16 | 2011-01-26 | Ge Healthcare Ltd | Radioiodinated fatty acids |
| GB201021517D0 (en) | 2010-12-20 | 2011-02-02 | Ge Healthcare Ltd | Radioiodinated guanidines |
| WO2012087912A1 (en) | 2010-12-22 | 2012-06-28 | Ge Healthcare Limited | Her2 binding peptides labelled with a 18f - containing organosilicon compound |
| MX2013007365A (es) | 2010-12-22 | 2013-09-26 | Ge Healthcare Ltd | Péptidos de enlace her2 etiquetados con fluoruro de aluminio- [18] combinados mediante nota. |
| EP2680889B1 (en) | 2011-03-01 | 2019-06-19 | GE Healthcare Limited | Radiolabelled octreotate analogues as pet tracers |
| US20120251448A1 (en) * | 2011-03-03 | 2012-10-04 | Hefti Franz F | Compounds for Use in the Detection of Neurodegenerative Diseases |
| US9023318B2 (en) * | 2011-06-08 | 2015-05-05 | Siemens Medical Solutions Usa, Inc. | Compounds with matrix-metalloproteinase inhibitory activity and imaging agents thereof |
| WO2013048832A1 (en) | 2011-09-29 | 2013-04-04 | Ge Healthcare Limited | 18 f - labelled 6 - ( 2 - fluoroethoxy) - 2 - naphthaldehyde for detecting cancer stem cells |
| WO2013048811A1 (en) | 2011-09-30 | 2013-04-04 | Ge Healthcare Limited | Imaging and radiotherapy methods for tumour stem cells |
| US20140335019A1 (en) * | 2011-12-02 | 2014-11-13 | The Regents Of The University Of Michigan | Compositions and methods for the treatment and analysis of neurological disorders |
| GB201121911D0 (en) | 2011-12-20 | 2012-02-01 | Ge Healthcare Ltd | Radiofluorination method |
| US20150017093A1 (en) * | 2012-02-03 | 2015-01-15 | Aarhus Universitet | Radiolabeled bile acids and bile acid derivatives |
| EP2657213A1 (en) * | 2012-04-24 | 2013-10-30 | Institut National de la Santé et de la Recherche Medicale | Labelled quinoxaline derivatives as multimodal radiopharmaceuticals and their precursors |
| US20140065070A1 (en) * | 2012-08-28 | 2014-03-06 | Mcmaster University | Methods of preparing triazole-containing radioiodinated compounds |
| US20160137639A1 (en) * | 2012-10-26 | 2016-05-19 | Japan Tobacco Inc. | Triazole-isoxazole compound and medical use thereof |
| US20150023877A1 (en) * | 2013-07-18 | 2015-01-22 | The Board Of Trustees Of The Leland Stanford Junior University | Methods of parkinsons disease diagnosis and monitoring treatment |
| ES2700348T3 (es) * | 2014-01-05 | 2019-02-15 | Univ Washington | Trazadores radioetiquetados para poli (ADP-ribosa) polimerasa-1 (PARP-1), métodos y usos para estos |
| US20160022846A1 (en) * | 2014-07-22 | 2016-01-28 | Ge Healthcare Limited | Iodine radiolabelling method |
| PT3310816T (pt) * | 2015-06-19 | 2020-10-19 | Eisai R&D Man Co Ltd | Imunoglobulinas conjugadas cys80 |
| WO2017023999A1 (en) * | 2015-08-03 | 2017-02-09 | Emory University | Methylsulfonamide derivatives and uses related thereto |
| WO2019227490A1 (en) | 2018-06-01 | 2019-12-05 | Tayu Huaxia Biotech Medical Group Co., Ltd. | Compositions and methods for imaging |
| CN112638415B (zh) * | 2018-07-26 | 2024-07-02 | 大有华夏生物医药集团有限公司 | 用于成像的组合物和方法 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003006491A2 (en) * | 2001-07-10 | 2003-01-23 | Amersham Health As | Peptide-based compounds for targeting intergin receptors |
| WO2004055160A2 (en) * | 2002-12-13 | 2004-07-01 | The Trustees Of Columbia University In The City Of New York | Biomolecular coupling methods using 1,3-dipolar cycloaddition chemistry |
| WO2004094593A2 (en) * | 2003-04-17 | 2004-11-04 | The Scripps Research Institute | Expanding the eukaryotic genetic code |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4913891A (en) * | 1986-04-17 | 1990-04-03 | The United States Of America As Represented By The United States Department Of Energy | Positron emitter labeled enzyme inhibitors |
| HK1056164B (en) | 2000-03-24 | 2013-06-21 | Euro-Celtique S.A. | Aryl-substituted pyrazole, triazole and tetrazole, and their uses |
| US6350360B1 (en) | 2000-04-07 | 2002-02-26 | Sandia Coroporation | Method of fabricating a 3-dimensional tool master |
| CN1230441C (zh) * | 2000-04-12 | 2005-12-07 | 安盛药业有限公司 | 结合整联蛋白的肽衍生物 |
| GB0115927D0 (en) | 2001-06-29 | 2001-08-22 | Nycomed Amersham Plc | Solid-phase nucleophilic fluorination |
| EP2226316B1 (en) | 2002-05-30 | 2016-01-13 | The Scripps Research Institute | Copper-catalysed ligation of azides and acetylenes |
| CA2527877A1 (en) * | 2003-06-18 | 2005-01-13 | The Scripps Research Institute | Unnatural reactive amino acid genetic code additions |
| NO20033115D0 (no) | 2003-07-08 | 2003-07-08 | Amersham Health As | Peptid-baserte forbindelser |
| EP1799273A2 (en) * | 2004-10-07 | 2007-06-27 | Koninklijke Philips Electronics N.V. | Use of the staudinger ligation in imaging and therapy end kits for imaging and therapy |
| GB0428012D0 (en) * | 2004-12-22 | 2005-01-26 | Hammersmith Imanet Ltd | Radiolabelling methods |
-
2004
- 2004-12-22 GB GBGB0428012.9A patent/GB0428012D0/en not_active Ceased
-
2005
- 2005-12-09 EP EP20100179449 patent/EP2275145A1/en not_active Withdrawn
- 2005-12-09 EP EP05818037A patent/EP1830890A2/en not_active Withdrawn
- 2005-12-09 CN CNA2005800441130A patent/CN101084020A/zh active Pending
- 2005-12-09 RU RU2007122804/04A patent/RU2419627C2/ru not_active IP Right Cessation
- 2005-12-09 EP EP20100179459 patent/EP2258403A1/en not_active Withdrawn
- 2005-12-09 MX MX2007007560A patent/MX2007007560A/es active IP Right Grant
- 2005-12-09 CA CA2817636A patent/CA2817636A1/en not_active Abandoned
- 2005-12-09 US US11/721,694 patent/US7972588B2/en active Active
- 2005-12-09 CN CN201510494983.3A patent/CN105012972A/zh active Pending
- 2005-12-09 JP JP2007547612A patent/JP5743372B2/ja not_active Expired - Lifetime
- 2005-12-09 BR BRPI0519317-6A patent/BRPI0519317A2/pt not_active Application Discontinuation
- 2005-12-09 WO PCT/GB2005/004729 patent/WO2006067376A2/en not_active Ceased
- 2005-12-09 CA CA2589136A patent/CA2589136C/en not_active Expired - Fee Related
- 2005-12-09 KR KR1020077014048A patent/KR101314460B1/ko not_active Expired - Fee Related
- 2005-12-09 EP EP10179446.9A patent/EP2266629B1/en not_active Expired - Lifetime
- 2005-12-09 AU AU2005317903A patent/AU2005317903C1/en not_active Ceased
-
2007
- 2007-06-20 NO NO20073157A patent/NO341638B1/no not_active IP Right Cessation
-
2011
- 2011-06-13 US US13/158,555 patent/US8679455B2/en not_active Expired - Lifetime
-
2012
- 2012-07-30 JP JP2012167865A patent/JP2012254998A/ja active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003006491A2 (en) * | 2001-07-10 | 2003-01-23 | Amersham Health As | Peptide-based compounds for targeting intergin receptors |
| WO2004055160A2 (en) * | 2002-12-13 | 2004-07-01 | The Trustees Of Columbia University In The City Of New York | Biomolecular coupling methods using 1,3-dipolar cycloaddition chemistry |
| WO2004094593A2 (en) * | 2003-04-17 | 2004-11-04 | The Scripps Research Institute | Expanding the eukaryotic genetic code |
Also Published As
| Publication number | Publication date |
|---|---|
| MX2007007560A (es) | 2007-11-21 |
| AU2005317903C1 (en) | 2012-05-10 |
| WO2006067376A3 (en) | 2007-07-26 |
| CA2589136C (en) | 2015-10-06 |
| GB0428012D0 (en) | 2005-01-26 |
| KR20070091626A (ko) | 2007-09-11 |
| US20090311177A1 (en) | 2009-12-17 |
| US7972588B2 (en) | 2011-07-05 |
| KR101314460B1 (ko) | 2013-10-10 |
| AU2005317903B2 (en) | 2011-12-01 |
| RU2007122804A (ru) | 2009-01-27 |
| AU2005317903B8 (en) | 2012-01-19 |
| AU2005317903A1 (en) | 2006-06-29 |
| EP2275145A1 (en) | 2011-01-19 |
| US20110236311A1 (en) | 2011-09-29 |
| CN105012972A (zh) | 2015-11-04 |
| RU2419627C2 (ru) | 2011-05-27 |
| WO2006067376A2 (en) | 2006-06-29 |
| EP1830890A2 (en) | 2007-09-12 |
| CA2817636A1 (en) | 2006-06-29 |
| EP2258403A1 (en) | 2010-12-08 |
| JP2008528445A (ja) | 2008-07-31 |
| JP2012254998A (ja) | 2012-12-27 |
| CN101084020A (zh) | 2007-12-05 |
| BRPI0519317A2 (pt) | 2009-01-13 |
| JP5743372B2 (ja) | 2015-07-01 |
| US8679455B2 (en) | 2014-03-25 |
| EP2266629B1 (en) | 2015-12-09 |
| EP2266629A1 (en) | 2010-12-29 |
| NO20073157L (no) | 2007-06-20 |
| CA2589136A1 (en) | 2006-06-29 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| CREP | Change of representative |
Representative=s name: ZACCO NORWAY AS, POSTBOKS 2003 VIKA |
|
| CHAD | Change of the owner's name or address (par. 44 patent law, par. patentforskriften) |
Owner name: GE HEALTHCARE LIMITED, GB |
|
| MM1K | Lapsed by not paying the annual fees |