WO2005079864A2 - Improvement in the ligand protection for mercaptoacetyl triglycine - Google Patents
Improvement in the ligand protection for mercaptoacetyl triglycine Download PDFInfo
- Publication number
- WO2005079864A2 WO2005079864A2 PCT/US2005/004349 US2005004349W WO2005079864A2 WO 2005079864 A2 WO2005079864 A2 WO 2005079864A2 US 2005004349 W US2005004349 W US 2005004349W WO 2005079864 A2 WO2005079864 A2 WO 2005079864A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- dimer
- mercaptoacetyl triglycine
- solution
- triglycine
- mercaptoacetyl
- Prior art date
Links
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
- A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
-
- 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
- A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
- A61K51/1282—Devices used in vivo and carrying the radioactive therapeutic or diagnostic agent, therapeutic or in vivo diagnostic kits, stents
-
- 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
- C07B59/008—Peptides; Proteins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2123/00—Preparations for testing in vivo
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Definitions
- the present invention relates to a method for preparing mercaptoacetyl triglycine labeled with a radionuclide.
- the invention further relates to a S-protected mercaptoacetyl triglycine compound and a kit for use in this method, and to a formulation comprising radiolabeled mercaptoacetyl triglycine.
- Mercaptoacetyl triglycine (MAG3) labeled with Tc-99m is a diagnostic radiopharmaceutical .
- Tc-99m mertiatide (disodium [N- [N- [N- (mercaptoacetyl) glycyl] glycyl] glycinato- (2-) -N,N ' ,N", S ' ] oxotechnetate (2-) ) which is formed is suitable for intravenous administration.
- Tc-99m mertiatide is a renal imaging agent for example for use in the diagnosis of congenital and acquired kidney abnormalities, such as renal failure, urinary tract obstruction, and calculi in adults and children. It is a diagnostic aid in providing information about renal function, split function, renal angiograms and renogram curves for whole kidney and renal cortex. It is furthermore used in functional studies of the kidney after transplantation in which repeated doses are administered.
- MAG3 99m Tc-mercaptoacetyl triglycine
- the thiol is protected by a benzoyl group, which, in turn is removed during the 10 minutes' boiling step to allow coordination to the metal center.
- the invention thus relates to a method for preparing mercaptoacetyl triglycine labeled with a radionuclide, comprising the steps of adding a radionuclide to a solution that comprises a mercaptoacetyl triglycine dimer of formula VI
- the radiolabeled mercaptoacetyl triglycine is obtained in solution.
- the solution that comprises the mercaptoacetyl triglycine dimer, the reducing agent and the optional transfer ligand is obtained by reconstitution from a lyophilisate .
- the radionuclide for use in the method of the invention can be any radionuclide that can be bound to the mertiatide complex, and is suitable for radiodiagnostic or radiotherapeutic purposes and is preferably technetium-99m .
- Technetium-99m is the preferred radionuclide as Tc-99m is the most desirable radioactive label for diagnostic applications.
- the reducing agent is a stannous salt, preferably stannous (II) chloride.
- Other examples are Fe(III)-, Sb(III)-, Mo(III)- and W (III) -salts .
- the transfer ligand is suitably selected from sodium tartrate, glycine, citrate, malonate, gluconate, alate, lactate, pyrophosphate, glucoheptonate . Of these tartrate is preferred. It was found that Tc-99m complex is only formed when the solution is heated to 80-120°C, preferably to 100°C during 5-60 minutes, preferably during about 10 minutes.
- the method of the invention avoids the use of benzoyl protecting group.
- the invention further relates to the dimer of mercaptoacetyl triglycine according to formula VI and its use in the method.
- the invention also provides a kit for the preparation of a radiolabeled mercaptoacetyl triglycine complex, comprising a dimer of mercaptoacetyl triglycine according to formula VI, a reducing agent and optionally a transfer ligand.
- the kit comprises in lyophilized form: 0.05 mg MAG3-dimer
- the kit is in lyophilised form as this leads to a better stability and longer shelf-life.
- the invention relates to a formulation of mercaptoacetyl triglycine labeled with a radionuclide, which is obtainable by the method. Since the mercaptoacetyl triglycine is not protected with a benzoyl potecting group, the formulation that is obtained does not contain benzoic acid as a part of the injectable, while being formulated at physiologically acceptable pH (no need to neutralize prior injection into the patient) .
- the formulation may further comprise the usual constituents.
- Figure 1 shows the 1 H-NMR spectrum of the MAG3 dimer precursor.
- Figure 2 shows the 13 C-NMR spectrum of the MAG3 dimer precursor.
- Figure 3 shows the 13 C-NMR spectrum of the MAG3 dimer .
- Figure 4 shows the 1 H-NMR spectrum of the MAG3 dimer.
- Figure 5 shows the HPLC profile of the MAG3 dimer.
- Figure 6 shows the HPLC chromatogram obtained by co-injecting the MAG3 dimer and its monomer.
- Figure 7 shows two examples of HPLC chromatograms obtained (1) for the official product Technescan MAG3 after labeling and (2) for the labeled "wet" formulation containing the dimer as active ingredient.
- the activated ester is vacuum dried and purified, first by column chromatography (on silica gel with 10% methanol in dichloromethane as eluent) and finally by recrystallization from ethyl acetate.
- the purified product (2g, 5.4 mmol) is obtained in 49% yield .
- FIG. 1 shows the 1 H-NMR spectrum.
- the corresponding chemical shifts are as follows:
- the reaction mixture is stirred at room temperature for 2 hours to yield a yellow solution, which is vacuum dried to remove the THF.
- the remaining aqueous solution is acidified with HCl 2N until precipitation starts (V 3 ml) .
- the precipitate formed is collected by filtration and washed several times with water, until the pH of the filtrate is 5.
- the white solid obtained is vacuum dried to afford 195 mg (0.37 mmol) of the final product.
- the yield is 69%.
- This step can also be performed with triethylamine (NEt 3 ) instead of sodium hydroxide (NaOH) .
- the yield is then a bit lower, 59%.
- MAG3-dimer formulation of the invention contains for example: 0.05 mg MAG3-dimer 0.14 mg tin (II) chloride 17.2 mg disodium tartrate
- Figure 7 shows two examples of HPLC chromatograms obtained (1) for the official product Technescan MAG3 after labeling and (2) for the labeled "wet" formulation containing the dimer as active ingredient.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Physics & Mathematics (AREA)
- Optics & Photonics (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Dispersion Chemistry (AREA)
- Heart & Thoracic Surgery (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/585,792 US20080228004A1 (en) | 2004-02-13 | 2005-02-11 | Ligand Protection for Mercaptoacetyl Triglycine |
EP05731139A EP1720580A2 (en) | 2004-02-13 | 2005-02-11 | Improvement in the ligand protection for mercaptoacetyl triglycine |
AU2005215500A AU2005215500A1 (en) | 2004-02-13 | 2005-02-11 | Improvement in the ligand protection for mercaptoacetyl triglycine |
JP2006553253A JP2007537152A (en) | 2004-02-13 | 2005-02-11 | Improved ligand protection for mercaptoacetyltriglycine |
CA002555953A CA2555953A1 (en) | 2004-02-13 | 2005-02-11 | Improvement in the ligand protection for mercaptoacetyl triglycine |
IL177387A IL177387A0 (en) | 2004-02-13 | 2006-08-09 | Improvement in the ligand protection for mercaptoacetyl triglycine |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP04075448.3 | 2004-02-13 | ||
EP04075448 | 2004-02-13 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2005079864A2 true WO2005079864A2 (en) | 2005-09-01 |
WO2005079864A3 WO2005079864A3 (en) | 2006-01-19 |
Family
ID=34878264
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2005/004349 WO2005079864A2 (en) | 2004-02-13 | 2005-02-11 | Improvement in the ligand protection for mercaptoacetyl triglycine |
Country Status (9)
Country | Link |
---|---|
US (1) | US20080228004A1 (en) |
EP (1) | EP1720580A2 (en) |
JP (1) | JP2007537152A (en) |
KR (1) | KR20060122925A (en) |
CN (1) | CN1917906A (en) |
AU (1) | AU2005215500A1 (en) |
CA (1) | CA2555953A1 (en) |
IL (1) | IL177387A0 (en) |
WO (1) | WO2005079864A2 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008115337A1 (en) * | 2007-03-19 | 2008-09-25 | Mallinckrodt Inc. | Sulfur-protected mercaptoacetylglycylglycylglycine |
EP2444800A3 (en) * | 2010-10-21 | 2012-05-02 | Institute of Nuclear Energy Research Atomic Energy Council | A direct solid sample analytical technology for determining a content and a uniformity thereof in a lyophilized kit of a sulfur-containing chelator with a stable complex capacity for radiotechnetium (Tc-99m) and radiorhenium (Re-186, Re-188) |
WO2015118498A1 (en) * | 2014-02-07 | 2015-08-13 | The South African Nuclear Energy Corporation Limited | A kit for preparing a radiopharmaceutical |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0483704A1 (en) * | 1990-10-31 | 1992-05-06 | Nihon Medi-Physics Co., Ltd. | Process for preparing a radiopharmaceutical composition |
-
2005
- 2005-02-11 US US10/585,792 patent/US20080228004A1/en not_active Abandoned
- 2005-02-11 KR KR1020067016232A patent/KR20060122925A/en not_active Application Discontinuation
- 2005-02-11 JP JP2006553253A patent/JP2007537152A/en active Pending
- 2005-02-11 AU AU2005215500A patent/AU2005215500A1/en not_active Abandoned
- 2005-02-11 EP EP05731139A patent/EP1720580A2/en not_active Withdrawn
- 2005-02-11 CA CA002555953A patent/CA2555953A1/en not_active Abandoned
- 2005-02-11 WO PCT/US2005/004349 patent/WO2005079864A2/en not_active Application Discontinuation
- 2005-02-11 CN CNA2005800048809A patent/CN1917906A/en active Pending
-
2006
- 2006-08-09 IL IL177387A patent/IL177387A0/en unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0483704A1 (en) * | 1990-10-31 | 1992-05-06 | Nihon Medi-Physics Co., Ltd. | Process for preparing a radiopharmaceutical composition |
Non-Patent Citations (3)
Title |
---|
BORMANS G ET AL: "Investigation of the Labelling Characteristics of <99m>Tc-Mercaptoacetyltriglycine" NUCLEAR MEDICINE AND BIOLOGY, ELSEVIER SCIENCE PUBLISHERS, NEW YORK, NY, US, vol. 22, no. 3, April 1995 (1995-04), pages 339-349, XP004051796 ISSN: 0969-8051 * |
NOLL B ET AL: "Sources of radiochemical impurities in the <99m>TcS-unprotected MAG3 system" NUCLEAR MEDICINE AND BIOLOGY, ELSEVIER SCIENCE PUBLISHERS, NEW YORK, NY, US, vol. 22, no. 8, November 1995 (1995-11), pages 1057-1062, XP004051713 ISSN: 0969-8051 * |
STALTERI M A ET AL: "COMPARISON OF THE STABILITY OF TECHNETIUM-LABELED PEPTIDES TO CHALLENGE WITH CYSTEINE" BIOCONJUGATE CHEMISTRY, AMERICAN CHEMICAL SOCIETY, WASHINGTON, US, vol. 10, no. 1, January 1999 (1999-01), pages 130-136, XP009003810 ISSN: 1043-1802 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008115337A1 (en) * | 2007-03-19 | 2008-09-25 | Mallinckrodt Inc. | Sulfur-protected mercaptoacetylglycylglycylglycine |
EP2444800A3 (en) * | 2010-10-21 | 2012-05-02 | Institute of Nuclear Energy Research Atomic Energy Council | A direct solid sample analytical technology for determining a content and a uniformity thereof in a lyophilized kit of a sulfur-containing chelator with a stable complex capacity for radiotechnetium (Tc-99m) and radiorhenium (Re-186, Re-188) |
WO2015118498A1 (en) * | 2014-02-07 | 2015-08-13 | The South African Nuclear Energy Corporation Limited | A kit for preparing a radiopharmaceutical |
AU2015213553B2 (en) * | 2014-02-07 | 2019-01-31 | The South African Nuclear Energy Corporation Limited | A kit for preparing a radiopharmaceutical |
Also Published As
Publication number | Publication date |
---|---|
CA2555953A1 (en) | 2005-09-01 |
WO2005079864A3 (en) | 2006-01-19 |
CN1917906A (en) | 2007-02-21 |
JP2007537152A (en) | 2007-12-20 |
KR20060122925A (en) | 2006-11-30 |
EP1720580A2 (en) | 2006-11-15 |
IL177387A0 (en) | 2006-12-10 |
AU2005215500A1 (en) | 2005-09-01 |
US20080228004A1 (en) | 2008-09-18 |
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