EP1742898A1 - Complexes metalliques a bases de ligands de tetrathiol et leur utilisation dans le cadre du diagnostic en medecine nucleaire et de la therapie a endoradionucleides, et procede pour produire les complexes metalliques - Google Patents

Complexes metalliques a bases de ligands de tetrathiol et leur utilisation dans le cadre du diagnostic en medecine nucleaire et de la therapie a endoradionucleides, et procede pour produire les complexes metalliques

Info

Publication number
EP1742898A1
EP1742898A1 EP05755479A EP05755479A EP1742898A1 EP 1742898 A1 EP1742898 A1 EP 1742898A1 EP 05755479 A EP05755479 A EP 05755479A EP 05755479 A EP05755479 A EP 05755479A EP 1742898 A1 EP1742898 A1 EP 1742898A1
Authority
EP
European Patent Office
Prior art keywords
metal complexes
tetrathiol
substituted
mmol
unsubstituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05755479A
Other languages
German (de)
English (en)
Inventor
Tobias Heinrich
Bernd Johannsen
Hans-Jürgen Pietzsch
Sepp Seifert
Hartmut Spies
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Helmholtz Zentrum Dresden Rossendorf eV
Original Assignee
Forschungszentrum Dresden Rossendorf eV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Forschungszentrum Dresden Rossendorf eV filed Critical Forschungszentrum Dresden Rossendorf eV
Publication of EP1742898A1 publication Critical patent/EP1742898A1/fr
Withdrawn legal-status Critical Current

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
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A61K51/0478—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group complexes from non-cyclic ligands, e.g. EDTA, MAG3
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic Table
    • C07F13/005—Compounds without a metal-carbon linkage

Definitions

  • the invention relates to the field of radiopharmaceuticals, in particular metal complexes of tetrathiol ligands and their use as radioactive pharmaceuticals for diagnosis and in endoradionuclide therapy, as well as a method for producing the metal complexes.
  • Rhenium isotopes are of interest for therapeutic use in endoradionuclide therapy.
  • rhenium radiopharmaceuticals Another limiting factor in the development of rhenium radiopharmaceuticals is the lack of suitable complexing agents with which the radioactive metal can be stably coupled to biomolecules.
  • the stability of many rhenium chelates with regard to hydrolysis, re-oxidation to perrhenate and radiolysis, which proceeds with the release of the radioactive metal from the target-binding radiopharmaceutical is inadequate for therapeutic use.
  • dimercaptosuccinic acid has been proposed as agents for the labeling of proteins and antibodies with technetium-99m and rhenium-186 or rhenium-188 (US Pat. No. 5,175,256, 1992). This technical solution also does not lead to clearly defined connections. With regard to the stability criteria mentioned, the systems described and other systems do not yet meet the requirements for a broad in-vivo application.
  • the object of the invention is to propose radiolytically and metabolically stable metal complexes which are suitable for conjugation with biomolecules and to specify a process for their preparation.
  • the invention relates to the compounds described in claim 1, and to their use for binding radiometals, preferably technetium and rhenium, to biomolecules and a process for the preparation of the compounds according to claim 1.
  • An important feature of the compounds according to the invention is that they have improved chemical and radiolytic stability compared to the known DMSA complexes with technetium and rhenium. Furthermore, the formation of isomers is controlled specifically by a special configuration of the complexing agent instead of the statistical isomer distribution in the known DMSA complexes.
  • dimercaptosuccinic acid is used as a good complexing agent for technetium and rhenium.
  • the general synthesis strategy is shown in Scheme 1.
  • a new complexing agent is synthesized that contains four mercapto groups that are capable of coordinating with a metal, and this is reacted with technetium (V) or rhenium (V) to form the corresponding complex.
  • the length of the carbon chain is chosen so that the mercapto groups are sterically favorable to the metal.
  • An electron acceptor group (X) is built into the carbon chain, which further stabilizes the complex as a whole through interaction with the metal oxo group or the metal nitrido group. With this and through the choice of chain length, the formation of isomers can be controlled in a targeted manner.
  • Biologically active units are coupled either via the electron acceptor group (X) or via the carboxyl groups (COOR).
  • Example 1 4,4 '- (octane-1,8-diyldiimino) bis (2,3-dimercapto-4-oxobutanoic acid) (4)
  • ligand 14 dissolved in a mixture of 0.5 ml of methanol and 0.2 ml of propylene glycol, is mixed with 1.0 ml of perrhenate generator eluate. After adding 1.0 mg of SnCl 2 , dissolved in 0.1 ml of 0.1
  • Acetic acid and 28.0 mg sodium oxalate are mixed with 0.5 ml perrhenate generator eluate (10-30 mCi) and kept at room temperature for 15 min. Then the pH of the
  • Tetrathiols 14 (1 mg in 0.25 ml methanol) are heated at 70 ° C. for 30 min. Radiochemical
  • Acetic acid and 28.0 mg sodium oxalate are mixed with 0.5 ml pertechnetate generator eluate (10-30 mCi) and kept at room temperature for 15 min. Then the pH of the
  • Tetrathiols 14 (1 mg in 0.25 ml methanol) are heated at 70 ° C. for 30 min. Radiochemical

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Physics & Mathematics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Optics & Photonics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente invention a pour objet la mise au point de complexes métalliques qui sont stables d'un point de vue radiolytique et métabolique et conviennent à la conjugaison de biomolécules, et d'un procédé pour les produire. La solution réside dans des complexes métalliques à base de ligands de tétrathiol de formule (I) dans laquelle (CH-R<1>) représente des ponts de méthylène substitués ou non, R<1> H représente des groupes alkyles substitués ou non ou des groupes aryle substitués ou non, m et n représentent le nombre de groupes méthylène, la somme de m et n valant entre 4 et 10, R<2> représente H, OR<1> ou NHR<1>, Y représente 4 fois H, <99m>TcO, <186>ReO, <188>ReO, <99m>TcN, <186>ReN ou <188>ReN, X représente (CH)2, les groupes amino non substitués (N-H) ou les groupes amino substitués (N-Z), l'unité guanidyle de formule (II) ou le groupe urée de formule (III), Z représentant -(CH-R<1>)-A, p représentant le nombre de groupes méthylène et valant entre 2 et 8, A représentant une unité apte au couplage telle que COOH, COR<3>, -NCS, et R<3> représentant OH, OR<1> ou NHR<1>. L'invention concerne également l'utilisation des complexes métalliques conformément à la revendication (1), dans le cadre du diagnostic en médecine nucléaire et de la thérapie à endoradionucléides, ainsi qu'un procédé pour produire les complexes métalliques.
EP05755479A 2004-05-06 2005-04-28 Complexes metalliques a bases de ligands de tetrathiol et leur utilisation dans le cadre du diagnostic en medecine nucleaire et de la therapie a endoradionucleides, et procede pour produire les complexes metalliques Withdrawn EP1742898A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102004022461A DE102004022461B4 (de) 2004-05-06 2004-05-06 Metallkomplexe auf der Basis von Tetrathiol-Liganden und deren Anwendung in der nuklearmedizinischen Diagnostik und Endoradionuklidtherapie sowie Verfahren zur Herstellung der Metallkomplexe
PCT/DE2005/000868 WO2005108330A1 (fr) 2004-05-06 2005-04-28 Complexes metalliques a bases de ligands de tetrathiol et leur utilisation dans le cadre du diagnostic en medecine nucleaire et de la therapie a endoradionucleides, et procede pour produire les complexes metalliques

Publications (1)

Publication Number Publication Date
EP1742898A1 true EP1742898A1 (fr) 2007-01-17

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP05755479A Withdrawn EP1742898A1 (fr) 2004-05-06 2005-04-28 Complexes metalliques a bases de ligands de tetrathiol et leur utilisation dans le cadre du diagnostic en medecine nucleaire et de la therapie a endoradionucleides, et procede pour produire les complexes metalliques

Country Status (4)

Country Link
US (1) US7731936B2 (fr)
EP (1) EP1742898A1 (fr)
DE (1) DE102004022461B4 (fr)
WO (1) WO2005108330A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102004022461B4 (de) 2004-05-06 2006-07-06 Forschungszentrum Rossendorf E.V. Metallkomplexe auf der Basis von Tetrathiol-Liganden und deren Anwendung in der nuklearmedizinischen Diagnostik und Endoradionuklidtherapie sowie Verfahren zur Herstellung der Metallkomplexe
DE102009029033A1 (de) 2008-10-16 2010-06-24 Forschungszentrum Dresden - Rossendorf E.V. Tetrathiol-Liganden, Metallkomplexe, Konjugate und Kits, deren Verwendung in der nuklearmedizinischen Diagnostik und Endoradionuklidtherapie sowie Verfahren zur Herstellung der Tetrathiol-Liganden und Metallkomplexe

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0344724A2 (fr) * 1988-05-31 1989-12-06 Neorx Corporation Chelates pour radionucléides métalliques améliorant la cinétique de chelatation

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06505795A (ja) * 1990-09-27 1994-06-30 リサーチ・コーポレイション・テクノロジーズ キレート化剤
US5175256A (en) * 1990-09-28 1992-12-29 Neorx Corporation Protein labeling reagents
PT1072198E (pt) * 1999-07-28 2008-06-17 Swiss Caps Rechte & Lizenzen Preparado, especialmente para utilização como medicamento e/ou como suplemento alimentar
DE102004022461B4 (de) 2004-05-06 2006-07-06 Forschungszentrum Rossendorf E.V. Metallkomplexe auf der Basis von Tetrathiol-Liganden und deren Anwendung in der nuklearmedizinischen Diagnostik und Endoradionuklidtherapie sowie Verfahren zur Herstellung der Metallkomplexe

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0344724A2 (fr) * 1988-05-31 1989-12-06 Neorx Corporation Chelates pour radionucléides métalliques améliorant la cinétique de chelatation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO2005108330A1 *

Also Published As

Publication number Publication date
WO2005108330A1 (fr) 2005-11-17
DE102004022461A1 (de) 2005-12-01
US7731936B2 (en) 2010-06-08
DE102004022461B4 (de) 2006-07-06
US20080279770A1 (en) 2008-11-13

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