GB2214507A - 2,3-dithiosuccinic acid derivative and their use - Google Patents
2,3-dithiosuccinic acid derivative and their use Download PDFInfo
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- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
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- 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
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- 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
- A61K51/081—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins the protein being an albumin, e.g. human serum albumin [HSA], bovine serum albumin [BSA], ovalbumin
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
- A61K51/1093—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 conjugates with carriers being antibodies
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- 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
- C07C323/52—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 the carbon skeleton being acyclic and saturated
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2123/00—Preparations for testing in vivo
Abstract
Metal and metal oxide labelled substances are provided for the diagnosis and treatment of pathological conditions, Chelated radionuclide conjugated to targeting substances are employed for medical diagnosis by means of nuclear medicine techniques. Also, chelated radio-nuclides conjugated to targeting substances are employed for radiotherapy of tumors. Chelated paramagnetic and ferromagnetic metal and metal oxides are proved for medical diagnosis by means of magnetic resonance techniques.
Description
NEW CHEMICAL COMPOUNDS AND THEIR USE.
BACKGROUND OF THE INVENTION
Radiolabelled compounds are important to medical diagnosis and treatment. Such compounds are used as radioactive pharmaceuticals for imaging by means of gammacameras or for radiation treatment. Most of such compounds are used for imaging or therapy purposes because they may accumulate in diseased tissue. Such compounds are employed in a variety of techniques including diagnosis of deep venous thromboses, the detection, staging and treatment of cancer, or for localizing and imaging of infections, inflammations and necrosis. A number of these compounds include metal radionuclides such as technetium-99m or Indium-111. When using radionuclides in vivo it is desirable that the radionuclides localize in a target organ or diseased locus.
Therefore, radionuclides are usually formulated to provide preferential binding to or absorption by the particular organ or tissue. Several diseased cells and tissues expose antigens or receptors that are different from non-diseased cells. Proteins, naturally occurring or artificially made, may bind to such antigens or receptors. Polyclonal antibodies or monoclonal antibodies that bind to specific antigens may be produced. Hormones or enzymes that bind to receptors may be isolated from biological material or artificially manufactured. By radiolabelling such substances the accumulation in the diseased cells and tissues may be visualized by gammacamera imaging. For therapy purposes, radioactive nuclides with radiation of high energy and short range may be used.
To increase target to background ratio, to reduce the radiation doses, and to minimize undesirable side effects, the radionuclides should dissociate from the radiolabelled compound to a very small extent. If the radionuclides are too loosely bound to the labelled compound, lower target to background ratios are achieved, and the images will be of less quality and will be less informative. Correspondingly, if used for radiation therapy, less radiation doses to the diseased cells will be obtained, and higher radiation doses will be received in non-diseased cells.
Proteins may be labelled with metallic radionuclides directly (Goodwin DA, Goode R, Brown L & al: 111-In labelled transferrin for the detection of tumors. Radiology 100: 175-179, 1971. Kazem I, Maier-Borst W: Zur 99m-Tc-Markierung von serumalbumin. Nucl Med 5: 285-289, 1966. Burchiel SW, Rhodes BA & Crochford DR. US Patent 4, 472, 371). However, increased stability in the linkage between the radioactive nuclide and the compound labelled may be obtained by use of bifunctional linkers: The term bifunctional is used on chemical molecules or moieties that on one hand bind to the molecule to be labelled and on the other hand bind to the metallic radionuclide.US patent 4.668.503 (Donald Hnatowich, May 26, 1987) has demonstrated that amines, including proteins and polypeptides, covalently coupled with a chelating agents such as diethylenetriaminepentaacetic acid can be labelled with technetium-99m in presence of a stannous reducing agent at near neutral pH. Krejcarek (Biochemical and Biophysical
Research Communications no.2, 1977 page 581) demonstrated that DTPA anhydride may be coupled to proteins for the binding of metallic items. Eckelmann (J. of Pharmaceutical sciences, 64,1975, page 704) demonstrated that DTPA may be coupled to fatty acids by means of cyclic anhydride chemistry, for binding of metallic cations. Covalently coupling with DTPA may cross link proteins, and several acid moieties are introduced.
Metallic cations differ markedly in their charge to radius ratio. The alkali metals, like sodium and potassium, have high ratios because they hydrolyse to a little extent, contrary to i.e. technetium, which hydrolyses and forms cations of low charge and high radius. Molecules with carboxylic acid residues interact best with metallic cations with a high charge to radius ratio forming ionic bonds. Softer metallic cations with a lower charge to radius ratio coordinate better with less ionic but more polarizable ligands, such as amines and thiols. This is the background for the good results obtained by Alan R. Fritzberg (European
Patent Application 0 188 256 A2 published July 23, 1986).He describes radionuclide metal chelates, where the chelating agent is a N,N'bis-mercaptaocetyl w,w-l-diamino aliphatic carboxylic acid or amine.Similarly, 2,3-dithio-succinic acid which, labelled with technetium-99m, is a commonly used pharmaceutical for kidney imaging purposes.(Arnold & BR< al: J Nucl Med: 1975, 16: 357-367).
Unprotected sulphur containing moieties are, however, highly reactive and must be protected when the bifunctional complexing agents are linked to the compound to be radiolabelled. Alan Fritzberg (ibid) describes several ways to reversibly protect the sulphur-containing moieties.
Paramagnetic and ferromagnetic complexes for magnetic resonance imaging is taught in EP-0071564 83.02.09,
EP-169299-A1 86.01.29, DE-443252-A186.05.28 and EP-130934-A 85.01.09. When paramagnetic metal ions are chelated, they are kept in solution at neutral pH and protected from hydrolysis and precipitation. Paramagnetic metal ion complexes perturbate the magnetic resonance of hydrogen and thus alter the resonance signals obtained by nuclear magnetic resonance instruments. Such complexes may then be applied in vivo to gain increased contrast in images obtained by magnetic resonance imaging devices.
DETAILED DESCRIPTION OF THE INVENTION
Theoretical calculations demonstrated that the binding strength between cations having a low electric charge to ionic radius ratio and sulphur containing ligands increases with alkylation of the sulphur atom. Since alkylation can solve many of the chemical problems connected with the application of thiolated ligands for metallic ion binding, a family of complexing agents utilizing this principle was synthesized. Alkylation of the sulphur atom of a ligand compound increases its chemical stability, which is especially favo-rable when such ligands/complexing agents are to be linked to other substances (polymers, peptides, proteins and other pharmaceuticals). Therefore we have provided a family of complexing agents of the formula,
Where the R (2) and R (3) are aliphatic moieties of from 1-6 carbon atoms with from 0 to 2 heteroatoms.
Heteroatoms may favorably be introduced into these aliphatic moieties to stabilize the binding between the chelating agent and the metal or metal oxide ions capable of being chelated. Such heteroatoms may be nitrogen or oxygen, preferentially as amines, amides, hydroxyls or carboxylic acid. Alkylated sulphur atoms are thus combined with free electron pairs of nitrogen or oxygen. The cationic electric charge of the metal or metal-oxide cations may favorably be stabilized by the anionic charge of carboxylic acid moieties.
The R (1) and R (4) may be hydroxyl, an oxysalt, metal oxides an amine, an amide, - NHNH2 or polypeptides or protein. These residues serve the following purposes: 1. To increase the solubility of the complexes formed with metal or metal oxide ions capable of being chelated.
2. To obtain the distribution volume and the pharmacokinetics desired for the pharmaceutical.
3. To obtain a chemical affinity for the targeting cells or tissues.
Hydroxyls, oxysalt and ester groups are specially valuable when soluble complexes of low molecular weight are to be formed, to study perfusion of organs, kidney function and leakage through the blood brain barrier. So also with amines and amides. However, polypeptides and proteins are a special group of very interesting amines. Polypeptides can be made with affinity for a long range of different receptors on the surface of cells and tissues. Thus accumulation of signal forming metal ions or metal oxide ions (radioactive, paramagnetic or ferromagnetic ions), complexed to the complex forming agent, may be obtained in targeted cells or tissues. So also if R (1) or R (4) is a protein of the immunoglobulin class, having an affinity for antigens (soluble, cellular or tissue antigens) to be targeted.R(1) or R (4) may also be protein hormones that bind to special receptors, or plasma proteins, if vascular or organ perfusion studies are to be performed. When R (1) or R (4) are polypeptides or proteins, the chemical linking between R (1) or R (4) and the rest of the complexing agent may be, but are not limited to, an amide linkage.
The synthesis of the compounds of the invention may preferentially start out with 2,3-dithiosuccinic acid. The alkylation of the two thiol moieties of 2, 3-dithiosuccinic acid may be performed by means of, but are not limited to, iodinated alkyl derivatives. If amides are wanted in the place of R (2) and/or R (3), iodinated alkyl-amides are added to react with 2,3-dithiosuccinic acid to form (S,S'bis - alkylamide) - 2,3-dithiosuccinic acid.
If carboxylic acid moieties are desired for R (2) and/or R (3), the 2,3-dithiosuccinic acid may be brought to react with iodinated carboxylic acids forming (S,S'-bis carboxylic acid) 2,3-dithiosuccinic acids.
The alkylated dithiosuccinic acids may be purified by crystallization, ion exchange techniques or other purification methods.
The residues desired for R (1) or R (4) may be introduced by a number of numerous different coupling reagents. An amide linkage may be obtained by means of carbodiimides. In aqueous solution, water soluble carbodiimides like 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide or 1-cyclohexyl-3-(2-morpholino-ethyl)-carbodiimide may be used. Homobifunctional complexing agents like bis-sulfosuccinimidyl suberate and glutardialdehyd may be used, so also heterobifunctional agents such is succinimides and N-succinimidyl-3-(2-pyridyl-dithio) propionate. A binding may also be obtained by diazotization of amines. A survey of such coupling is given in "Practice and theory of enzyme immunoassay" (P.Tijssen, Elseveir, Amsterdam 1985).
When proteins or polypeptides are to be introduced for R (1) or R (4), an anhydride of the alkylated 2, 3-dithiosuccinic acid may be preferred. A cyclic anhydride of the alkylated 2, 3-dithiosuccinic acid may be formed in organic solution by means of carbodiimides.
Symmetric anhydrides of alkylated 2, 3-dithiosuccinic acid may also be formed. A mixed anhydride with another carboxylic acid may also be formed.
The anhydrides formed may, if desired, be purified and separated from the organic solution.
When mixed with proteins or polypeptides, the anhydrides will react with the polypeptides or proteins and form a covalent linkage. Thus anhydride coupling is one way of coupling polypeptides or proteins in the place of R (1) or R (4) in the compounds of this invention. If a carboxylic acid residue has been introduced in the place of R (2) and/or R (3), this carboxylic acid may also have participated in the anhydride formation and will thus participate in the formation of a linkage to peptides or proteins.
The coupling by means of preformed symmetric mixed or cyclic anhydride may be preferred to direct coupling because it induces less alterations of peptides or proteins.
The compounds taught by this invention chelate radionuclide metal ions and metal oxide ions. For nuclear medicine imaging purposes, this invention provides compounds where the radioactive metal or metal oxide cations are firmly attached to the compound to be labelled, thus images of high quality are obtained and physiological and patophysiological measurements may be made with high signal to background ratio.
Technetium-99m is the far most used radionuclide for medical imaging purposes. It is supplied to nearly every nuclear medicine department as a generator from which technetium in a pertechnetate anionic form is a decay product from molybdenum-99. Compounds which are to be labelled with technetium-99m are usually mixed with the technetium-99m eluate. With a reducing agent present, the anionic pertechnetate in oxidation state VII is reduced to lower oxidation states where technetium tends to form metal oxide cations. Preferentially, the reducing agent and the compound to be labelled are in a lyophilized form as so called "cold kit", in a sterile vial and of pharmaceutical quality.
Stannous ions are the most common reducing agent, and often the stannous ions are chemically bound to the compound to be labelled if this compound has a chelating ability. Usually the complexing agent is in molar excess to the stannous ions to ensure that there are enough complexing agents to bind the reduced technetium. Technetium is usually in a very low concentration, but still has a high radiation output due to its short physical halflife of 6.02 hours. This invention provides compounds that on one hand have the pharmacokinetic characteristics wanted and on the other hand bind both reducing metallic cations and reduced technetium metal oxide cations formed when pertechnetate is exposed to reducing agent. Reducing stannous ions may also be present as separate carboxylic acid complexes. Stannous tartrates and stannous citrates are often used.
When residues of low molecular weight constitute R (1) and R (4) and a reducing agent is present, technetium complexes with the compounds of this invention are formed which have high clearance rate from plasma and are suited for studies of kidney function and of the blood-brain-barrier. When substances of higher molecular weight constitute R (1) and R (4), much lower plasma clearance rates are obtained. Vascular studies and perfusion studies may be performed after intravenous injection of the technetium chelated to the compounds of this invention. If hormones, immunoglobulins or peptides of specific affinity for antigens, receptors or other specific structures of cells or tissues to be targeted constitute R (1) or R (4), such antigens, receptors, cells or tissues may be imaged by means of the compounds provided by this invention.
The compounds provided by this invention may also be used with other metal or metal oxide radionuclide cations.
Indium-ill may be preferred if a longer halflife of the radionuclide is wanted. For therapeutic purposes, radionuclides with longer halflife and/or particulate radiation (electrons, alpha particles or other particulate radiation)may be used. If studies with positron cameras are to be performed, metal or metal oxide ions of positron emitting nuclides are used.
The compounds provided by this invention may also be used in combination with metal or metal oxide cations of paramagnetic or ferromagnetic nuclides for magnetic resonance studies. The compounds provided by this invention chelate cations of gadolinium, manganese, iron and europium and many other metals. In most magnetic resonance techniques, ferromagnetic ions give a negative contribution and paramagnetic ions give positive contribution to the nuclear magnetic resonance of hydrogen in nuclear magnetic resonance imaging. By the present techniques the modification of the magnetic resonance signal is obtained by perturbation of hydrogen resonance signal, since most magnetic resonance imaging techniques utilize the magnetic resonance signal obtained from hydrogen. From the compounds provided by this invention, compounds with suitable pharmacokinetic characteristics for the purpose of the application wanted are selected. If low molecular weight moieties constitute R (1) and R (4), high plasma clearance rates are obtained, and after initial vascular perfusion studies, studies of kidney function and blood-brain-barrier studies can take place. If higher molecular weight moieties constitute R (1) or R (4) lower plasma clearance rates are obtained, which are preferred for prolonged vascular studies and perfusion studies. If hormones or immunoglobulins or polypeptides or other moieties with specific affinity for antigens, receptors and other cellular of tissue determinants are used for R (1) and/or R (4) targeting molecules are obtained for magnetic resonance imaging purposes.Since it is necessary to target quite a high concentration of paramagnetic or magnetic metal or metal oxide ions to the cells, tissues or organs to be targeted, this invention also provides compounds of polymer nature:
The compounds provided by this invention can comprise multiple moieties of the formula given, chemically linked together between R (1) and/or R (4). This linkages may be, but are not limited to, ester or amides and may be proteins or polypeptides. This invention thus provides compounds that bind at more than one site metal or metal oxide cations capable of being chelated, thus giving a stronger signal. This is not limited to paramagnetic or ferromagnetic metal or metal oxide cations, as more than one radionuclide cation may be chelated to each compound in a corresponding way.When hormones, polypeptides, immunoglobulins or other targeting molecules or parts of such molecules are used as linkers between R (1) or R(4) in this invention, it is of utmost importance that the protein structure is modified as little as possible. Then the advantage of the anhydride form of compounds provided by the invention may be preferred.
The compounds of this invention may be provided in lyophilized form or in solution of pharmaceutical quality.
For combination with radionuclides the radionuclide metal or metal oxide cations preferentially are added at the users site, i.e. at the nuclear medicine department or in the nuclear pharmacy. When the compounds provided are for magnetic resonance imaging use, the compounds are preferentially provided with the paramagnetic or ferromagnetic metal or metal oxide cations chelated, ready for use as a complete pharmaceutical. The compounds provided may be mixed with balancing salts or other additives to provide chemical and pharmaceutical stability and usability.
When the compounds provided are made for radiopharmaceutical use in combination with technetium-99m, the compounds preferentially comprise stannous ions.
EXAMPLES: 1. Synthesis of (S,S-'bis-ethylamid)-2,3-dithiosuccinic acid: 300 mg 2,3-dithiosuccinic acid is suspended in purified water. 3 g iodoacetamide is dissolved in 120 ml 0.1 M phosphate buffer pH=7. The iodoacetamide solution is mixed with the 2,3-dithiosuccinic acid suspension. pH is adjusted to 7.0, and an ideal solution is obtained. After 60 minutes at room temperature (S,S'bis-ethylamid)-2,3-dithiosuccinic acid can be crystallized and recrystallized from the solution, washed and dried to white crystalline powder. The product has been characterized by mass spectroscopy, nuclear magnetic resonance analyses, potentiometric titration and quantitative analyses of the different elements of the compounds.
2. Synthesis of (s,S'-bis-acetic acid)-2,3-dithio-succinic acid: 25 mg 2,3-dithiosuccinic acid is suspended in 5 ml water, 250 mg iodoacetic acid is dissolved in 10 ml 0.1 M sodium phosphate buffer and added to the dithiosuccinic acid solution. An ideal solution is obtained and pH is adjusted to 7.0. Subsequent to 60 minutes incubation at room temperature, the (S,S'-bis-acetic acid)-2,3-dithiosuccinic acid formed is purified by ion exchange chromatography and lyophilized and analyzed.
3. Formation of anhydrides from (S,S'-bis-ethylamid)-2,3-dithiosuccinic acid:
One equivalent of (S,S'bis-ethylamid)-2,3-dithiosuccinic acid is suspended in pyridine. 0.9 equivalent of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide is suspended in pyridine and is added to the (S,S'-bis-ethylamid)-2,3-dithiosuccinic acid under the formation of (S,S'-bis-ethylamid)-2,3-dithiosuccinic acid anhydride, obtained in an ideal solution.
4. Formation of Gd(III)-complexes with (S,S'-bis-ethylamid)-2,3-dithiosuccinic acid: 148 mg (S,S'-bis-ethylamid)-2,3-dithiosuccinic acid is suspended in 10 ml purified water. Sodium hydroxide solution is added to obtain pH=4.4, and an ideal solution is obtained. 18 mg gadolinium oxide is dissolved in dilute hydrochloric acid and added to the (S,S'-bis-ethylamid)-2,3-dithiosuccinic acid solution, and pH is maintained at pH= 4.4. Gd (III)-complexes with (S,S'-bis-ethylamid)-2,3-dithiosuccinic acid are formed, precipitate, and may be removed by simple filtration.
5. Formation of Eu(III)-complexes with (S,S'-bis-ethylamid)-2,3-dithiosuccinic acid:
This example is identical to example 4, but the gadolinium ions have been replaced by europium.
6. Formation of Tc-99m-complexes with (S,S'-bis-ethylamid)-2,3-dithiosuccinic acid: (S,S'-bis-ethylamid)-2,3-dithiosuccinic acid is dissolved to 1.5 mg/ml solution in 0.006 M sodium hydroxide solution. Add hydrochloric acid until pH=4, and add purified water until the (S,S'-bis-ethylamid)-2,3-dithiosuccinic acid is in a concentration of 1.3 mg/ml. To 1 ml of this solution 0.2 ml concentration of sodium tartrate monohydrate 0.75 mg/ml solution and 0.2 ml of a stannous chloride dihydrate 0.1 mg/ml solution are added. To 1 ml of the resulting composition, 1 ml of eluate from a tc-99m-generator is added. After a short incubation at room temperature, the resulting Tc-99m-complexes may be studied by radiochromatographic methods.A high radiochemical purity of
Tc-99m-complexes with (S,S'-bis-ethylamid)-2,3 dithiosuccinic acid, typically more than 90 of the Tc-99m present is obtained.
7. Formation of Tc-99m-complexes with (S,S'-bis acetic acid)-2,3 dithiosuccinic acid:
This example is identical to example 6, but the (S,S'-bis-ethylamid)-2,3 dithiosuccinic acid has been replaced by (S,S'-bis acetic acid)-2,3 dithiosuccinic acid.
8. Formation of bovine serum albumin conjugates with (S,S'-bis-ethylamid)-2,3-dithiosuccinic acid:
To an aqueous bovine serum albumin solution, (S,S'-bis-ethylamid)-2,3-dithiosuccinic acid is added to a concentration of 66 mg per 100 mg bovine serum albumin.
Subsequent to pH adjustment to 6, 1-cyclohexyl-32(2-morpholino-ethyl)-carbodiimide is added to ad concentration of 32 mg during period of 30 minutes, and pH is maintained at pH 6 by addition of sodium hydroxide solution. Subsequent to 4 hours incubation at room temperature, the protein conjugates are purified by repeated dialysis.
9. Formation of immunoglobulin conjugates with (S,S'-bis-ethylamid)-2,3-dithiosuccinic acid:
This example is identical to example 8, but the serum albumin has been replaced by immunoglobulin antibodies, and all solutions have a sodium chloride concentration of 0.15
M.
10. The immunoglobulin conjugates with (S,S'-bis-ethylamid)-2,3-dithiosuccinic acid are labelled with Tc-99m:
Immunoglobulin is dissolved to 10 mg/ml solution in saline solution and pH-adjusted to 4.0. To 1 ml of this solution 2 ml of a sodium tartrate monohydrate 0.75 mg/ml solution and 0.2 ml of a stannous chloride dihydrate 0.1 mg/ml solution are added. To 1 ml of the resulting composition, 1 ml of eluate from a Tc-99m-generator is added. After a short incubation at room temperature, the resulting
Tc-99m-labelled conjugates may be studied by radiochromatographic methods. A high radiochemical purity of
Tc-99m-labelled immunoglobulin is obtained, typically more than 90 OD of the Tc-99m present as labelled immunoglobulin.
Claims (13)
1. A compound of the formula
where R(1) hydroxyl, an oxysalt, an ester group, an amine, an amide, -NHNH2 or a polypeptide or a protein, R(2) is an aliphatic moiety of from 1 to 6 carbon atoms and from 0 to 2 heteroatoms, R(3) is an aliphatic moiety of from 1 to 6 carbon atoms and from 0 to 2 heteroatoms, R(4)is hydroxyl, an oxysalt, an ester group, an amine,an amide, - NHNH2 or a polypeptide or protein.
2. The cyclic, symmetric or mixed asymmetric anhydrides of the compound according to claim 1.
3. A compound according to claim 1 and 2, where R(2) and or
R(3) are an amid of from 1 to 4 carbon atoms.
4. A compound according to claim 1 and 2, where R(2) and/or
R(3) are a carboxylic acid of from 1 to 4 carbon atoms.
5. A compound according to claim 4, where R(1) or R(4) is an immunoglobulin or specific binding fragment there off.
6. A compound according to claim 1 - 5, characterized by the presence of several units of the compound according to claim 1, 2, 3 and 4, chemically linked together, preferentially between R(1) and/or R(4), but R(2) or R(3) may also be involved, the chemical forms of these linkages preferably being in the form of esters, amides, polypeptides, proteins or parts of a protein or proteins.
7. A compound according to claim 1-6, where the metals or metal oxide ions comprise paramagnetic or ferromagnetic nuclides.
8.A compound according to claim 1-6, where the metals or metal oxide ions comprise radionuclides, or the compounds are to be combined with radionuclides.
9. A compound according to any of claims 1 to 8, bound to a metal or metal oxide ion.
10. The use of the compounds according to any of claims 1-9 for diagnostic or therapeutic purposes.
11. A compound according to any of claims 1 to 8, for binding of metal or metal oxide ions capable of being chelated, for use in diagnosis and treatment in medicine.
12. A compound according to claim 9, for use in diagnosis and treatment in medicine.
13. A pharmaceutical composition comprising a compound according to any of claims 1 to 9, in admixture with a pharmaceutically acceptable, solid or liquid, adjuvant, diluent or carrier.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8801096A GB2214507A (en) | 1988-01-19 | 1988-01-19 | 2,3-dithiosuccinic acid derivative and their use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8801096A GB2214507A (en) | 1988-01-19 | 1988-01-19 | 2,3-dithiosuccinic acid derivative and their use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB8801096D0 GB8801096D0 (en) | 1988-02-17 |
| GB2214507A true GB2214507A (en) | 1989-09-06 |
Family
ID=10630171
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8801096A Withdrawn GB2214507A (en) | 1988-01-19 | 1988-01-19 | 2,3-dithiosuccinic acid derivative and their use |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2214507A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5175256A (en) * | 1990-09-28 | 1992-12-29 | Neorx Corporation | Protein labeling reagents |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB593257A (en) * | 1945-05-28 | 1947-10-13 | Standard Oil Dev Co | Improved lubricating oil or grease compositions |
| GB908986A (en) * | 1960-02-26 | 1962-10-24 | Hoffmann La Roche | Sulphur-containing dicarboxylic acids and derivatives thereof and a process for the manufacture of same |
-
1988
- 1988-01-19 GB GB8801096A patent/GB2214507A/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB593257A (en) * | 1945-05-28 | 1947-10-13 | Standard Oil Dev Co | Improved lubricating oil or grease compositions |
| GB908986A (en) * | 1960-02-26 | 1962-10-24 | Hoffmann La Roche | Sulphur-containing dicarboxylic acids and derivatives thereof and a process for the manufacture of same |
Non-Patent Citations (3)
| Title |
|---|
| CA104(23):206653Q * |
| CA109(1):1951S * |
| CA91(5):38886K * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5175256A (en) * | 1990-09-28 | 1992-12-29 | Neorx Corporation | Protein labeling reagents |
Also Published As
| Publication number | Publication date |
|---|---|
| GB8801096D0 (en) | 1988-02-17 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |