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WO1992010214A1 - Procede de marquage isotopique de cellules du sang et kit pour ce faire - Google Patents

Procede de marquage isotopique de cellules du sang et kit pour ce faire Download PDF

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Publication number
WO1992010214A1
WO1992010214A1 PCT/US1991/009244 US9109244W WO9210214A1 WO 1992010214 A1 WO1992010214 A1 WO 1992010214A1 US 9109244 W US9109244 W US 9109244W WO 9210214 A1 WO9210214 A1 WO 9210214A1
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WO
WIPO (PCT)
Prior art keywords
dithiocarbamate
mixture
composition
reducing agent
approx
Prior art date
Application number
PCT/US1991/009244
Other languages
English (en)
Inventor
Wim Th. Goedemans
Original Assignee
Mallinckrodt Medical, Inc.
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 Mallinckrodt Medical, Inc. filed Critical Mallinckrodt Medical, Inc.
Publication of WO1992010214A1 publication Critical patent/WO1992010214A1/fr

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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
    • A61K51/12—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
    • A61K51/1203—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 in a form not provided for by groups A61K51/1206 - A61K51/1296, e.g. cells, cell fragments, viruses, virus capsides, ghosts, red blood cells, viral vectors
    • 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
    • A61K51/0476—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 monodendate ligands, e.g. sestamibi
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • the invention relates to a method of radioactive labelling of blood cells and to a composition therefor.
  • the invention further relates to a method of preparing said composition and to a kit, suitable for the radioactive labelling of blood cells.
  • Radioactive labelled blood cells such as leukocytes and erythrocytes form an important diagnostic tool, e.g. in abscess localization and blood pool studies.
  • indium-111 labelled compounds such as indium-111 oxinate, indium-111 tropolonate and indium-111 pyrithionate have been described for this purpose, e.g. in European patent specifications 17355 and 131327.
  • Technetium-99m labelled compounds are to be preferred, because of the radiation characteristics of this radionuclide and the availability of technetium-99m in the form of a
  • pertechnetate solution can simply be obtained by the user from a molybdenum - technetium generator which is at his disposal.
  • Tc-99m labelled blood cells for the above purposes, e.g. inflammation scintigraphy and blood pool studies, and consequently to provide a method of preparing Tc-99m labelled blood cells.
  • This object can be achieved according to the present invention, in that a suspension of blood cells is treated with a composition, obtained by adding a Tc-99m
  • R is a hydrogen atom, an unsubstituted or
  • R 1 is an unsubstituted or substituted C 1 -C 8 alkyl group, a C 3 -C 7 cycloalkyl group, or an
  • R and R 1 together with the N atom to which they are connected constitute a five- or six- membered heterocyclic ring, which ring may be substituted and which ring may comprise a second hetero atom selected from N, O and S; and wherein further:
  • n 1 - 5 ;
  • M n+ is a metal cation with the indicated valency; or to an at least substantially aqueous solution of said mixture;
  • reaction mixture so obtained, preferably at room temperature.
  • composition obtained as described above is very suitable for the radioactive labelling of blood cells, such as leukocytes and erythrocytes.
  • blood cells such as leukocytes and erythrocytes.
  • Suitable substituents of the benzyl group and of the alkyl group are: hydroxy, amino, carboxy, C 1 -C 4 - alkoxy- carbonyl, C 1 -C 4 - alkylcarbonyl, C 1 -C 4 - alkoxy, sulfo and C 1 - C 4 - alkoxysulfonyl.
  • Suitable metallic reducing agents to be used for the preparation of the above composition are Sn(II), Fe(II), Ce(III), Cu(I), Ti(III) and Sb(III). Of these is Sn(II) excellently suitable because of its reducing ability. It has been found, that an extremely small quantity of Sn(II) as the metallic reducing agent, viz. of approx. 0.1 to approx. 10 ⁇ g of metal per 0.2 mg of dithiocarbamate, is not only sufficient, but that the labelling efficiency as well as the stability of the composition obtained are considerably improved when such a small quantity of reducing agent is used.
  • R' and R' 1 are both methyl groups or ethyl groups if desired substituted by hydroxy
  • R' is a hydrogen atom and R' 1 is a benzyl group, or R' and R' 1 together with the N atom to which they are connected constitute an unsubstituted or substituted heterocyclic ring selected from pyrrolidine, morpholine, thiomorpholine,
  • dithiocarbamates are dimethyldithiocarbamate, diethyldithiocarbamates, benzyldithiocarmate, pyrrolidyldithiocarbamate,
  • piperazyldithiocarbamate 4-benzylpi ⁇ erazyldithiocarbamate and 4-(1-piperidino)piperidyldithiocarbamate.
  • Benzyl and piperidino are examples of substituents of the
  • heterocyclic ring suitable substituents are in general C 1 -C 4 alkyl, phenyl (C 1 -C 4 ) alkyl, C 5 -C 7 cycloalkyl, and a heterocyclic group, connected to the heterocyclic ring directly or through a C 1 -C 4 alkyl spacing group.
  • suitable heterocyclic groups are pyrrolidinyl,
  • the invention further relates to a composition for the radioactive labelling of blood cells, obtained as described above, and a method of preparing said composition.
  • technetium-99m dithiocarbamates are potential brain imaging agents, e.g. for cerebral perfusion imaging with SPECT. It should be noted, that the composition, obtained as described above, in addition can be used for brain imaging.
  • chelating agents can be used as exchange ligands.
  • suitable chelating agents are 8-hydroxyquinoline or derivatives thereof; dicarboxylic acids, polycarboxylic acids or hydroxycarboxylic acids, for example, oxalic acid, malonic acid, succinic acid, maleic, acid, ortho-phthalic acid, malic acid, lactic acid,
  • tartaric acid citric acid, ascorbic acid, salicylic acid or derivatives of these acids; pyrophosphates; phosphonates or polyphosphonates, for example methylene diphosphonate, hydroxyethylene diphosphonate or hydroxymethylene
  • ß-diketone such as acetyl acetone, furoyl acetone, thenoyl acetone, benzoyl acetone, dibenzoyl methane, tropolone or
  • a suitable buffer can be used, for example, a phosphate buffer, a citrate buffer, a HEPES buffer, or an ammonium hydrogen carbonate buffer.
  • composition according to the invention can be prepared so easily and simply, said preparation can be performed particulary readily by the user himself.
  • the relatively short half-life of the metal-radionuclide in question viz. technetium-99m having a half-life of 6 hours
  • the various non-radioactive reaction components are then offered to him in a so-called cold kit.
  • the operations to be performed must be as simple as possible, so without elaborate separation or purification, in order to enable the user to prepare the radioactive labelled composition with the means available from the supplied kit.
  • a kit according to the present invention and suitable for the radioactive labelling of blood cells comprises the following ingredients: a metallic reducing agent,
  • kits further, comprises instructions for use with a
  • the pertechnetate solution can simply be obtained by the user from a molybdenum-technetium generator available for this purpose.
  • the ingredients of the kit indicated above may be supplied as a solution, for example, in the form of a physiological saline solution, or in some buffer solution, but is preferably present in a dry condition, for example, in a lyophilized condition.
  • the ingredients may be stabilised in a usual manner with suitable stabilizers like ascorbic acid, gentisic acid or salts of these acids, or inositol, or other auxiliary substances such as fillers, e.g. glucose, lactulose, mannitol, and the like, may be added.
  • the ingredients are combined in one vial.
  • Such a monocomponent kit, in which the combined ingredients are preferably lyophilized is excellently suitable for being reacted by the user with the Tc-99m pertechnetate solution in a simple manner.
  • a diethyldithiocarbamate solution is prepared by dissolving 2 mg sodium diethyldithiocarbamate, 20 mg disodiumtartrate .2H 2 O and 20 ⁇ g Sn(II) chloride in 10 ml water under oxygen-free conditions (nitrogen cabinet). The solution is dispensed in vials (1 ml/vial) and lyophilized under exclusion of oxygen.
  • pyrrolidine dithiocarbamate kit A pyrrolidine dithiocarbamate solution is prepared by dissolving 1.5 mg ammonium pyrrolidine dithiocarbamate, 20 mg disodiumtartrate .2H 2 O and 20 ⁇ g Sn(II) chloride in 10 ml water under oxygen-free conditions. The solution is dispensed in vials (1 ml/vial) and lyophilized under exclusion of oxygen.
  • Example I is labelled with Tc-99m by adding 1 ml Tc-99m pertechnetate solution from a commercial Mo-Tc generator. After 25 min incubation at room temperature, the labelling yield is determined by dichloromethane extraction: 98.3% of all radioactivity is found in the organic phase; this means that the labelling yield is 98.3%.
  • a paper chromatographic analysis (methyl ethyl ketone/physiological saline
  • Tc99m-DDC obtained according to Example III, is added in a quantity of 222 MBq to a 2 ml concentrated bovine erythrocytes suspension in a physiological saline solution. After 20 min incubation at room temperature the labelling yield is determined by centrifugation and
  • the labelling yield is 70.5%. In a second experiment a labelling yield of 92.0% is reached.
  • leukocytes suspensions are labelled with Tc99m-PDC, obtained according to Example III; the labelling yields are 70, 62 and 44%, respectively.
  • a diethyldithiocarbamate solution is prepared by dissolving 2 mg sodium diethyldithiocarbamate, 20 mg disodium tartrate 2H 2 O, 20 mg Sn(II)chloride and 100 mg inositol in 10 ml 15m NH 4 HCO 3 solution under oxygen-free conditions (nitrogen cabinet). The solution is dispensed in vials (1 ml/vial) and lyophilized under exclusion of oxygen.
  • inositol containing DDC kits The stability of inositol containing DDC kits was tested by incubation of these kits at 4 C and -26 C for 12 months. The 99mTc labelling ability was tested at intervals. A comparison was done with DDC kits without inositol. At 4oC all DDC kits are unstable if stored for longer than a month. At -26oC the inositol containing kits are stable for 12 months. The kits without inositol are stable for only 2 months.

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

Abstract

Cette invention concerne un procédé de marquage isotopique des cellules du sang. Dans ce procédé, on traite une suspension de cellules sanguines avec une composition que l'on obtient en ajoutant une solution de pertechnétate Tc-99m à un mélange comprenant (1) un agent métallo-réducteur, (ii) un ligand échangeur, (iii) un tampon approprié, si nécessaire, et (iv) un dithiocarbamate ou en ajoutant ladite solution à une solution au moins partiellement aqueuse dudit mélange; puis on fait incuber le mélange de réaction ainsi obtenu, de préférence dans des conditions de température ambiante. Cette invention concerne également une composition destinée au marquage isotopique des cellules sanguines et un kit pour effectuer ce marquage isotopique.
PCT/US1991/009244 1990-12-12 1991-12-11 Procede de marquage isotopique de cellules du sang et kit pour ce faire WO1992010214A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP90203266.3 1990-12-12
EP90203266 1990-12-12

Publications (1)

Publication Number Publication Date
WO1992010214A1 true WO1992010214A1 (fr) 1992-06-25

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ID=8205191

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1991/009244 WO1992010214A1 (fr) 1990-12-12 1991-12-11 Procede de marquage isotopique de cellules du sang et kit pour ce faire

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AU (1) AU9172191A (fr)
WO (1) WO1992010214A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2698272A1 (fr) * 1992-11-20 1994-05-27 Cis Bio Int Procédé de marquage cellulaire au moyen de complexes nitruro-bis (dithiocarbamato)Tc-99m et trousse pour la mise en Óoeuvre de ce procédé.
US5574140A (en) * 1993-09-03 1996-11-12 Resolution Pharmaceutical Inc. Hydrazino-type N2 S2 chelators
FR2736834A1 (fr) * 1995-07-17 1997-01-24 Cis Bio Int Produits radiopharmaceutiques a tropisme cardiaque comportant un complexe nitruro d'un metal de transition et ayant une clairance myocardique rapide
US5659041A (en) * 1993-07-19 1997-08-19 Resolution Pharmaceuticals, Inc. Hydrazino-type radionuclide chelators having an N3 S configuration
US5858327A (en) * 1993-09-03 1999-01-12 Resolutions Pharmaceuticals, Inc. Hydrazino-type N2 S2 radionuclide chelating compounds

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3683066A (en) * 1969-01-14 1972-08-08 Ivan Ascanio Technetium 99m colloidal composition
US4342740A (en) * 1980-08-18 1982-08-03 E. R. Squibb & Sons, Inc. Method and kit for labeling red blood cells with technetium-99m
US4411881A (en) * 1982-07-12 1983-10-25 New England Nuclear Corporation Composition and method for stabilizing radiolabeled compounds using thiocarbonylated diethylenetriamines
US4923969A (en) * 1983-12-29 1990-05-08 The Commonwealth Of Australia Preparation of 99m Tc radiopharmaceuticals
WO1990006137A1 (fr) * 1988-11-25 1990-06-14 Cis Bio International Produit radiopharmaceutique ayant notamment un tropisme cardiaque comportant un complexe nitruro d'un metal de transition, et son procede de preparation
US5037630A (en) * 1985-01-14 1991-08-06 Neorx Corporation Metal radionuclide labeled proteins for diagnosis and therapy
US5078985A (en) * 1989-08-09 1992-01-07 Rhomed, Incorporated Radiolabeling antibodies and other proteins with technetium or rhenium by regulated reduction

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3683066A (en) * 1969-01-14 1972-08-08 Ivan Ascanio Technetium 99m colloidal composition
US4342740A (en) * 1980-08-18 1982-08-03 E. R. Squibb & Sons, Inc. Method and kit for labeling red blood cells with technetium-99m
US4411881A (en) * 1982-07-12 1983-10-25 New England Nuclear Corporation Composition and method for stabilizing radiolabeled compounds using thiocarbonylated diethylenetriamines
US4923969A (en) * 1983-12-29 1990-05-08 The Commonwealth Of Australia Preparation of 99m Tc radiopharmaceuticals
US5037630A (en) * 1985-01-14 1991-08-06 Neorx Corporation Metal radionuclide labeled proteins for diagnosis and therapy
WO1990006137A1 (fr) * 1988-11-25 1990-06-14 Cis Bio International Produit radiopharmaceutique ayant notamment un tropisme cardiaque comportant un complexe nitruro d'un metal de transition, et son procede de preparation
US5078985A (en) * 1989-08-09 1992-01-07 Rhomed, Incorporated Radiolabeling antibodies and other proteins with technetium or rhenium by regulated reduction

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
NUCL. MED. BIOL., Vol. 16(7), 1989, BALLINGER et al., pages 721-725; & CHEMICAL ABSTRACTS CA 112(15):135316j. *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2698272A1 (fr) * 1992-11-20 1994-05-27 Cis Bio Int Procédé de marquage cellulaire au moyen de complexes nitruro-bis (dithiocarbamato)Tc-99m et trousse pour la mise en Óoeuvre de ce procédé.
US5659041A (en) * 1993-07-19 1997-08-19 Resolution Pharmaceuticals, Inc. Hydrazino-type radionuclide chelators having an N3 S configuration
US5574140A (en) * 1993-09-03 1996-11-12 Resolution Pharmaceutical Inc. Hydrazino-type N2 S2 chelators
US5858327A (en) * 1993-09-03 1999-01-12 Resolutions Pharmaceuticals, Inc. Hydrazino-type N2 S2 radionuclide chelating compounds
FR2736834A1 (fr) * 1995-07-17 1997-01-24 Cis Bio Int Produits radiopharmaceutiques a tropisme cardiaque comportant un complexe nitruro d'un metal de transition et ayant une clairance myocardique rapide
WO1997003705A1 (fr) * 1995-07-17 1997-02-06 Cis Bio International Produits radiopharmaceutiques a tropisme cardiaque comportant un complexe nitruro d'un metal de transition et ayant une clairance myocardique rapide

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Publication number Publication date
AU9172191A (en) 1992-07-08

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