WO1994023757A1 - Utilisation d'acides cyclopentadienylcarbonyle carboxyliques de metal de transition et de leurs derives pour marquer des proteines - Google Patents

Utilisation d'acides cyclopentadienylcarbonyle carboxyliques de metal de transition et de leurs derives pour marquer des proteines Download PDF

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Publication number
WO1994023757A1
WO1994023757A1 PCT/EP1994/001250 EP9401250W WO9423757A1 WO 1994023757 A1 WO1994023757 A1 WO 1994023757A1 EP 9401250 W EP9401250 W EP 9401250W WO 9423757 A1 WO9423757 A1 WO 9423757A1
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Prior art keywords
acid
group
radioactive
cor
metallocene
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PCT/EP1994/001250
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German (de)
English (en)
Inventor
Martin Wenzel
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INSTITUT FÜR DIAGNOSTIKFORSCHUNG GMBH an der FU BERLIN KLINIKUM RUDOLF VIRCHOW
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Priority to JP6522787A priority Critical patent/JPH08508985A/ja
Priority to EP94915087A priority patent/EP0696207A1/fr
Publication of WO1994023757A1 publication Critical patent/WO1994023757A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/531—Production of immunochemical test materials
    • G01N33/532—Production of labelled immunochemicals
    • G01N33/534—Production of labelled immunochemicals with radioactive label
    • 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
    • A61K51/0487—Metallocenes, i.e. complexes based on a radioactive metal complexed by two cyclopentadienyl anions
    • 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
    • C07F17/00—Metallocenes

Definitions

  • the invention relates to the subject matter characterized in the claims, that is to say the use of radioactive metallocene carboxylic acids and their derivatives and methods for the radioactive labeling of proteins and other NH-active compounds.
  • the invention further relates to new metallocene carboxylic acids and carboxylic acid derivatives of Cr-51, Mn-52, Ru-97, Ru-103, Re-186, Re-188 or Ir-191.
  • Radioactive labeled compounds are widely used in many areas of technology.
  • radioactively labeled substances such as labeled proteins - used for both diagnostic and therapeutic purposes.
  • a known method of labeling proteins is that chelating agents are bound to proteins or oligopeptides in such a way that they do not lose their chelating property if possible.
  • Corresponding chelating agents can be, for example, ethylenediaminetetraacetic acid (EDTA) or diethylenetriaminepentaacetic acid (DTPA).
  • EDTA ethylenediaminetetraacetic acid
  • DTPA diethylenetriaminepentaacetic acid
  • the actual labeling is then carried out by reaction with radioactive ions such as radioactive indium or technetium isotopes.
  • a disadvantage of using chelating agents for binding the radioactive isotopes is that the biological function of the protein can be changed by the chelating agent. In addition, part of the radioisotope that is primarily bound to the protein can be lost again by "re-chelating" by the body's complexing agents. However, the permanent binding of radioisotopes is the decisive prerequisite for radio-immunoassays - here the binding to proteins such as immunoglobulins - or a nuclear medicine application.
  • Protein labeling has also been carried out using iodine-labeled esters of N-hydroxysuccinimide (AEBolton, WM Hunter, Biochem. J., 133, 529, 1973).
  • iodine-labeled esters of N-hydroxysuccinimide AEBolton, WM Hunter, Biochem. J., 133, 529, 1973.
  • radioactive iodine isotopes are poorly suited for use in nuclear medicine for various reasons. Iodine-125 has too low an energy and a too long half-life, iodine-131 leads to a high radiation exposure due to its particle radiation and the iodine-123 is too expensive because its relatively short half-life requires extensive logistics.
  • the structure of the protein can also be partially changed during iodination in such a way that the biological functions of the protein are only partially preserved.
  • Tc-cyclopentydienyl-carbonyl complexes with different side chains are known.
  • the complexes described there are notable for high in vivo stability, so that "re-chelating" by the body's own complexing agents is not observed.
  • the enrichment behavior determined by the side chain is also only slightly influenced by the complexing agent (cyclopentadienyl ring).
  • R 1 , R 2 , R 3 each represent a CO group or together represent a cyclopentadienyl radical which is optionally substituted by R 5 ', R 4 represents a hydrogen atom, a C r C 10 alkyl radical or a group
  • -SR 7 is, with R 7 meaning hydrogen, a C 1 -C 10 alkyl
  • R 8 in the meaning given for R 7 with the exception of hydrogen and a Cj-Ci Q alkyl radical and M is a radioactive metal isotope of an element of atomic numbers 21-29,
  • marker molecules any basic group-carrying molecules, in particular biomolecules - such as proteins, proteohormones or polypeptides - into stable, radioactively labeled substances which are both in the Radioimmune diagnostics as well as in nuclear medicine - for example for the in vivo display of receptors or antibody-binding structures, especially for the localization of tumors - can be used.
  • metallocene carboxylic acids of the formula I are also suitable for introducing positron emitters into proteins.
  • Suitable radicals R 1 , R 2 , R 3 are in each case a carbonyl group or a pentahapto-bonded - if desired R 5 ' substituted - second cyclopentadienyl ring, the carbonyl groups being preferred.
  • the radical R 4 is a -CO-CH 3 group, a straight-chain or branched-chain Cj-CjQ-alkyl radical such as, for example, a methyl, ethyl, propyl, isopropyl, buty-1, isobutyl, tert. -Butyl, isopentyl, neopenty-1, hexyl or in particular a hydrogen atom.
  • Preferred radicals R 5 according to the invention are a -COOH -, a -CO- (CH2) 2-COOH - group, but in particular activated acid groups such as, for example, a -COC1 -, a -CO- (CH 2 ) 2 -CO-R 8 -, a -CO- (CH 2 ) 2 -COOR 8 -, a -CO-OR 8 - or a -CO-R 8 group with R 8 in the meaning of a succinimide or phthalimide radical.
  • activated acid groups such as, for example, a -COC1 -, a -CO- (CH 2 ) 2 -CO-R 8 -, a -CO- (CH 2 ) 2 -COOR 8 -, a -CO-OR 8 - or a -CO-R 8 group with R 8 in the meaning of a succinimide or phthalimide radical.
  • the free carboxylic acid groups can, however, also be activated by other methods known to the person skilled in the art, for example by acid anhydride formation, which takes place with elimination of water by dimerization of two (intermolecular) carboxylic acid groups originating from different molecules.
  • acid anhydride formation which takes place with elimination of water by dimerization of two (intermolecular) carboxylic acid groups originating from different molecules.
  • R 1 , R 2 , R 3 represent a pentahapto-bonded second cyclopentadienyl ring which also contains a carboxylic acid group in the substituent R 5 '
  • the anhydride formation can also take place intramolecularly.
  • the radioactive metal ions M used are preferably Mn-52, Tc-99m, Re-186, Re-188, Fe-52, Ru-95, Ru-97, Ru-103, Ir-191, including in particular Tc-99m, Ru-97 and Re-168.
  • the invention further relates to a method for the radioactive labeling of molecules containing basic groups using complexes of the formula I.
  • the labeling is generally carried out in two stages.
  • the corresponding cyclopentadienl complexes of the formula II are first - analogously to the methods known to the person skilled in the art (see, for example, WO 91/18908 and examples 1-4) - in a metal exchange reaction
  • R 1 , R 2 , R 3 , R 4 and R 5 have the meanings given, but M 1 is a non-radioactive isotope of the elements iron, cobalt or chromium, with metal oxides or metal salts of the desired metal ions of the elements of the atomic numbers 21-29, 31, 42-44, 49 or 57-83 implemented.
  • the radioactive compound of the formula I is generally purified by means of thin layer chromatography or HPLC. The localization of the compounds on the plates and the determination of the yield are carried out via radioactivity measurements.
  • the actual labeling of the desired molecule follows.
  • any substance which can be selected from NH groups such as a protein, a proteohormone or a polypeptide, is reacted with the (the) radioactive metallocene carboxylic acid (derivative) of the formula I, if appropriate with the addition of an activator.
  • the implementation is analogous to the methods described in Analytica Chimica Acta, 1992, 2, 145-159.
  • activators for in situ activation of the carboxylic acid groups are dicyclohexylcarbodiimide (DDC), alkoxyacethylene, isobutylchlorocarbonate, benzotriazol-1-yl-tetramethyluronium tetrafluorate (TBTU). Bodanszky et. al., Principles of peptide synthesis, 1984.
  • the second reaction step takes place quickly and in good radiochemical yields, even at temperatures in the range from 20 to 40 ° C. and is usually carried out in aqueous buffer solutions, so that the conditions for routine use in the clinic are created.
  • marker molecules of the formula I and the method described above are suitable for the radioactive labeling of any NH-active compounds, such as proteins, immunoglobulins, antibodies, in particular antibodies against tumor tissue, Fab fragments,
  • Protein fragments, oligopeptides such as, for example, endothelin or partial endothelin sequences, amino acids, neurotransmitters, proteohormones, biogenic amines such as, for example, serotonin, histamine, ⁇ -aminobutyric acid and derivatives of steroids and estrogenic steroids containing amino groups, amino sugars, ergoline compounds and other dopamine genes.
  • the compounds labeled using the metallocene carboxylic acids and carboxylic acid derivatives of the formula I according to the process mentioned can be used directly in in vivo diagnostics and therapy, the labeled compounds being formulated in a physiologically tolerable manner by the methods customary in galenics. This can e.g. by suspending or dissolving the respective compound in a physiologically compatible suspension medium such as water, electrolyte solutions, etc. respectively.
  • Compounds are generally dosed in amounts of less than 10 ** 10 mol / kg body weight, the exact dose depending on the region of the body being examined but in particular also on the examination method chosen in each case being able to vary widely. Based on an average body weight of 70 kg, the amount of radioactivity for diagnostic applications is between 180 and 1100 MBq, preferably 500-800 MBq per application.
  • the application is usually intravenous, intraarterial, peritoneal or intratumoral, with intravenous application being preferred. Generally 0.1 to 2 ml of the agent in question are administered per test.
  • the choice of the respective radioisotope depends on the desired diagnostic method in which the radioactively labeled NH-active compounds are to be used.
  • the radio isotopes Tc-99m and Ru-97 are used in particular for the SPECT method.
  • Ru-97 has the advantage over the short-lived Tc-99m that (due to its longer half-life of 2.88 days) it is already available as a finished "marker molecule" - for example in the form of the metallocene acid chloride or preferably as the N-succinimide ester. can be delivered to the clinics.
  • the isotopes Re-186 or Re-188 are used in particular for the labeling of proteins for radiation therapy.
  • Metallocenecarboxylic acids labeled with Fe-52, Mn-52 or Ru-95 are suitable for introducing positron emitters into proteins.
  • the invention therefore also relates to new metallocene carboxylic acids and derivatives of the general formula I.
  • R 1 , R 2 , R 3 each represent a CO group or together represent a cyclopentadienyl radical which is optionally substituted by R 5 ' , R 4 represents a hydrogen atom, a C 1 -C 10 -alkyl radical or a group
  • -SR 7 with -R 7 and -R 8 mean a succinimide or phthalimide residue and M is a Cr-51, Mn-52, Ru-97, Ru-103, Re-186, Re-188 or a Ir-191 stands.
  • the marker molecules of the formula I are distinguished in particular by the fact that they
  • the method according to the invention is characterized in particular by the fact that the marking step takes place quickly and almost quantitatively under mild conditions.
  • the method is therefore easy to carry out in the clinic on the one hand, but on the other hand it also enables the labeling of molecules, in particular those that are not particularly thermally stable, such as e.g. Proteins. Such molecules would not be radiolabelable using other known methods (see e.g. WO 91/18908).
  • Cyclopentadienylcarbonyl-Technetium compounds are hereinafter referred to as “Cytectrene”.
  • Cyclopentadienylcarbonyl-Re compounds are referred to as “Cyrhetrene” and "Rutheniumdicyclopentadienyl compounds” as “Ruthenocene” designated.
  • Examples 1-4 describe the synthesis of various "marker molecules” used according to the invention
  • Examples 5-7 describe the derivatization (activation) of some “marker molecules” containing carboxylic acid groups
  • Examples 8-13 describe the radioactive labeling of various NH-active compounds.
  • Tc-99m-cytctrenecarboxylic acid 1 mg ferrocenecarboxylic acid and 0.8 mg Mn (CO) 5 Br are mixed with 10-20 MBq Tc-99m pertechnetate in 50 ⁇ l tetrahydrofuran, melted in a glass ampoule under reduced pressure and 1 h at 170 ° C. heated.
  • the contents of the ampoule are applied in a line to an ICW silicone rapid plate F 254 and chromatographed in methylene chloride / methanol (90:10).
  • the cytctrenecarboxylic acid is eluted with 2-3 ml of chloroform / methanol (1: 1) and the eluate is evaporated to dryness under a nitrogen atmosphere.
  • Ru-103-Cl3 melted in 50 ⁇ l dioxane with 3% HC1.
  • the contents of the ampoule are heated to 130 ° C. for 1 h and then applied to thin-layer silica gel plates.
  • the cytctrenecarboxylic acid obtained from Example 2 is taken up in 200 ⁇ l of tetrahydrofuran and reacted at room temperature with 0.25 mg of N-hydroxysuccinimide and 0.5 mg of dicyclohexylcarboxylic acid diimide for 30 minutes with stirring.
  • the cytctrenecarboxylic acid obtained from Example 2 is taken up in 200 ⁇ l of tetrahydrofuran and reacted at room temperature with 0.25 mg of N-hydroxysuccinimide and 0.5 mg of dicyclohexylcarboxylic acid diimide for 30 minutes with stirring.
  • Example 6 Tc-99m-Cytectrenoylpropionsä re-N-succinimide ester 200 ⁇ l eluate of the Tc-99m-Cytectrenoylpropionic acid from Example 3, 4 mg of N-hydroxysuccinimide and 8 mg of dicyclohexylcarboxylic acid diimide are left under repeated shaking at room temperature. After 2 h the N-succinimide ester is obtained by chromatography in 79% yield. The purification is carried out by thin layer chromatography in methylene chloride / methanol (95: 5).
  • the solution of the cytctrenecarboxylic acid N-succirimide ester obtained from Example 5 is concentrated to 10 .mu.l under a nitrogen atmosphere and mixed with 3 .mu.mol glycine - dissolved in 100 .mu.l borate buffer [0.1 molar, pH 8.5]. After stirring for 1 h at room temperature, the product is isolated by chromatography in ethanol and then purified by thin layer chromatography in chloroform acetone / formic acid (75: 20: 5).

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Abstract

On décrit l'utilisation d'acides carboxyliques de métallocène radioactifs et leurs dérivés ayant la formule (I), dans laquelle R?1, R2 R3, R4 et R5¿ ont des notations différentes et M désigne un isotope métallique radioactif des éléments ayant les numéros atomiques 21-29, 31, 42-44, 49 ou 57-83, pour le marquage de composés à activité N-hydroxyle. On décrit également un procédé de marquage et de nouveaux dérivés d'acides carboxyliques de métallocène ayant la formule (I), dans laquelle M désigne un isotope de Cr-51, Mn-52, Ru-97, Ru-103, Re-186, Re-188 et Ir-191.
PCT/EP1994/001250 1993-04-22 1994-04-20 Utilisation d'acides cyclopentadienylcarbonyle carboxyliques de metal de transition et de leurs derives pour marquer des proteines WO1994023757A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP6522787A JPH08508985A (ja) 1993-04-22 1994-04-20 遷移金属のシクロペンタジエニルカルボニルカルボン酸及びその誘導体のタンパク質標識化への使用
EP94915087A EP0696207A1 (fr) 1993-04-22 1994-04-20 Utilisation d'acides cyclopentadienylcarbonyle carboxyliques de metal de transition et de leurs derives pour marquer des proteines

Applications Claiming Priority (2)

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DE19934313670 DE4313670A1 (de) 1993-04-22 1993-04-22 Radioaktive Metallocen-carbonsäuren und deren Homologe zur Proteinmarkierung
DEP4313670.2 1993-04-22

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EP (1) EP0696207A1 (fr)
JP (1) JPH08508985A (fr)
CA (1) CA2160979A1 (fr)
DE (1) DE4313670A1 (fr)
WO (1) WO1994023757A1 (fr)

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WO2006026855A1 (fr) * 2004-09-07 2006-03-16 Triumf, Operating As A Joint Venture By The Governors Of The University Of Alberta, The University Of British Columbia, Carleton Synthese de complexes sucre/metal radiomarques

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991018908A1 (fr) * 1990-06-01 1991-12-12 Institut für Diagnostikforschung GmbH an der Freien Universität Berlin COMPLEXES 99mTc DE CARBONYLE DE CYCLOPENTADIENYLE, PROCEDE POUR LEUR FABRICATION, AINSI QUE LEUR UTILISATION DANS LE DIAGNOSTIC MEDICAL

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991018908A1 (fr) * 1990-06-01 1991-12-12 Institut für Diagnostikforschung GmbH an der Freien Universität Berlin COMPLEXES 99mTc DE CARBONYLE DE CYCLOPENTADIENYLE, PROCEDE POUR LEUR FABRICATION, AINSI QUE LEUR UTILISATION DANS LE DIAGNOSTIC MEDICAL

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
M. WENZEL ET AL.: "BIOCHEMIE VON AMINOSÄURE-DERIVATEN DES [103 RU] RUTHENOCENS. VERGLEICH MIT 131J-HIPPURAN.", APPL. RADIAT. ISOT., vol. 37, no. 6, 1986, pages 491 - 495 *
M. WENZEL ET AL.: "BIOCHEMISTRY OF METALOCENES. I. DISTRIBUTION OF 59FE OR 103RU-LABELED METALOCENE CARBOXYLIC ACID IN MICE.", JOURNAL OF NUCLEAR MEDECINE, vol. 18, no. 4, 1977, NEW YORK US, pages 367 - 372 *
M. WENZEL ET AL.: "ÖSTRADIOL-ESTER DER [103-RU]-RUTHENOCENCARBONSÄURE.", DIE NATUR WISSENSCHAFTEN, vol. 66, no. 6, June 1979 (1979-06-01), pages 313 - 314 *
M. WENZEL ET AL.: "RU-LABELED RUTHENOCENOYL-GLYCINE: COMPARISON OF CLEARNACE WITH HIPPURAN.", EUR. J. NUCL. MED., vol. 10, 1985, pages 138 - 142 *

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CA2160979A1 (fr) 1994-10-27
EP0696207A1 (fr) 1996-02-14
DE4313670A1 (de) 1994-10-27
JPH08508985A (ja) 1996-09-24

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