DE19515212A1 - Prodn. of radiofluorinated 2-fluoro-2-deoxy-glucose or -galactose - Google Patents

Prodn. of radiofluorinated 2-fluoro-2-deoxy-glucose or -galactose

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DE19515212A1
DE19515212A1 DE1995115212 DE19515212A DE19515212A1 DE 19515212 A1 DE19515212 A1 DE 19515212A1 DE 1995115212 DE1995115212 DE 1995115212 DE 19515212 A DE19515212 A DE 19515212A DE 19515212 A1 DE19515212 A1 DE 19515212A1
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fluoro
acetyl
deoxy
glucose
hydrolysis
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DE19515212C2 (en
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Frank Dr Fuechtner
Joerg Dr Steinbach
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Forschungszentrum Juelich GmbH
Forschungszentrum Dresden Rossendorf eV
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Forschungszentrum Dresden Rossendorf eV
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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
    • A61K51/0491—Sugars, nucleosides, nucleotides, oligonucleotides, nucleic acids, e.g. DNA, RNA, nucleic acid aptamers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
    • C07H5/02—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to halogen

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Abstract

Prodn. of <18>F-2-fluoro-2-deoxy-D-glucose (Ia) or <18>F-2-fluoro-2-deoxy-D-galactose (Ib) via the precursor <18>F-2-fluoro-1,3,4,6-tetra-O-acetyl-2-deoxy-D-glucose (IIa) or <18>F-2-fluoro-1,3,4,6-tetra-O-acetyl-2-deoxy-D-galactose (IIb) comprises removing the acetyl protecting gps. by alkaline hydrolysis in the presence of an alkali metal hydroxide, NH4OH, amine, alkylammonium hydroxide or arylammonium hydroxide soln.

Description

Die Herstellung des Radiopharmakons 2-[¹⁸F]Fluor-2-desoxy-D-glucose ([¹⁸F]FDG) und 2- [¹⁸F]Fluor-2-desoxy-D-galactose ([¹⁸F]FDGal) erfolgt bekanntermaßen in den folgenden drei Prozeßschriften: /Stöcklin G. and Pike V. W. (1993) Radiopharmaceuticals for PET. Kluwer Academic Publisher, Dordrecht, Boston, London; Coenen H. H., Pike V. W., Stöcklin G. and Wagner R. (1987) Recommendation for a practical production of [2-¹⁸F]Fluoro-2-Desoxy-D- Glucose. Appl. Radiat. Isot. 38, 605-610/The manufacture of the radiopharmaceutical 2- [¹⁸F] fluoro-2-deoxy-D-glucose ([¹⁸F] FDG) and 2- [¹⁸F] Fluoro-2-deoxy-D-galactose ([¹⁸F] FDGal) is known to occur in the following three Process documents: / Stöcklin G. and Pike V. W. (1993) Radiopharmaceuticals for PET. Kluwer Academic Publisher, Dordrecht, Boston, London; Coenen H.H., Pike V.W., Stöcklin G. and Wagner R. (1987) Recommendation for a practical production of [2-¹⁸F] fluoro-2-deoxy-D- Glucose. Appl. Radiat. Isot. 38, 605-610 /

  • - Fluorierung einer Vorläufersubstanz (Präkursor) mit ¹⁸F zur 2-[¹⁸F]Fluor-1,3,4,6-tetra-O-acetyl- D-glucose bzw. 2-[¹⁸F]Fluor-1,3,4,6-tetra-O-acetyl-D-galactose- Fluorination of a precursor (precursor) with ¹⁸F to give 2- [¹⁸F] fluoro-1,3,4,6-tetra-O-acetyl- D-glucose or 2- [¹⁸F] fluoro-1,3,4,6-tetra-O-acetyl-D-galactose
  • - Hydrolytische Abspaltung von Schutzgruppen (Acetylgruppen),Hydrolytic removal of protective groups (acetyl groups),
  • - Isolierung und Konditionierung des Endproduktes.- Isolation and conditioning of the end product.

Die Fluorierung kann im Falle des [¹⁸F]FDG entweder durch nukleophiles oder elektrophiles Einführen von ¹⁸F in den Präkursor erfolgen, wobei 2-[¹8F]Fluor-1,3,4,6-tetra-O-acetyl-D-glucose entsteht. Im Falle des [¹⁸F]FDGal erfolgt die Fluorierung durch elektrophiles Einführen von ¹⁸F in den Präkursor, wobei 2-[¹⁸F]Fluor-1,3,4,6-tetra-O-acetyl-D-galactose entsteht.Fluorination in the case of [¹⁸F] FDG can be done either by nucleophilic or electrophilic Introduce ¹⁸F into the precursor, using 2- [¹8F] fluoro-1,3,4,6-tetra-O-acetyl-D-glucose arises. In the case of [¹⁸F] FDGal, fluorination is carried out by electrophilic introduction of ¹⁸F into the precursor, producing 2- [¹⁸F] fluoro-1,3,4,6-tetra-O-acetyl-D-galactose.

Anschließend werden die Schutzgruppen der 2-[¹⁸F]Fluor-1,3,4,6-tetra-O-acetyl-D-glucose bzw. 2-[¹8F]Fluor-1,3,4,6-tetra-O-acetyl-D-galactose durch saure Hydrolyse mit vorzugsweise HCl bei Temperaturen um 120°C abgespalten.The protective groups of 2- [¹⁸F] fluoro-1,3,4,6-tetra-O-acetyl-D-glucose or 2- [18F] fluoro-1,3,4,6-tetra-O-acetyl-D-galactose by acidic hydrolysis with preferably HCl Cleave temperatures around 120 ° C.

Durch eine Kombination von Flüssigkeits-Chromatographieschritten erfolgt die Isolierung des Endproduktes, das anschließend isotonisch eingestellt wird.A combination of liquid chromatography steps is used to isolate the End product, which is then set isotonic.

Mit der Erfindung soll der bisher sowohl apparativ als auch zeitlich aufwendige Schritt der hydrolytischen Abspaltung der Schutzgruppen vereinfacht werden.The aim of the invention is to take the step, which has been time-consuming both in terms of equipment and time hydrolytic removal of the protective groups can be simplified.

Nach dem erfindungsgemäßen Verfahren zur Herstellung von [¹⁸F]FDG bzw. [¹⁸F]FDGal erfolgt die Abspaltung der Schutzgruppen durch alkalische Hydrolyse der 2-[¹⁸F]Fluor-1,3,4,6-tetra-O- acetyl-D-glucose bzw. 2-[¹⁸F]Fluor-1,3,4,6-tetra-O-acetyl-D-galactose in Gegenwart von Alkalihydroxid-, Ammoniak-, Amin- sowie Alkyl- oder Arylammoniumhydroxid-Lösungen bei Raumtemperatur bzw. der im Ergebnis der vorangegangenen Verfahrensschritte vorliegenden Temperatur des Reaktionsgemisches.According to the inventive method for the production of [¹⁸F] FDG or [¹⁸F] FDGal takes place the deprotection by alkaline hydrolysis of 2- [¹⁸F] fluoro-1,3,4,6-tetra-O- acetyl-D-glucose or 2- [¹⁸F] fluoro-1,3,4,6-tetra-O-acetyl-D-galactose in the presence of  Alkali hydroxide, ammonia, amine and alkyl or arylammonium hydroxide solutions Room temperature or the result of the previous process steps Temperature of the reaction mixture.

Die Hydrolyse von 2-[¹8F]Fluor-1,3,4,6-tetra-O-acetyl-D-glucose bzw. 2-[¹⁸F]Fluor-1,3,4,6-tetra- O-acetyl-D-gaIactose in Gegenwart o.g. Lösungen zeichnet sich durch kurze Reaktionszeiten bei Raumtemperatur und hohe Ausbeuten aus. Mit dem Wegfall der bisher erforderlichen Aufheizung des Reaktionsgemisches ist eine Vereinfachung der apparativen Ausrüstungen für die [¹⁸F]FDG bzw. [¹⁸F]FDGal-Herstellung verbunden. Das Verfahren kann damit auch in jeder existierenden Anlage realisiert werden.The hydrolysis of 2- [¹8F] fluoro-1,3,4,6-tetra-O-acetyl-D-glucose or 2- [¹⁸F] fluoro-1,3,4,6-tetra- O-acetyl-D-galactose in the presence of the above Solutions are characterized by short response times Room temperature and high yields. With the elimination of the previously required heating of the reaction mixture is a simplification of the equipment for the [¹⁸F] FDG or [¹⁸F] FDGal production connected. The procedure can also be used in any existing Plant can be realized.

Durch das Vermeiden der thermischen Belastung während der Hydrolyse und der guten Stabilität des Endproduktes in alkalischen Lösungen werden Zersetzungsreaktionen vermieden. Daraus resultierend ist im Falle des nukleophilen Einführens von ¹⁸F in den Präkurser der anschließende Hydrolyseschrift vollständig, während nach elektrophilem Einführen von ¹⁸F in den Präkurser die Ausbeute der alkalischen Hydrolyse im Vergleich zur herkömmlichen sauren Hydrolyse um 20% höher liegt. Außerdem wird die Bildung des bisher entstehenden, in seiner pharmakologischen Wirkung unklaren Nebenproduktes 2-Desoxy-2-chloro-D-glucose bzw. 2-Desoxy-2-chloro-D- galactose ausgeschlossen.By avoiding thermal stress during hydrolysis and good stability decomposition reactions of the end product in alkaline solutions are avoided. Out of it the result is the following in the case of nucleophilic introduction of ¹⁸F into the precursor Hydrolysis writing completely, while after electrophilic introduction of ¹⁸F in the precursor the Alkaline hydrolysis yield by 20% compared to conventional acid hydrolysis is higher. In addition, the formation of what is emerging, in its pharmacological Effect of unclear by-product 2-deoxy-2-chloro-D-glucose or 2-deoxy-2-chloro-D- galactose excluded.

Die Erfindung wird nachstehend anhand von Ausführungsbeispielen näher erläutert.The invention is explained in more detail below on the basis of exemplary embodiments.

In den Beispielen 1 und 2 wird die Hydrolyse mit NaOH-Lösung ausgehend von den üblicherweise angewandten [¹⁸F]FDG-Herstellungsverfahren beschrieben. Im Unterschied dazu wird im Beispiel 3 ausgehend vom nukleophilen Austausch die Hydrolyse in Gegenwart von Tetrabulylammoniumhydroxid-Lösung erläutert.In Examples 1 and 2, the hydrolysis with NaOH solution is based on the commonly used [¹⁸F] FDG manufacturing process described. In contrast to in Example 3, starting from the nucleophilic exchange, the hydrolysis in the presence of Tetrabulylammonium hydroxide solution explained.

Im Beispiel 4 wird ausgehend von der elektrophilen Fluorierung für die Herstellung von [¹⁸F]FDGal die Hydrolyse mit NaOH-Lösung dargestellt.Example 4 is based on the electrophilic fluorination for the production of [¹⁸F] FDGal shown the hydrolysis with NaOH solution.

Beispiel 1example 1

Als Vorläufersubstanz wird 1,3,4,6-Tetra-O-acetyl-2-O-trifluormethansulphonyl-beta-D-manno­ pyranose (FDG-Präkursor) eingesetzt, deren Fluorierung bekanntermaßen durch nukleophilen Austausch der Trifluormethansulfongruppe gegen [¹⁸F]Fluorid in Gegenwart von KryptifixTM 2.2.2 in Acetonitril bei ca. 90°C erfolgt. Anschließend wird das Lösungsmittel bei ca. 80°C abgedampft.1,3,4,6-Tetra-O-acetyl-2-O-trifluoromethanesulphonyl-beta-D-mannopyranose (FDG precursor) is used as the precursor, the fluorination of which is known to occur through nucleophilic exchange of the trifluoromethanesulfone group for [¹⁸F] fluoride in Kryptifix TM 2.2.2 is present in acetonitrile at approx. 90 ° C. The solvent is then evaporated off at approx. 80 ° C.

Zum erfindungsgemäßen Abspalten der Schutzgruppen (Acetylgruppen) durch alkalische Hydrolyse werden dem Reaktionsgemisch 2 ml 0,3 M NaOH zugefügt. Die Hydrolyse erfolgt schon bei Raumtemperatur oder der sich aus der Prozeßführung ergebenden Temperatur. Nach Vermischen der Reaktanten ist die Hydrolyse innerhalb von nur einer Minute vollständig abgeschlossen. Die Reaktionsausbeute des Hydrolyseschrittes liegt bei 100%.For splitting off the protective groups (acetyl groups) according to the invention by alkaline ones Hydrolysis, 2 ml of 0.3 M NaOH are added to the reaction mixture. The hydrolysis takes place even at room temperature or the temperature resulting from the process control. To Mixing the reactants completes the hydrolysis in just one minute completed. The reaction yield of the hydrolysis step is 100%.

Beispiel 2Example 2

Als Vorläufersubstanz wird Tri-O-acetyl-D-glucal (FDG-Präkursor) eingesetzt, dessen Fluorierung bekanntermaßen durch elektrophile Addition von [¹⁸F]Acetylhypofluorit in Freon 11 bei Raumtemperatur erfolgt. Anschließend wird das Lösungsmittel bei Raumtemperatur abgedampft.Tri-O-acetyl-D-glucal (FDG precursor), whose Fluorination is known to occur through electrophilic addition of [¹⁸F] acetyl hypofluorite in freon 11 at room temperature. Then the solvent at room temperature evaporated.

Das anschließende Abspalten der Schutzgruppen (Acetylgruppen) erfolgt nach der Erfindung durch alkalische Hydrolyse, indem zum Reaktionsgemisch 2 ml 0,3 M NaOH hinzugefügt werden. Die Hydrolyse erfolgt bei Raumtemperatur. Nach Vermischen der Reaktanten ist die Hydrolyse innerhalb von nur einer Minute vollständig abgeschlossen. Die Reaktionsausbeute des Hydrolyseschrittes ist im Vergleich zur bisher angewandten sauren Hydrolyse um etwa 20% höher.The protective groups (acetyl groups) are subsequently split off in accordance with the invention by alkaline hydrolysis by adding 2 ml of 0.3 M NaOH to the reaction mixture will. The hydrolysis takes place at room temperature. After mixing the reactants, the Hydrolysis completely completed in just one minute. The reaction yield of the Hydrolysis step is about 20% compared to the previously used acid hydrolysis higher.

Beispiel 3Example 3

Die Fluorierung der als Vorläufersubstanz eingesetzten 1,3,4,6-Tetra-O-acetyl-2-O-trifluorme­ thansulphonyl-beta-D-mannopyranose (FDG-Präkursor) erfolgt nach /Brodack J. W., Dence C. S., Kilbourn M. R., Welch M. J. (1988) Robotic production of 2-Desoxy-2-[¹⁸F]fluoro-D- glucose: A routine method of synthesis using Tetrabutylammonium [¹⁸F]Fluoride. Appl. Radiat. Isot. 39, 699-703) / durch nukleophilen Austausch der Trifluormethansulfongruppe gegen [¹⁸F]Fluorid in Gegenwart von Tetrabutylammoniumsalz in Acetonitril bei ca. 90°C. Anschließend wird das Lösungsmittel bei ca. 80°C abgedampft.The fluorination of the 1,3,4,6-tetra-O-acetyl-2-O-trifluorme used as a precursor thansulphonyl-beta-D-mannopyranose (FDG precursor) occurs according to / Brodack J. W., Dence C. S., Kilbourn M.R., Welch M.J. (1988) Robotic production of 2-deoxy-2- [¹⁸F] fluoro-D- glucose: A routine method of synthesis using tetrabutylammonium [¹⁸F] fluoride. Appl. Radiat. Isot. 39, 699-703) / by nucleophilic exchange of the trifluoromethanesulfone group for [¹⁸F] fluoride in the presence of tetrabutylammonium salt in acetonitrile at approx. 90 ° C. The solvent is then evaporated off at approx. 80 ° C.

Die erfindungsgemäße Herstellung des [¹⁸F]FDG erfolgt wiederum durch Abspalten der Schutz­ gruppen (Acetylgruppen) durch alkalische Hydrolyse. Dazu werden zum Reaktionsgemisch 1 ml 0,5 M Tetrabutylammoniumhydroxid-Lösung hinzugefügt. Die Hydrolyse erfolgt schon bei Raumtemperatur oder der sich aus der Prozeßführung ergebenden Temperatur. Nach Vermischen der Reaktanden ist die Hydrolyse innerhalb von nur einer Minute vollständig abgeschlossen. Die Reaktionsausbeute des Hydrolyseschrittes ist etwa 100%.The production of the [¹⁸F] FDG takes place again by splitting off the protection  groups (acetyl groups) by alkaline hydrolysis. For this purpose, 1 ml 0.5 M tetrabutylammonium hydroxide solution added. The hydrolysis already takes place at Room temperature or the temperature resulting from the process control. After mixing the reactants complete the hydrolysis in just one minute. The Reaction yield of the hydrolysis step is about 100%.

Beispiel 4Example 4

Als Vorläufersubstanz wird Tri-O-acetyl-D-galactal (FDGal-Präkursor) eingesetzt, dessen Fluorierung bekanntermaßen durch elektrophile Addition von [¹⁸F]Acetylhypofluorit in Freon 11 bei Raumtemperatur erfolgt. Anschließend wird das Lösungsmittel bei Raumtemperatur abgedampft.Tri-O-acetyl-D-galactal (FDGal precursor), whose Fluorination is known to occur through electrophilic addition of [¹⁸F] acetyl hypofluorite in freon 11 at room temperature. Then the solvent at room temperature evaporated.

Das anschließende Abspalten der Schutzgruppen (Acetylgruppen) erfolgt nach der Erfindung durch alkalische Hydrolyse, indem zum Reaktionsgemisch 2 ml 0,3 M NaOH hinzugefügt werden. Die Hydrolyse erfolgt bei Raumtemperatur. Nach Vermischen der Reaktanten ist die Hydrolyse innerhalb von nur einer Minute vollständig abgeschlossen. Die Reaktionsausbeute des Hydrolyseschrittes ist im Vergleich zur bisher angewandten sauren Hydrolyse um etwa 20% höher.The protective groups (acetyl groups) are subsequently split off in accordance with the invention by alkaline hydrolysis by adding 2 ml of 0.3 M NaOH to the reaction mixture will. The hydrolysis takes place at room temperature. After mixing the reactants, the Hydrolysis completely completed in just one minute. The reaction yield of the Hydrolysis step is about 20% compared to the previously used acid hydrolysis higher.

Die Isolierung des Endproduktes erfolgt in allen Beispielen bekanntermaßen anschließend an die Hydrolyse durch eine Kombination von Flüssigkeits-Chromatographieschritten. Danach wird die Lösung isotonisch eingestellt.In all examples, the isolation of the end product is known to follow after the Hydrolysis through a combination of liquid chromatography steps. After that the Solution isotonic adjusted.

Da bei der Einstellung der Isotonie NaCl zum Einsatz kommt, wird mit der Verwendung des Natriumhydroxids bei der Hydrolyse das Eintragen von Fremdionen vermieden, und damit den Regeln der "Guten Herstellungspraxis" für Pharmaka /Commission of the European Communities IIIB/6, "The rules governing medical products in the European Community, Vol. IV; Guide to good manufacturing practice for medical products." No. III/3973/89-EN, (1990), Brussels, Belgium/ entsprochen.Since NaCl is used to adjust the isotonicity, the use of Sodium hydroxide avoided the entry of foreign ions during hydrolysis, and thus the Rules of "Good Manufacturing Practice" for Pharmaceuticals / Commission of the European Communities IIIB / 6, "The rules governing medical products in the European Community, Vol. IV; Guide to good manufacturing practice for medical products. "No. III / 3973/89-EN, (1990), Brussels, Belgium / met.

Claims (1)

Verfahren zur Herstellung von 2-[¹⁸F]Fluor-2-desoxy-D-glucose und 2-[¹⁸F]Fluor-2-desoxy- D-galactose über den fluorierten Präkursor 2-[¹⁸F]Fluor-1,3,4,6-tetra-O-acetyl-D-glucose bzw. 2-[¹⁸F]Fluor-1,3,4,6-tetra-O-acetyl-D-galactose und der sich anschließenden hydrolytischen Abspaltung der Acetyl-Schutzgruppen, dadurch gekennzeichnet, daß die Abspaltung der Schutz­ gruppen durch alkalische Hydrolyse in Gegenwart von Alkalihydroxid-, Ammoniak-, Amin- sowie Alkyl- oder Arylammoniumhydroxid-Lösungen erfolgt.Process for the preparation of 2- [¹⁸F] fluoro-2-deoxy-D-glucose and 2- [¹⁸F] fluoro-2-deoxy-D-galactose via the fluorinated precursor 2- [¹⁸F] fluoro-1,3,4, 6-tetra-O-acetyl-D-glucose or 2- [¹⁸F] fluoro-1,3,4,6-tetra-O-acetyl-D-galactose and the subsequent hydrolytic cleavage of the acetyl protective groups, characterized that the removal of the protecting groups by alkaline hydrolysis in the presence of alkali metal hydroxide, ammonia, amine and alkyl or Arylammoniumhydroxid solutions takes place.
DE1995115212 1995-04-28 1995-04-28 Process for the preparation of 2- [· 1 ·· 8 · F] fluoro-2-deoxy-D-glucose and 2- [· 1 ·· 8 · F] fluoro-2-deoxy-D-galactose Revoked DE19515212C2 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005028490A1 (en) * 2003-09-19 2005-03-31 Theseus Imaging Corporation Halogenated deoxy-glucose labeled targeting molecules

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Title
BUTCHARD,G.C., KENT,P.W.: Fluorocarbohydrates- XXVIII. In: Tetra, Vol.35, No.20-H. S.2439-2443 *
Chemical Abstracts: Vol.121, 1994, Ref. 9919f *
KORYTNYK,W., VALENTEKOVIC-HORVAT,S.: Reactions Of Glycals With Xenon Fluoride: An Improved Synthesis Of 2-Deoxy-2-Fluorosaccharides. In: Tetrahedron Letters Vol.21, S.1493-1496 *
KOVAC,PAVOL: A short synthesis of 2-deoxy- 2-fluoro-D-glucose. In: Carbohydrate Research, 153, 1986, S.168-170 *
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WHISTLER,Roy L., et.al.: Methods In Carbohydrate Chemistry, Academic Press, New York, 1963, Vol.II., S.215-220 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005028490A1 (en) * 2003-09-19 2005-03-31 Theseus Imaging Corporation Halogenated deoxy-glucose labeled targeting molecules

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