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WO2002090298A2 - Procede de synthese de composes marques au 18f et a faible teneur en entraineurs - Google Patents

Procede de synthese de composes marques au 18f et a faible teneur en entraineurs Download PDF

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Publication number
WO2002090298A2
WO2002090298A2 PCT/DE2002/001548 DE0201548W WO02090298A2 WO 2002090298 A2 WO2002090298 A2 WO 2002090298A2 DE 0201548 W DE0201548 W DE 0201548W WO 02090298 A2 WO02090298 A2 WO 02090298A2
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WO
WIPO (PCT)
Prior art keywords
low
compounds
fluorination
carriers
marked
Prior art date
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Ceased
Application number
PCT/DE2002/001548
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German (de)
English (en)
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WO2002090298A3 (fr
Inventor
Kurt Hamacher
Marianne Jelinski
Heinz H. Coenen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Forschungszentrum Juelich GmbH
Original Assignee
Forschungszentrum Juelich GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Forschungszentrum Juelich GmbH filed Critical Forschungszentrum Juelich GmbH
Publication of WO2002090298A2 publication Critical patent/WO2002090298A2/fr
Publication of WO2002090298A3 publication Critical patent/WO2002090298A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se

Definitions

  • the invention relates to a process for the synthesis of low-carrier 18 F-labeled compounds.
  • the production of 18 F-labeled radiopharmaceuticals for nuclear medical diagnostics using positron emission tomography is the focus of radiopharmaceutical research and development.
  • the nucleophilic, phase transfer-catalyzed (PTK) 18 F fluorination is the only way to date to produce 18 F-labeled radiotracers with high molar activity (> 3.7. 10 16 Bq / mol) for nuclear medical diagnostics.
  • Perfluoroalkylsulfonimides of the general formula (C n F 2n + ⁇ S0 2 ) 2 NR with R substituted or unsubstituted aromatic residues (e.g. phenyl, dimethylphenyl) or alkylaryl residues (e.g.
  • p-tolyl, 1-N-naphthyl, 2-N-naphthyl) and n ⁇ 1, preferably 1 to 4 are added to the under the conditions of a nucleophilic, phase transfer-catalyzed, low-carrier fluorination at temperatures of, for example, 100 ° C to 150 ° C, preferably 130 ° C, with or without solvent corresponding Perf luoralkyl - 1 -sulfonyl - [ 18 F] f luorid implemented.
  • a solution of 18 F " water and a phase transfer catalyst eg consisting of Potassium carbonate and Kryptofix ® or tetraalkylammonium carbonate or tetraalkylammonium hydrogen carbonate and the solvent acetonitrile are dried in an inert gas (eg He, Ar) at a temperature of 80 to 100 ° C.
  • an inert gas eg He, Ar
  • N-aryl-perfluoroalkyl-sulfonimide in solvent (for example toluene, dichloromethane, n-pentane, trichlorofluoromethane) or alternatively dissolved in ether is then added and heated.
  • solvent for example toluene, dichloromethane, n-pentane, trichlorofluoromethane
  • All aprotic solvents eg toluene
  • low-boiling solvents eg diethyl ether
  • the active product evaporates in the course of the fluorination reaction and can be removed from the reaction mixture by distillation in this way.
  • the product can be condensed in a second reaction vessel.
  • the perfluoroalkyl-1-sulfonyl- [ 18 F] fluoride can be driven out of the mixture using an inert gas stream. If the N-aryl-perfluoroalkylsulfonimide has been added dissolved in ether (e.g. diethyl ether), the ether can be evaporated in a stream of inert gas at about 0 ° C. within a few minutes (about 2 minutes). Subsequently, the perfluoroalkyl-1-sulfonyl- [ 18 F] fluoride, which forms when the solvent-free residue is heated from approximately 40 ° C.
  • ether e.g. diethyl ether
  • reaction equation (A) shows schematically the synthesis of perfluoroalkyl-1-sulfonyl
  • the amounts of substance are such that the amount of perfluoroalkyl-1-sulfonyl- [ 19 F] fluoride added is approximately is equimolar to the hydroxy compound regardless of the amount of activity of the perfluoroalkyl-1-sulfonyl- [ 18 F] fluoride. So that a relatively high molar activity of the 18 F-labeled perfluoroalkylsulfonic acid fluoride can be achieved in spite of the necessary amount of carrier, the reaction is carried out with the smallest possible amounts of the starting materials of the hydroxy compounds and perfluoroalkylsulfonic acid fluorides in small reaction volumes (for example ⁇ 0.3 ml) , At room temperature, the reaction proceeds within a few minutes (approx. 5 min) with a radiochemical yield of approx. 40-50%.
  • reaction equation (B) shows schematically the reaction of the 18 F-label of hydroxy compounds.
  • the base used in the reaction was abbreviated to "B”:
  • the esterification reaction can be carried out using aliphatic hydroxy functions.
  • peptides with aliphatic hydroxy functions for. B. the amino acid units threonine, serine, or hydroxyproline, as well as partially protected sugar (eg 1.3.4.6-tetra-O-acetyl-ß-D-mannose) or oligosaccharides or OH-containing peptide mimetics with 18 F are marked.
  • partially protected sugar eg 1.3.4.6-tetra-O-acetyl-ß-D-mannose
  • oligosaccharides or OH-containing peptide mimetics with 18 F are marked.
  • not only can naturally occurring peptides with an aliphatic hydroxy function be labeled with 18 F, but also peptides with hydro- xyfunctions are synthesized.
  • the location of the 18 F mark can be specified.
  • Existing hydroxyl functions that are not to be fluorinated can first be protected before the desired substitution of
  • the low-carrier nonafluorobutane-1-sulfonyl- [ 18 F] fluoride is reacted with a hydroxylated tetrapeptide.
  • To 10 mg Z-Pro-Leu-Gly-Hyp-OMe are dissolved with 240 ⁇ l low-carrier nonafluorobutane-1-sulfonyl- [ 18 F] fluoride in toluene (absolute), 9 ⁇ l 1,8-diazabicyclo [5.4.0] undec- 7-enes as a base and an equimolar amount (3.5 ⁇ l) of nonafluorobutane-1-sulfonyl- [ 19 F] fluoride were added. At room temperature, the fluorination reaction proceeds within 5 min with a radiochemical yield of 40 ⁇ 8%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

L'invention concerne un procédé de synthèse de composés marqués au 18F et à faible teneur en entraîneurs. La fluoration nucléophile, catalysée par transfert de phase, avec 18F était jusqu'à présent la seule façon de produire des radiotraceurs d'activité moléculaire supérieure (> 3,7 . 1016 Bq/mol) et marqués au 18F pour le diagnostic en médecine nucléaire. Cette méthode de marquage suppose toutefois que des éduits, présentant des groupes de sortie hautement nucléofuges, soient accessibles et que la stabilité chimique requise de ces composés soit garantie dans ces conditions de marquage. Des substances naturelles complexes et leur dérivés ne remplissent pas ces conditions. Ils sont endommagés ou dénaturés de façon irréversible. Grâce au présent procédé, il est désormais possible de marquer au 18F des substances naturelles et leurs dérivés, notamment de manière stéréosélective, dans des conditions de réaction douces. Ce procédé permet de synthétiser des composés marqués au 18F et à faible teneur en entraîneurs, en fluorant au 18F des perfluoroalkyl-sulfonimides puis en les estérifiant avec une fonction hydroxy. Ce procédé permet en outre de travailler avec de faibles quantités d'éduits, de manière à augmenter la rentabilité dudit procédé.
PCT/DE2002/001548 2001-05-04 2002-04-26 Procede de synthese de composes marques au 18f et a faible teneur en entraineurs Ceased WO2002090298A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10121741.2 2001-05-04
DE2001121741 DE10121741A1 (de) 2001-05-04 2001-05-04 Verfahren zur Synthese trägerarmer ·18·F markierter Verbindungen

Publications (2)

Publication Number Publication Date
WO2002090298A2 true WO2002090298A2 (fr) 2002-11-14
WO2002090298A3 WO2002090298A3 (fr) 2003-03-06

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DE2002/001548 Ceased WO2002090298A2 (fr) 2001-05-04 2002-04-26 Procede de synthese de composes marques au 18f et a faible teneur en entraineurs

Country Status (2)

Country Link
DE (1) DE10121741A1 (fr)
WO (1) WO2002090298A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010000409A3 (fr) * 2008-07-03 2010-03-04 Bayer Schering Pharma Aktiengesellschaft Composés et procédés pour la production d’agents radiopharmaceutiques
WO2010007363A3 (fr) * 2008-07-15 2010-07-01 Isis Innovation Limited Préparation de composés marqués par du fluor

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3424525A1 (de) * 1984-07-04 1986-01-16 Kernforschungsanlage Jülich GmbH, 5170 Jülich Verfahren zur herstellung von (pfeil hoch)1(pfeil hoch)(pfeil hoch)8(pfeil hoch)f-alkyl- und arylverbindungen durch halogenaustausch
DE4313664C2 (de) * 1993-04-20 1996-12-05 Schering Ag N-Fluormethansulfonimid, Verfahren zu seiner Herstellung sowie dessen Verwendung
DE69837095T2 (de) * 1997-09-03 2007-11-22 Immunomedics, Inc. Fluorierung von proteinen und peptiden für positronemissionstomographie
US6248889B1 (en) * 1998-11-20 2001-06-19 3M Innovative Properties Company Process for converting an alcohol to the corresponding fluoride

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010000409A3 (fr) * 2008-07-03 2010-03-04 Bayer Schering Pharma Aktiengesellschaft Composés et procédés pour la production d’agents radiopharmaceutiques
JP2011526267A (ja) * 2008-07-03 2011-10-06 バイエル ファーマ アクチエンゲゼルシャフト 化合物および放射性医薬品の製造方法
WO2010007363A3 (fr) * 2008-07-15 2010-07-01 Isis Innovation Limited Préparation de composés marqués par du fluor

Also Published As

Publication number Publication date
DE10121741A1 (de) 2002-11-14
WO2002090298A3 (fr) 2003-03-06

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