WO2002090298A2 - Method for the synthesis of 18f marked compounds which are low in carriers - Google Patents
Method for the synthesis of 18f marked compounds which are low in carriers Download PDFInfo
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- 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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- 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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Abstract
The invention relates to a method for the synthesis of 18F marked compounds which are low in carriers. Nucleophilic phase-transfer catalyzed 18F- fluoridation was previously the only way to produce 18F marked radiotracers having a high molar activity (> 3,7 . 1016 Bq/mol) for nuclear medicinal diagnosis. However, this marking method pre-supposes that educts having high nucleofugic leaving groups are accessible and that the requisite chemical stability of said compounds is guaranteed in said marking conditions. Complex natural substances and the derivatives thereof do not fulfil said conditions. They are irreversibly damaged or denatured. The inventive method makes it possible to mark natural substances and the derivatives thereof with 18F, especially in a stereoselective manner in mild reaction conditions. According to the inventive method, 18F marked compounds which are low in carriers can be synthesized, by 18F fluoridating perfluoroalkyl sulfonimides and by subsequent esterization with a hydroxy function. According to the inventive method it is also possible to work with small amounts of educts and therefore to increase the cost-effectiveness of the method.
Description
B e s c h r e i b u n g Description
Verfahren zur Synthese trägerarmer 18F markierterProcess for the synthesis of low-carrier 18 F labeled
Ve r b i ndung e nLinks
Die Erfindung betrifft ein Verfahren zur Synthese von trägerarmen 18F markierten Verbindungen.The invention relates to a process for the synthesis of low-carrier 18 F-labeled compounds.
Die Herstellung 18F-markierter Radiopharmaka für die nuklearmedizinische Diagnostik mittels Positronen- Emissions-Tomographie steht im Mittelpunkt der radiopharmazeutischen Forschung und Entwicklung. Die nukle- ophile, phasentransfer-katalysierte (PTK) 18F-Fluorierung ist die bislang einzige Möglichkeit, 18F-markierte Radiotracer hoher molarer Aktivität (> 3,7 . 1016 Bq/mol) für die nuklearmedizinische Diagnostik herzustellen.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.
Diese Methode der Markierung setzt jedoch voraus, daß Edukte mit Abgangsgruppen hoher Nukleofugie zugänglich sind und die notwendige chemische Stabilität dieser Verbindungen unter den Markierungsbedingungen gewährleistet ist. Komplexe Naturstoffe und deren Derivate erfüllen diese Bedingungen nicht. Durch die basischen Reaktionsbedingungen der PTK-gestützten 18F-Fluorierung bei Reaktionstemperaturen von 50 bis 160°C, besteht die Gefahr, daß die (chiralen) Naturstoffe racemisiert werden bzw. denaturieren.However, this method of labeling presupposes that starting materials with leaving groups of high nucleofugia are accessible and that the necessary chemical stability of these compounds is guaranteed under the labeling conditions. Complex natural products and their derivatives do not meet these conditions. Due to the basic reaction conditions of PTK-supported 18 F fluorination at reaction temperatures of 50 to 160 ° C, there is a risk that the (chiral) natural products will be racemized or denatured.
Es ist daher Aufgabe der Erfindung ein Verfahren zu schaffen, mit dem es möglich ist, organische Verbindun-
gen ohne Strukturveränderungen oder Veränderung ihrer ursprünglichen Funktion mit 18F zu markieren.It is therefore an object of the invention to provide a method with which it is possible to without marking structural changes or changing their original function with 18 F.
Ausgehend vom Oberbegriff des Anspruchs 1 wird die Aufgabe erfindungsgemäß gelöst mit den im kennzeichnenden Teil des Anspruchs 1 angegebenen Merkmalen.Starting from the preamble of claim 1, the object is achieved according to the invention with the features specified in the characterizing part of claim 1.
Mit dem erfindungsgemäßen Verfahren ist es nunmehr möglich, unter schonenden Reaktionsbedingungen Naturstoffe und deren Derivate mit 18F, insbesondere stereoselektiv, zu markieren. Weiterhin ist es möglich, mit gerin- gen Eduktmengen zu arbeiten und damit die Wirtschaftlichkeit des Verfahrens zu erhöhen.With the method according to the invention it is now possible to label natural substances and their derivatives with 18 F, in particular stereoselective, under gentle reaction conditions. It is also possible to work with small quantities of starting material and thus to increase the economics of the process.
Vorteilhafte Weiterbildungen sind in den Unteransprüchen angegeben.Advantageous further developments are specified in the subclaims.
Im folgenden soll die Erfindung beispielhaft beschrie- ben werden.The invention will be described below by way of example.
Perfluoralkylsulfonimide der allgemeinen Formel (CnF2n+ιS02) 2N-R mit R = substituierte oder unsubstitu- ierte aromatische Reste (z. B. Phenyl , Dimethylphenyl) oder Alkylarylreste (z. B. p-Tolyl, 1-N-Naphthyl , 2-N- Naphthyl) und n ≥ 1, bevorzugt 1 bis 4, werden unter den Bedingungen einer nucleophilen, phasentransferkatalysierten, trägerarmen Fluorierung bei Temperaturen von beispielsweise 100°C bis 150°C, bevorzugt 130°C, mit oder ohne Lösungsmittel zu dem entsprechenden Perf luoralkyl - 1 -sulfonyl - [18F] f luorid umgesetzt .Perfluoroalkylsulfonimides of the general formula (C n F 2n + ιS0 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.
Zunächst wird eine Lösung aus 18F" haltigem Wasser und einem Phasentransferkatalysator, z. B. bestehend aus
Kaliumcarbonat und Kryptofix® oder Tetraalkylammonium- carbonat bzw. Tetraalkylammoniumhydrogencarbonat sowie dem Lösungsmittel Acetonitril in einem Inertgas (z. B. He, Ar) bei einer Temperatur von 80 bis 100°C getrock- net .First, 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.
Anschließend wird eine Lösung aus N-Aryl-perfluoralkyl- sulfonimid in Lösungsmittel (z. B. Toluol , Dichlor- methan, n-Pentan, Trichlorfluormethan) oder alternativ in Ether gelöst zugegeben und erwärmt. Als Lösungs- mittel eignen sich alle aprotischen Lösungsmittel (z. B. Toluol) oder niedrig siedende Lösungsmittel (z. B. Diethylether), die keine Reaktion mit den N-Aryl-perfluoralkylsulfonimiden eingehen. Auf Grund des hohen Dampfdrucks der sich bildenden Perfluoralkyl- 1-sulfonyl- [18F] fluoride verdampft das Aktivprodukt bereits im Verlauf der Fluorierungsreaktion und kann auf diese Art destillativ aus dem Reaktionsgemisch entfernt werden. Zur weiteren Umsetzung kann das Produkt in einem zweiten Reaktionsgefäß kondensiert werden.A solution of N-aryl-perfluoroalkyl-sulfonimide in solvent (for example toluene, dichloromethane, n-pentane, trichlorofluoromethane) or alternatively dissolved in ether is then added and heated. All aprotic solvents (eg toluene) or low-boiling solvents (eg diethyl ether) which do not react with the N-aryl-perfluoroalkylsulfonimides are suitable as solvents. Due to the high vapor pressure of the perfluoroalkyl-1-sulfonyl- [ 18 F] fluorides which form, the active product evaporates in the course of the fluorination reaction and can be removed from the reaction mixture by distillation in this way. For further reaction, the product can be condensed in a second reaction vessel.
Das Perfluoralkyl-1-sulfonyl- [18F] fluorid kann mit Hilfe eines Inertgasstroms aus dem Gemisch ausgetrieben werden. Wenn das N-Aryl-perfluoralkylsulfonimid in Ether (z. B. Diethylether) gelöst zugegeben wurde, kann der Ether bereits bei etwa 0°C innerhalb weniger Minuten (ca. 2 min) im Inertgasstrom verdampft werden. Anschließend kann das Perfluoralkyl-1-sulfonyl- [18F] fluorid, das sich beim Erwärmen des lösungsmittelfreien Rückstands von ca. 40°C auf 130°C bildet, beispielsweise durch Absorption in ein organisches Lösungsmittel oder Adsorption an eine polymere Phase (z. B. Polystyrol) durch Tieftemperaturkondensation
(z. B. bei -60 bis -180°C) isoliert werden. Wenn die Umsetzung der N-Aryl-perfluoralkyl-sulfonimide unter lösungsmittelfreien Bedingungen durchgeführt wird, kann eine besonders gute Abscheidbarkeit und Isolation der Perfluoralkyl-1-sulfonyl- [18F] fluoride gewährleistet werden, da insbesondere bei der Adsorption des Produktes an eine polymere Phase die Porosität des Polymers nicht beeinträchtigt wird.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. to 130 ° C., for example by absorption in an organic solvent or adsorption on a polymeric phase (e.g. B. polystyrene) by low temperature condensation (e.g. at -60 to -180 ° C) are isolated. If the reaction of the N-aryl-perfluoroalkyl-sulfonimides is carried out under solvent-free conditions, particularly good separability and isolation of the perfluoroalkyl-1-sulfonyl- [ 18 F] fluorides can be ensured, in particular when the product is adsorbed onto a polymeric phase the porosity of the polymer is not affected.
Die folgende Reaktionsgleichung (A) zeigt schematisch die Synthese von Perfluoralkyl-1-sulfonyl-The following reaction equation (A) shows schematically the synthesis of perfluoroalkyl-1-sulfonyl
[18F] fluoriden aus Perfluoralkylsulfonimiden. Dabei soll die in der Gleichung verwendete Bezeichnung[ 18 F] fluorides from perfluoroalkyl sulfonimides. The term used in the equation is meant to be
„ (PTK) " den Phasentransferkatalysator symbolisieren."(PTK)" symbolize the phase transfer catalyst.
( CnF2n+1S02 ) 2N- R + ( PTK) 18F -> R(C n F 2n + 1 S0 2 ) 2 N- R + (PTK) 18 F -> R
( CnF2n+1S02 ) 18F + ( PTK) N- S02CnF2n+1 (A)(C n F 2n + 1 S0 2 ) 18 F + (PTK) N- S0 2 C n F 2n + 1 (A)
Das 18F- arkierte Perfluoralkyl-1-sulfonyl- [18F] fluorid wird mit Perfluoralkyl-1-sulfonyl- [19F] fluorid geträ- gert und in einer Veresterungsreaktion mit Hydroxyver- bindungen, wie z. B. Alkohole, partiell geschützte, hydroxyaminosäurehaltige Peptide bzw. Proteine und Zucker, in Gegenwart einer Base, z. B. DBU (= 1,8- Diazabicyclo [5.4.0] undec-7-en) , zum entsprechenden Perfluoralkyl-1-sulfonsäureester umgesetzt. Dabei kommt es zur Freisetzung von Fluorid. In einer Folgereaktion substituiert das Fluorid die nucleofuge Gruppe, so daß die entsprechende Fluorverbindung resultiert. Die Stoffmengen werden so bemessen, daß die zugesetzte Menge des Perfluoralkyl-1-sulfonyl- [19F] fluorids annähernd
äquimolar zu der Hydroxyverbindung ist, unabhängig von der Aktivitätsmenge des Perfluoralkyl-1-sulfonyl- [18F] fluorids . Damit trotz der notwendigen Trägermenge eine relativ hohe molare Aktivität des 18F-markierten Perfluoralkylsulfonsäurefluorids erreicht werden kann, wird die Reaktion mit möglichst kleinen Stoffmengen der Edukte der Hydroxyverbindungen und Perfluoralkylsulfon- säurefluoriden in kleinen Reaktionsvolumina (z. B. < 0,3 ml) durchgeführt. Bei Raumtemperatur verläuft die Reaktion innerhalb weniger Minuten (ca. 5 min) mit einer radiochemischen Ausbeute von ca. 40-50%.The 18 F-fused perfluoroalkyl-1-sulfonyl- [ 18 F] fluoride is supported with perfluoroalkyl-1-sulfonyl- [ 19 F] fluoride and in an esterification reaction with hydroxy compounds, such as. B. alcohols, partially protected, hydroxyamino-containing peptides or proteins and sugar, in the presence of a base, for. B. DBU (= 1,8-diazabicyclo [5.4.0] undec-7-ene), to the corresponding perfluoroalkyl-1-sulfonic acid ester. This leads to the release of fluoride. In a subsequent reaction, the fluoride substitutes the nucleofugic group, so that the corresponding fluorine compound results. 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%.
Die folgende Reaktionsgleichung (B) zeigt schematisch die Reaktion der 18F-Markierung von Hydroxyverbindungen. Die in der Reaktion verwendete Base wurde mit „B" abgekürzt:The following 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":
R- OH + ( CnF2n+ιS02 ) 18F + B -» [R-0- S02CnF2n+1 + 18F" + HB+] -> R- 18F + CnF2n+1S03- HB+ ( B )R- OH + (C n F 2n + ιS0 2 ) 18 F + B - »[R-0- S0 2 C n F 2n + 1 + 18 F " + HB + ] -> R- 18 F + C n F 2n +1 S0 3 - HB + (B)
Die Veresterungsreaktion kann mit aliphatischen Hydro- xyfunktionen durchgeführt werden. Mit dem erfindungsgemäßen Verfahren können so beispielsweise Peptide mit aliphatischen Hydroxyfunktionen z. B. den Aminosäureeinheiten Threonin, Serin, oder Hydroxyprolin, sowie partiell geschützte Zucker (z. B. 1.3.4.6-Tetra-O- acetyl-ß-D-mannose) oder Oligosaccharide oder auch OH- haltige Peptidmimetika mit 18F markiert werden. Darüber hinaus können nicht nur natürlich vorkommende Peptide mit einer aliphatischen Hydroxyfunktion mit 18F markiert werden, sondern es können auch Peptide mit Hydro-
xyfunktionen synthetisiert werden. So kann beispielsweise der Ort der 18F Markierung festgelegt werden. Dabei können bereits vorhandene, nicht zu fluorierende Hydroxyfunktionen zunächst geschützt werden bevor die gezielte Substitution der gewünschten Hydroxyfunktion durch 18F erfolgt .The esterification reaction can be carried out using aliphatic hydroxy functions. With the method according to the invention, for example, 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. In addition, not only can naturally occurring peptides with an aliphatic hydroxy function be labeled with 18 F, but also peptides with hydro- xyfunctions are synthesized. For example, 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 desired hydroxyl function by 18 F takes place.
Ausführungsbeispiel :Design example:
Synthese von trägerarmem Nonafluorbutan-1-sulfonyl [18F] FluoridSynthesis of low-carrier nonafluorobutane-1-sulfonyl [ 18 F] fluoride
I) 0,1-0,3 ml 18F haltiges Wasser, 1,7 mg Kaliumcar- bonat (suprapur) und 10 mg Kryptofix® 2.2.2 sowie 1 ml Acetonitril werden in einem zylindrischen Gefäß aus Glaskohlenstoff bei einer Temperatur von 80 bis 100°C im Inertgasstrom (z. B. He) getrocknet. Anschließend wird eine Lösung von 10 mg N,N- Bis (perfluorbutansulfonyl) anilin in 0,5 ml Toluol zugegeben. Der Reaktor wird auf 130°C erwärmt und das entstehende trägerarme Nonfluorbutan-1- sulfonyl- [18F] fluorid mit Hilfe des Inertgasstroms ausgetrieben. Das Aktivprodukt kann sowohl in einem organischen Lösungsmittel absorbiert werden als auch auf polymerer Phase (vernetztes Polystyrol) oder an der Wandung einer Kapillarleitung durch Tieftemperaturkondensation (-60 bis -180°C) adsorbiert werden.I) 0.1-0.3 ml of water containing 18 F, 1.7 mg of potassium carbonate (suprapur) and 10 mg of Kryptofix ® 2.2.2 and 1 ml of acetonitrile are placed in a cylindrical glass-carbon vessel at a temperature of 80 to 100 ° C in an inert gas stream (e.g. He) dried. A solution of 10 mg of N, N-bis (perfluorobutanesulfonyl) aniline in 0.5 ml of toluene is then added. The reactor is heated to 130 ° C. and the resulting low-carrier nonfluorobutane-1-sulfonyl- [ 18 F] fluoride is driven off using the inert gas stream. The active product can be absorbed both in an organic solvent and adsorbed on the polymer phase (cross-linked polystyrene) or on the wall of a capillary line by low-temperature condensation (-60 to -180 ° C).
II) In einem zweiten Verfahrensabschnitt wird das trägerarme Nonafluorbutan-1-sulfonyl- [18F] fluorid mit einem hydroxylierten Tetrapeptid umgesetzt. Dazu
werden 10 mg Z-Pro-Leu-Gly-Hyp-OMe mit 240 μl trägerarmem Nonafluorbutan-1-sulfonyl- [18F] fluorid gelöst in Toluol (absolut), 9 μl 1,8- Diazabicyclo [5.4.0] undec-7-en als Base und einer äquimolaren Menge (3,5 μl) an Nonafluorbutan-1- sulfonyl- [19F] fluorid versetzt. Bei Raumtemperatur verläuft die Fluorierungsreaktion innerhalb von 5 min mit einer radiochemischen Ausbeute von 40±8%.
II) In a second process step, 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 μl low-carrier nonafluorobutane-1-sulfonyl- [ 18 F] fluoride in toluene (absolute), 9 μl 1,8-diazabicyclo [5.4.0] undec- 7-enes as a base and an equimolar amount (3.5 μl) 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%.
Claims
1. Verfahren zur Synthese von trägerarmen 18F-markier- ten Verbindungen, dadurch gekennzeichnet, daß Perf luoralkylsulf onimide der allgemeinen Formel (CnF2n+ιS02)2N-R (I) mit n > 1 und1. A process for the synthesis of low-carrier 18 F-labeled compounds, characterized in that Perf luoralkylsulf onimide of the general formula (C n F 2n + ιS0 2 ) 2 NR (I) with n> 1 and
R: substituierte oder unsubstituierte aromatische bzw. Alkylarylreste,R: substituted or unsubstituted aromatic or alkylaryl radicals,
18F- fluoriert und anschließend mit einer Hydroxy- Verbindung verestert werden. 18 F- fluorinated and then esterified with a hydroxy compound.
2. Verfahren nach Anspruch 1 , dadurch gekennzeichnet, daß die 18F-Fluorierung der Perf luoralkylsulfonimi- de der allgemeinen Formel (CnF2n+1S02)2N-R (I) unter Erwärmung in An- oder Abwesenheit eines organischen Lösungsmittels erfolgt.2. The method according to claim 1, characterized in that the 18 F-fluorination of Perf luoralkylsulfonimi- de of the general formula (C n F 2n + 1 S0 2 ) 2 NR (I) is carried out with heating in the presence or absence of an organic solvent ,
3. Verfahren nach Anspruch 2 , dadurch gekennzeichnet, daß die Verbindung3. The method according to claim 2, characterized in that the connection
N,N-Bis (perfluorbutansulfonyl) anilin eingesetzt wird.N, N-bis (perfluorobutanesulfonyl) aniline is used.
4. Verfahren nach einem der Ansprüche 1 bis 3, dadurch gekennzeichnet, daß die Fluorierung bei einer Temperatur von 100 bis 150 °C durchgeführt wird. 4. The method according to any one of claims 1 to 3, characterized in that the fluorination is carried out at a temperature of 100 to 150 ° C.
5. Verfahren nach einem der Ansprüche 1 bis 4, dadurch gekennzeichnet, daß bei der Fluorierung aprotische Lösungsmittel eingesetzt werden.5. The method according to any one of claims 1 to 4, characterized in that aprotic solvents are used in the fluorination.
6. Verfahren nach Anspruch 5, dadurch gekennzeichnet, daß Toluol eingesetzt wird.6. The method according to claim 5, characterized in that toluene is used.
7. Verfahren nach einem der Ansprüche 1 bis 4, dadurch gekennzeichnet, daß bei der Fluorierung niedrig siedende Lösungsmittel eingesetzt werden.7. The method according to any one of claims 1 to 4, characterized in that low-boiling solvents are used in the fluorination.
8. Verfahren nach Anspruch 7, dadurch gekennzeichnet, daß Ether eingesetzt wird.8. The method according to claim 7, characterized in that ether is used.
9. Verfahren nach einem der Ansprüche 1 bis 8, dadurch gekennzeichnet, daß für die Veresterung aliphatische Hydroxyverbin- dungen eingesetzt werden.9. The method according to any one of claims 1 to 8, characterized in that aliphatic hydroxy compounds are used for the esterification.
10. Verfahren nach Anspruch 9, dadurch gekennzeichnet, daß Zuckerderivate oder OH-haltige Peptide und Proteine eingesetzt werden.10. The method according to claim 9, characterized in that sugar derivatives or OH-containing peptides and proteins are used.
11. Verfahren nach einem der Ansprüche 9 bis 10, dadurch gekennzeichnet, daß Alkohole eingesetzt werden.11. The method according to any one of claims 9 to 10, characterized in that alcohols are used.
12. Verfahren nach einem der Ansprüche 1 bis 11, dadurch gekennzeichnet, daß Basen eingesetzt werden. 12. The method according to any one of claims 1 to 11, characterized in that bases are used.
13. Verfahren nach Anspruch 12, dadurch gekennzeichnet, daß DBU eingesetzt wird.13. The method according to claim 12, characterized in that DBU is used.
14. Verfahren nach einem der Ansprüche 1 bis 13, dadurch gekennzeichnet, daß annähernd äquimolare Mengen an Hydroxyverbin- dungen und Perfluoralkylsulfonylfluoriden eingesetzt werden. 14. The method according to any one of claims 1 to 13, characterized in that approximately equimolar amounts of hydroxy compounds and perfluoroalkylsulfonyl fluorides are used.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2001121741 DE10121741A1 (en) | 2001-05-04 | 2001-05-04 | Process for the synthesis of low-carrier · 18 · F labeled compounds |
| DE10121741.2 | 2001-05-04 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2002090298A2 true WO2002090298A2 (en) | 2002-11-14 |
| WO2002090298A3 WO2002090298A3 (en) | 2003-03-06 |
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ID=7683635
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/DE2002/001548 WO2002090298A2 (en) | 2001-05-04 | 2002-04-26 | Method for the synthesis of 18f marked compounds which are low in carriers |
Country Status (2)
| Country | Link |
|---|---|
| DE (1) | DE10121741A1 (en) |
| WO (1) | WO2002090298A2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010000409A2 (en) * | 2008-07-03 | 2010-01-07 | Bayer Schering Pharma Aktiengesellschaft | Compounds and processes for production of radiopharmaceuticals |
| WO2010007363A2 (en) * | 2008-07-15 | 2010-01-21 | Isis Innovation Limited | Preparation of fluorine-labelled compounds |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994024098A1 (en) * | 1993-04-20 | 1994-10-27 | Schering Aktiengesellschaft | Ξ-fluorosulphonimides, method of preparing them and their use as fluorination agents |
| WO1999011590A1 (en) * | 1997-09-03 | 1999-03-11 | Immunomedics, Inc. | Fluorination of proteins and peptides for f-18 positron emission tomography |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3424525A1 (en) * | 1984-07-04 | 1986-01-16 | Kernforschungsanlage Jülich GmbH, 5170 Jülich | METHOD FOR PRODUCING (ARROW UP) 1 (ARROW UP) (ARROW UP) 8 (ARROW UP) F-ALKYL AND ARYL COMPOUNDS BY HALOGEN EXCHANGE |
| US6248889B1 (en) * | 1998-11-20 | 2001-06-19 | 3M Innovative Properties Company | Process for converting an alcohol to the corresponding fluoride |
-
2001
- 2001-05-04 DE DE2001121741 patent/DE10121741A1/en not_active Withdrawn
-
2002
- 2002-04-26 WO PCT/DE2002/001548 patent/WO2002090298A2/en not_active Application Discontinuation
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994024098A1 (en) * | 1993-04-20 | 1994-10-27 | Schering Aktiengesellschaft | Ξ-fluorosulphonimides, method of preparing them and their use as fluorination agents |
| WO1999011590A1 (en) * | 1997-09-03 | 1999-03-11 | Immunomedics, Inc. | Fluorination of proteins and peptides for f-18 positron emission tomography |
Non-Patent Citations (1)
| Title |
|---|
| BENNUA-SKALMOWSKI B ET AL: "A facile conversion of primary or secondary alcohols with n-perfluorobutanesulfonyl fluoride/1,8-diazabicyclo[5.4.0Üundec-7-en e into their corresponding fluorides" TETRAHEDRON LETTERS, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, Bd. 36, Nr. 15, 1995, Seiten 2611-2613, XP002120040 ISSN: 0040-4039 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010000409A2 (en) * | 2008-07-03 | 2010-01-07 | Bayer Schering Pharma Aktiengesellschaft | Compounds and processes for production of radiopharmaceuticals |
| WO2010000409A3 (en) * | 2008-07-03 | 2010-03-04 | Bayer Schering Pharma Aktiengesellschaft | Compounds and processes for production of radiopharmaceuticals |
| JP2011526267A (en) * | 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 | Compound and radiopharmaceutical production method |
| WO2010007363A2 (en) * | 2008-07-15 | 2010-01-21 | Isis Innovation Limited | Preparation of fluorine-labelled compounds |
| WO2010007363A3 (en) * | 2008-07-15 | 2010-07-01 | Isis Innovation Limited | Preparation of fluorine-labelled compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2002090298A3 (en) | 2003-03-06 |
| DE10121741A1 (en) | 2002-11-14 |
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