WO2004056725A1 - Solid-phase preparation of 18f-labelled amino acids - Google Patents
Solid-phase preparation of 18f-labelled amino acids Download PDFInfo
- Publication number
- WO2004056725A1 WO2004056725A1 PCT/GB2003/005576 GB0305576W WO2004056725A1 WO 2004056725 A1 WO2004056725 A1 WO 2004056725A1 GB 0305576 W GB0305576 W GB 0305576W WO 2004056725 A1 WO2004056725 A1 WO 2004056725A1
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- WO
- WIPO (PCT)
- Prior art keywords
- formula
- tracer
- compound
- removal
- labelled
- Prior art date
Links
- 0 C*[C@](C)C1CCCC1 Chemical compound C*[C@](C)C1CCCC1 0.000 description 6
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
-
- 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
- A61K51/0404—Lipids, e.g. triglycerides; Polycationic carriers
- A61K51/0406—Amines, polyamines, e.g. spermine, spermidine, amino acids, (bis)guanidines
-
- 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
- C07B59/001—Acyclic or carbocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
- C07C309/68—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a carbon skeleton substituted by singly-bound oxygen atoms
Definitions
- the present invention relates to novel solid-phase processes for the production of radiolabelled tracers, in particular for the production of 18 F-labelled amino acids which may be suitable for use as Positron Emission Tomography (PET) radiotracers.
- PET Positron Emission Tomography
- the invention also comprises radiopharmaceutical kits using these novel processes.
- the favoured radioisotope for PET, 18 F has a relatively short half-life of 110 minutes.
- 18 F-labelled tracers for PET therefore have to be synthesised and purified as rapidly as possible, and ideally within one hour of clinical use.
- Standard synthetic methods for introducing fluorine-18 are relatively slow and require post-reaction purification (for example, by HPLC) which means that it is difficult to obtain the 18 F-labelled tracer for clinical use in good radiochemical yield.
- post-reaction purification for example, by HPLC
- the present invention provides solid-phase processes for producing 18 F-labelled amino acids quickly and with high specific activity yet avoiding time-consuming purification steps, such that the resultant 18 F-labelled amino acid is suitable for use in PET.
- the solid-phase methods also lend themselves to automation with advantages of ease of production and greater throughput.
- the invention also comprises radiopharmaceutical kits which use such processes and thus provide the radiopharmacist or clinician with a convenient means of preparing an 18 F- labelled amino acid.
- 18 F-labelled amino acids useful for tumour imaging are described in US 5,808,146, an especially preferred example of such an amino acid being [ 18 F]-1- amino-3-fluorocyclobutane-1 -carboxylic acid ([ 18 F]-FACBC).
- Solid-phase nucleophilicfluorination methods are described in co-pending International Patent Application PCT/GB02/02505.
- the invention provides a process for the production of an 18 F- labelled tracer which comprises treatment of a solid support-bound precursor of formula (I):
- TRACER is of formula (A):
- P 1 is hydroxy or a protecting group
- P 2 and P 3 are independently hydrogen or a protecting group
- R 2 is hydrogen or together with R 1 forms R 3 ;
- R 1 , R 2 , y, z, P 1 , P 2 and P 3 are as defined for the compound of formula (I), optionally followed by
- R 1 and R 2 form the group R 3 , and more preferably, x is 0, y is 1 , z is 2, q is 1 , m is 0 and j is 0.
- the 18 F-labelled tracer of formula (II) may be cleaned up by removal of excess F " , for example by ion-exchange chromatography and/or by removal of any organic solvent, for example by evaporation. Any protecting groups may be removed, and other simple processing steps such as passing through a C purification column or evaporation may be performed.
- the resultant 18 F-labelled tracer of formula (II) may then be further made-up into an aqueous formulation for clinical use.
- the compound of formula (I) may be conveniently prepared from any suitable commercially available resin, such as Merrifield Resin, NovaSyn ® TG Bromo Resin, (Bromomethyl)phenoxymethyl polystyrene, or Wang Resin which may be reacted with a compound (the LINKER) that is functionalised with a sulphonyl fluoride or sulphonyl chloride at one end and with a reactive functionalisation, for example, a carboxylic acid, at the other end.
- a suitable commercially available resin such as Merrifield Resin, NovaSyn ® TG Bromo Resin, (Bromomethyl)phenoxymethyl polystyrene, or Wang Resin
- the LINKER that is functionalised with a sulphonyl fluoride or sulphonyl chloride at one end and with a reactive functionalisation, for example, a carboxylic acid, at the other end.
- This may be carried out by treating an amine functionalised resin with a linker compound having both a sulphonyl fluoride and an acid chloride functionality, in an appropriate inert solvent such as dichloromethane, chloroform, oracetonitrile, and heating at elevated temperature for a period of time.
- an appropriate inert solvent such as dichloromethane, chloroform, oracetonitrile
- the excess reagent may then be removed from the resin by washing with further portions of the inert solvent.
- the sulphonyl chloride resin may then be reacted with the alcohol analogue of the tracer to produce the resin-bound precursor of formula (I).
- This may be carried out by treating the resin with a solution of the alcohol in an inert solvent such as chloroform, dichloromethane, acetonitrile, dioxane, or tetrahydrofuran containing a non-nucleophilic soluble base such as sodium hydride or a trialkylamine, for example triethylamine or diisopropylethylamine.
- an inert solvent such as chloroform, dichloromethane, acetonitrile, dioxane, or tetrahydrofuran containing a non-nucleophilic soluble base such as sodium hydride or a trialkylamine, for example triethylamine or diisopropylethylamine.
- the reaction may be carried out at a temperature of 10 to 80°C, optimally at ambient temperature for a period of from around 1 to 72 hours.
- the excess alcohol and base may then be removed from the solid support by washing with further portions of an inert
- the "SOLID SUPPORT” may be any suitable solid-phase support which is insoluble in any solvents to be used in the process but to which the LINKER and/or TRACER can be covalently bound.
- suitable SOLID SUPPORT include polymers such as polystyrene (which may be block grafted, for example with polyethylene glycol), polyacrylamide, or polypropylene or glass or silicon coated with such a polymer.
- the solid support may be in the form of small discrete particles such as beads or pins, or as a coating on the inner surface of a cartridge or on a microfabricated vessel.
- the "LINKER” may be any suitable organic group which serves to space the reactive site sufficiently from the solid support structure so as to maximise reactivity.
- the LINKER comprises zero to four aryl groups (suitably phenyl) and/or a C ⁇ - ⁇ 6 alkyl (suitably C h alky!) or C ⁇ _ ⁇ 6 ha!oalkyl (suitably C ⁇ - 6 haloalkyl), typically C ⁇ _ ⁇ fluoroalkyl (suitably C ⁇ _ 6 fluoroalkyl) , or or Ci-i ⁇ haloalkoxy (suitably C ⁇ alkoxy or Ci- ⁇ haloalkoxy) typically C- M6 fluoroalkoxy (suitably C- ⁇ - 6 fluoroalkoxy) , and optionally one to four additional functional groups such as amide or sulphonamide groups.
- Examples of such linkers are well known to those skilled in the art of solid-phase chemistry, but include:
- k is an integer of 0 to 3
- n is an integer of 1 to 16
- R L is hydrogen or C- ⁇ - 6 alkyl.
- any protecting groups in the TRACER may be rerhoved by simple procedures which are also standard in the art. Suitable protection and deprotection methodologies may be found, for example, in Protecting Groups in Organic Synthesis, Theodora W. Greene and Peter G. M. Wuts, published by John Wiley & Sons Inc.
- Preferred carboxylic acid protecting groups, P 1 include C 1 - 6 alkyl esters.
- Preferred amine protecting groups P 2 and P 3 include butoxycarbonyl, formamide, tosylate, fluorenylmethoxy carbonyl, trifluoroacetamide, succinimide, and phthalimide.
- Treatment of the compound of formula (I) with 18 F " may be effected by treatment with any suitable source of 18 F ⁇ such as Na 18 F, K 18 F, Cs 18 F, tetraalkylammonium 18 F fluoride, or tetraalkylphosphonium 18 F fluoride.
- a phase transfer catalyst such as 4,7,13,16,21 ,24 hexaoxa-1 ,10- diazabicyclo[8,8,8] hexacosane may be added and the reaction performed in a non protic solvent. These conditions give reactive fluoride ions.
- the treatment with 18 F " is suitably effected in the presence of a suitable organic solvent such as acetonitrile, dimethylformamide, dimethylsulphox.de, tetrahydrofuran, dioxan, 1,2 dimethoxyethane, sulpholane, N-methylpyrolidinineone, at a non-extreme temperature, for example, 15°C to 180°C, preferably at elevated temperature.
- a suitable organic solvent such as acetonitrile, dimethylformamide, dimethylsulphox.de, tetrahydrofuran, dioxan, 1,2 dimethoxyethane, sulpholane, N-methylpyrolidinineone
- a suitable organic solvent such as acetonitrile, dimethylformamide, dimethylsulphox.de, tetrahydrofuran, dioxan, 1,2 dimethoxyethane, sulpholane, N-methylpyrolidinineone
- Any excess 18 F " may be removed from the solution of 18 F-tracer by any suitable means, for example by ion-exchange chromatography or solid phase absorbents.
- Suitable ion-exchange resins include BIO-RAD AG 1-X8 or Waters QMA and suitable solid phase absorbents include alumina.
- the excess 18 F " may be removed using such solid phases at room temperature in aprotic solvents.
- Any organic solvent may be removed by any standard method such as by evaporation at elevated temperature in vacuo or by passing a stream of inert gas such as nitrogen or argon over the solution.
- the 18 F-labelled tracer Before use of the 18 F-labelled tracer, it may be appropriate to formulate it, for example as an aqueous solution by dissolving the 18 F-labelled tracer in sterile isotonic saline which may contain up to 10% of a suitable organic solvent such as ethanol, or a suitable buffered solution such as a phosphate buffer. Other additives may be added such as ascorbic acid to reduce radiolysis.
- a suitable organic solvent such as ethanol
- a suitable buffered solution such as a phosphate buffer.
- Other additives may be added such as ascorbic acid to reduce radiolysis.
- the present invention provides, a process for the production of [ 18 F]-1-amino-3-fluorocyclobutane-1 -carboxylic acid ([ 18 F]-FACBC) which comprises treatment of a solid support-bound precursor of formula (la):
- P *2a . and P are each independently hydrogen or a protecting group
- P >1a is hydroxyl or a protecting group; with F " to produce the labelled tracer of formula (lla)
- P 1a , P 2a , and P 3a are each as defined in Formula (la); optionally followed by
- the LINKER is preferably
- R L is hydrogen or C ⁇ . 6 alkyl, n is 1 to 16, and k is 0 to 3.
- the SOLID SUPPORT is suitably a polystyrene resin.
- Removal of any protecting groups from the compound of formula (lla) may be effected by standard methods as referred to above.
- the carboxylic acid groups are protected as esters, suitably C 1 - 6 alkanoic esters, preferably as acetate esters, and the amine groups may be protected with an C-i- ⁇ alkoxy carbonyl, preferably t-butoxycarbonyl group.
- Such protecting groups may be conveniently removed by hydrolysis, for example in the presence of acid or base. Such deprotection may be effected on using solid supported acid or base catalysts that render the need for post deprotection neutralisation unnecessary
- the advantages of such solid-phase processes for preparation of 18 F-labelled tracers include the relative speed of the process, simplified purification methods and ease of automation- all of which mean that the processes are suitable for preparation of 18 F-labelled tracers for use in PET. Accordingly, the present invention provides the a process for the production of a 18 F-labelled tracer of formula (II) or (lla) for use in PET.
- the solid support bound precursor of formula (I) or (la) could be provided as part of a kit to a radiopharmacy.
- the kit may contain a cartridge which can be plugged into a suitably adapted automated synthesiser.
- the cartridge may contain, apart from the solid support-bound precursor, a column to remove unwanted fluoride ion, and an appropriate vessel connected so as to allow the reaction mixture to be evaporated and allow the product to be formulated as required.
- the reagents and solvents and other consumables required for the synthesis may also be included together with a compact disc carrying the software which allows the synthesiser to be operated in a way so as to meet the customers requirements for radioactive concentration, volumes, time of delivery etc.
- all components of the kit are disposable to minimise the possibilities of contamination between runs and may be sterile and quality assured.
- the invention further provides a radiopharmaceutical kit for the preparation of an 18 F-labelled tracer for use in PET, which comprises:
- the invention further provides a cartridge for a radiopharmaceutical kit for the preparation of an 18 F-labelled tracer for use in PET which comprises: (i) a vessel containing a compound of formula (I) or (la); and (ii) means for eluting the vessel with a source of 18 F " '
- a method for obtaining a diagnostic PET image which comprises the step of using a radiopharmaceutical kit or a cartridge for a radiopharmaceutical kit as described above.
- the pH of the reaction mixture was adjusted to 6.2 ⁇ 7.0 by adding 3N aqueous HCI and the mixture was stirred at 25 °C for another 20 min- It was extracted with CH 2 CI 2 , washed with water and concentrated under reduced pressure. The oil residue was dissolved in acetone (38 ml) and the solution was added to a stirring mixture of 2-methyl-butene-2 (36 ml), NaH 2 PO 4 (4.0 g, 30 mmol), NaCIO 2 (5.0 g, 55 mmol) and water (40 ml) at 0-5 °C. The reaction mixture was stirred at 10-15 °C for 2h.
- the acyl chloride (E) was prepared by adding 2 drops of dry DMF (Aldrich) to a dry DCM solution (4 mL; Aldrich)) of the corresponding acid (0.79 g, 2.2 mmol) and ; oxalyl chloride (0.38 mL, 4.4 mmol, Aldrich). Gas was released over ten minutes and the mixture stirred for 1 hour at room temperature. The resulting solution was evaporated under reduced pressure and the residue dissolved in 2 mL of dry DCM.
- Example 1 (vii) To a portion of the resin (prepared as described in Example 1 (vii)) held in a cartridge is added a solution in dry acetonitrile of kryptofix, potassium carbonate and [ 18 F]-fluoride. The suspension is heated to 85°C for 10 minutes and then the solution is filtered off. The solution is then passed onto a C ⁇ solid phase extraction cartridge and washed with water to remove acetonitrile, kryptofix and potassium carbonate. Addition of more acetonitrile washes the radiofluorinated product of the cartridge into a solution of 6 M HCI. This solution is heated for 5 minutes at 130°C before neutralization and analysis.
- the resin is swelled in pyridine/DCM (1:1) and to this is added 1-[/V-(f- butoxycarbonyl)amino]-3-hydroxymethyl-1 -cyclobutane-1 -carboxylic acid f-butyl ester.
- the reaction is monitored via a test for the complete consumption of the sulfonyl chloride: several beads are placed in a solution of 5% ethylenediamine in DMF for five minutes; these beads are then thoroughly washed (DMF x3, DCM x3, THFx3) and then is treated with a solution of 1% bromophenol blue in dimethylacetamine. The beads are then washed with DMF five times. Blue beads indicate the presence of sulfonyl chloride groups on the resin, but if the beads are white (or off white) the reaction has finished.
- [ 18 F] FMeACBC may be prepared from the intermediate of Example 3(i) with analogous chemistry using [ 18 F] potassium fluoride.
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE60315709T DE60315709T2 (en) | 2002-12-20 | 2003-12-19 | Solid Phase Preparation of 18F-labeled Amino Acids |
AU2003290295A AU2003290295A1 (en) | 2002-12-20 | 2003-12-19 | Solid-phase preparation of 18f-labelled amino acids |
US10/539,165 US7264792B2 (en) | 2002-12-20 | 2003-12-19 | Solid phase preparation of 18F-labelled amino acids |
JP2004561654A JP2006510706A (en) | 2002-12-20 | 2003-12-19 | Solid phase production of 18F-labeled amino acids |
EP03782656A EP1572601B1 (en) | 2002-12-20 | 2003-12-19 | Solid-phase preparation of 18 f-labelled amino acids |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB0229695.2A GB0229695D0 (en) | 2002-12-20 | 2002-12-20 | Solid-phase preparation of 18F-labelled amino acids |
GB0229695.2 | 2002-12-20 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2004056725A1 true WO2004056725A1 (en) | 2004-07-08 |
Family
ID=9950069
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB2003/005576 WO2004056725A1 (en) | 2002-12-20 | 2003-12-19 | Solid-phase preparation of 18f-labelled amino acids |
Country Status (9)
Country | Link |
---|---|
US (1) | US7264792B2 (en) |
EP (1) | EP1572601B1 (en) |
JP (1) | JP2006510706A (en) |
AT (1) | ATE370109T1 (en) |
AU (1) | AU2003290295A1 (en) |
DE (1) | DE60315709T2 (en) |
ES (1) | ES2290528T3 (en) |
GB (1) | GB0229695D0 (en) |
WO (1) | WO2004056725A1 (en) |
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WO2007066089A3 (en) * | 2005-12-06 | 2007-11-08 | Ge Healthcare Ltd | Radiolabelling method using polymers |
EP1893246A2 (en) * | 2005-06-23 | 2008-03-05 | Emory University | Stereoselective synthesis of amino acid analogs for tumor imaging |
WO2008075522A1 (en) | 2006-12-21 | 2008-06-26 | Nihon Medi-Physics Co., Ltd. | Radioactive diagnostic imaging agent |
WO2008078589A1 (en) | 2006-12-27 | 2008-07-03 | Nihon Medi-Physics Co., Ltd. | Process for production of precursor compound for radioactive halogen-labeled organic compound |
EP2080526A1 (en) * | 2006-11-09 | 2009-07-22 | Nihon Medi-Physics Co., Ltd. | Radioactive diagnostic imaging agent |
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WO2011099480A1 (en) * | 2010-02-12 | 2011-08-18 | 国立大学法人東京工業大学 | Method for producing 18f-labeled compound and high molecular compound to be used in the method |
US8269035B2 (en) | 2007-12-19 | 2012-09-18 | Nihon Medi-Physics Co., Ltd. | Process for production of radioactive-fluorine-labeled organic compound |
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- 2002-12-20 GB GBGB0229695.2A patent/GB0229695D0/en not_active Ceased
-
2003
- 2003-12-19 DE DE60315709T patent/DE60315709T2/en not_active Expired - Lifetime
- 2003-12-19 EP EP03782656A patent/EP1572601B1/en not_active Expired - Lifetime
- 2003-12-19 US US10/539,165 patent/US7264792B2/en not_active Expired - Fee Related
- 2003-12-19 WO PCT/GB2003/005576 patent/WO2004056725A1/en active IP Right Grant
- 2003-12-19 JP JP2004561654A patent/JP2006510706A/en not_active Ceased
- 2003-12-19 AT AT03782656T patent/ATE370109T1/en not_active IP Right Cessation
- 2003-12-19 AU AU2003290295A patent/AU2003290295A1/en not_active Abandoned
- 2003-12-19 ES ES03782656T patent/ES2290528T3/en not_active Expired - Lifetime
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US20060039855A1 (en) | 2006-02-23 |
JP2006510706A (en) | 2006-03-30 |
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EP1572601B1 (en) | 2007-08-15 |
AU2003290295A1 (en) | 2004-07-14 |
ATE370109T1 (en) | 2007-09-15 |
EP1572601A1 (en) | 2005-09-14 |
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