• 专利附录
  • 专利说明
  • 权利要求
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  • 优先权
    • 专利摘要:
    The present invention relates to a process for the purification of [18F] labeled choline analogues for solution for injection to a patient, prepared using non-gas synthetic routes, comprising a solid phase extraction purification step (SPE ) using a solid support, in which the solid support used in the purification by solid phase extraction has the particularity of retaining the impurities and reagents contained in said solution, but not the choline analogues labeled with {18F}.
    公开号:BE1021314B1
    申请号:E2014/0415
    申请日:2014-06-02
    公开日:2015-10-28
    发明作者:Muhammad Otabashi；Gauthier Philippart；Samuel Voccia；Jean-Luc Morelle
    申请人:Trasis S.A.；
    IPC主号:
    专利说明:

    Process for purifying M8F1-labeled choline analogs FIELD OF THE INVENTION
    The present invention relates to a simplified process for the purification of [18F] labeled choline analogs. This simplification makes it easier to automate such radiotracer syntheses. BACKGROUND AND TECHNOLOGY Positron emission tomography [0002] Positron emission tomography (PET) is an imaging method for obtaining quantitative molecular and biochemical information on physiological processes in the body. The most commonly used PET radiopharmaceutical today is [18F] -fluorodeoxyglucose ([18F] -FDG), a radiolabelled glucose molecule. [18F] -FDG PET imaging visualizes glucose metabolism and has a wide range of clinical indications. Among the positron emitters, [18F] is the most widely used today in the clinical environment. Today, due to increasing regulatory pressure, radiopharmaceuticals are usually prepared on single-use components assembled in ready-to-use cassettes.
    [18F] labeled choline analogs (data extracted from the MICAD database) Choline is an important component of phospholipids in cell membranes. Tissues with increased metabolism will result in increased absorption of choline. Choline is phosphorylated by choline kinases (CHK) to phosphorylcholine in cells, and is, after several biosynthetic processes, ultimately incorporated into phospholipids (Zeisel SH, Blusztajn JK Choline and human nutrition, Annu Rev Nutr 1994; 14: 269). -96.). Because tumor cells have a high metabolic rate, choline uptake is high in order to cope with the demand for phospholipid synthesis in their cell membranes (Podo F. Tumor Phospholipid Metabolism, NMR Biomed 1999; ): 413 - 39.).
    [0004] Positron emission tomography (PET) with [11C] -choline has proved useful for the detection and differential diagnosis of brain tumors, prostate cancer, lung cancer and cancer of the lungs. Esophagus (Hara T. [11C] -choline and 2-deoxy-2- [18F] fluoro-D-glucose in tumor imaging with positron emission tomography, Mol Imaging Biol.2002; 4 (4): 267-73). However, [11C] -choline has a strong absorption in the liver, kidneys and spleen. A [18F] -labeled choline analog was initially synthesized as [18F] -fluoroethylcholine to replace [11C] -choline as a PET scribe because of the short half-life of [11C] (Hara T., Yuasa M. Automated synthesis of fluorine-18 labeled choline analogue: 2-fluoroetheyl-dimethyl-2-oxyethylammonium J Nucl Med oxyethylammonium 1997; 38 Supplement: 44P). Although [18F] has a longer half-life (110 min.), [18F] -fluoroethylcholine has shown rapid accumulation in the bladder, making it less desirable for imaging prostate cancer and lymph nodes pelvic lymphatics. As a result, [18F] -fluorocholine (FCH) was designed to be a better biological analogue than [18F] -fluoroethylcholine (DeGrado TR, Coleman RE, Wang S., Baldwin SW, Orr MD, Robertson CN, Polascik TJ , DT Price Synthesis and Evaluation of 18F-labeled choline as an oncology tracer for positron emission tomography: initial findings in prostate cancer, Cancer Res 2001; 61 (1): 110-7). FCH PET studies have shown strong uptake in malignant tumors in prostate cancer, breast carcinoma, and brain tumor patients (DeGrado TR, Baldwin SW, Wang S, Orr MD, Liao RP, Friedman HS, Reiman R., Price DT, Coleman RE Synthesis and evaluation of (18) F-labeled choline analogs as oncology PET tracers J Nucl Med 2001; 42 (12): 1805-14; Hara T., Kondo T Hara T., Kosaka N. Use of 18F-choline and 11C-choline as contrast agents in positron emission tomography imaging-guided stereotactic biopsy sampling of gliomas J Neurosurg 2003; 99 (3): 474-9.).
    Methods of synthesis [0005] Standard method involving gaseous intermediates:
    [18F] -choline is generally synthesized from [18F] -fluorobromomethane and dimethylethanolamine (DMEA) with a radiochemical purity greater than 98% and a radiochemical yield (uncorrected for disintegration) for the synthesis and purification of about 20-40%. (DeGrado TR, Coleman RE, Wang S., Baldwin SW, Orr MD, Robert Robertson, Polascik TJ, Price DT Synthesis and evaluation of 18F-labeled choline as an oncology tracer for positron emission tomography: initial findings in prostate cancer. 2001; 61 (1): 110-7). In an article by D. Kryza et al. (Fully automated [18F] fluorocholine synthesis in the TracerLab MXFDG Coincidence synthesizer, Nucl.Med.Biol 35 (2), 2008: 255-260), [18F] -Fluorocholine was prepared by N-alkylation of the DMEA with [18F] -fluorobromomethane (BrCFhF), followed by purification on a CM cartridge.
    Another method of automated synthesis FCH was carried out from the formation of [18F] -fluoromethyltriflate and its reaction with the DMEA on a Sep-Pak column. The total time required to obtain the finished chemical was 30 min. The radiochemical yield (corrected for disintegration) was 80% with radiochemical purity and chemical purity of> 98%. (Iwata R., Pascali C., Bogni A., Furumoto S., Terasaki K., Yanai K. [18F] fluoromethyl triflate, a novel and reactive [18F] fluoromethylating agent: Preparation and application to the on-column preparation of [18F] fluorocholine, Appl Radiat lsot.2002; 57 (3): 347-52.).
    [0007] Alternative methods using ditosylates as a precursor: G.Smith et al. (Nucl Med Biol 2011 Jan, 38 (1): 39-51) compared the synthesis of [18F] -fluorocholine by alkylation of the appropriate precursor, ie, DMEA, with [18F] -fluorobromomethane or [18F] -fluorométhyltosylate. Alkylation with [18F] -fluorotomethylsylate has been shown to be the most reliable radiosynthetic route.
    In WO 2005/009928, J.Lim showed the preparation of [18F] -FCH in a two-step reaction: the fluorination of ditosylmethane with [18F] -fluoride followed by a reaction of alkylation between [18F] fluorinated methyltosylate and dimethylethanolamine using [18F] FCH which was purified using a silica column (Sep-Pak Catalog number WAT023537, Waters Corporation, Milford, MA). The column was washed with ethanol and water to remove all impurities and [18F] FCH was eluted with 2% acetic acid. Acetic acid was then removed using a weakly basic AG4-X4 ion exchange resin column (143-3341, Bio-Rad Laboratories, Inc., Hercules, CA).
    [0009] It has been shown by G. Pascali et al (Dose-on-demand of various 18F-fluorocholine derivatives through a two-step microfluidic approach, Nucl.Med.Biol 38 (5), 2011: 637-644) that the radiolabeling step results in the formation of two [18F] labeled species, among which [18F] -fluoromethane tosylate. In spite of the fact that this process uses non-gaseous intermediates, no purification method is carried out or proposed for the purpose of removing impurities and by-products resulting from this reaction route. Beyerlein et al have demonstrated that the second compound is [18F] -labeled Tosyl Fluoride (Beyerlein et al., J. Label Compd Radiopharm, Vol 56 (14), 2013).
    The presence of cold impurities generated during the quaternization reaction has recently been demonstrated (Rodnick et al., Applied Radiation and Isotopes 78 (2013) 26-32), for example, the reaction of methane ditosylate with DMEA, in particular during marking and quaternization "one-pot", these impurities being present in the final product. These impurities must be removed and until recently, the only method for performing reliable purification was high pressure liquid chromatography.
    PROBLEM TO SOLVE
    It has been demonstrated that [18F] choline is the best analog of choline labeled [18F], However, the most commonly used synthetic route for this tracer involves a step of gas chromatography, to know how to handle a gaseous radioactive compound. This gas chromatography step is very time-consuming to implement, in particular on systems based on single-use cassettes, and any leaks make the production of this radiopharmaceutical critical. Alternative synthesis methods are therefore highly desirable.
    Among the alternatives, the use of a non-gaseous synthesis route using non-gaseous quaternization agents, for example the use of [18F] -fluoromethyltosylate, has been proposed, but these alternative routes still require purification. by HPLC of the final product due to the presence in the crude product of undesirable impurities. Due to the short life of radioisotopes, the purification process is a key element in the production of a radiopharmaceutical. Thus, if long and non-recoverable steps of HPLC purification can be avoided, this represents a huge advantage. The method of choice must also be sufficiently effective and reliable to ensure a high level of radiochemical purity.
    PURPOSE OF THE INVENTION
    The present invention aims to make the non-gaseous pathways for the synthesis of [18F] labeled choline analogs, for example the pathway using ditosylate methane, easy to automate by allowing a "one pot" synthesis, while avoiding the need for HPLC purification of the crude analog of [18F] labeled choline,
    BRIEF DESCRIPTION OF THE DRAWINGS
    Figure 1 shows an impurity chromatogram for an example of synthesis of [18F] FCH before purification SPE.
    FIG. 2 represents an impurity chromatogram for the same example of the synthesis of [18F] FCH after purification with SPE.
    DESCRIPTION OF THE INVENTION
    The process of the present invention allows the synthesis and purification of [18F] labeled choline analogs prepared using non-gaseous synthetic pathways (as opposed to the pathway involving the phase chromatography step). gaseous with [18F] -bromofluoromethane), comprising the following successive steps: - reacting the fluoride [18F] in a solution of an alkylating agent having a tosylate as leaving group, to give a tosylate compound [18F]; reacting said tosylate compound [18F] with dimethylethanolamine (DMEA) to give a crude solution of fluorocholine analogues [18F]; performing a first purification of this crude solution of fluorocholine analogues [18F] on a solid cation-exchange support; carry out a second purification on the elution product of this first purification, on a solid support selected from the group consisting of solid phase extraction resins and liquid chromatography resins having a structure offering polar / non-polar properties polar and / or hydrophilic / lipophilic intermediates in order to retain impurities and reagents which are essentially non-polar products, including aromatic quaternization impurities, characterized in that the structure of the solid support of this second purification results from the copolymerization of divinylbenzene and / or styrene with a vinyl co-monomer compound, or comprises a graphite carbon phase.
    In addition, the resulting tracer solution is directly injectable to a patient. This has two advantages: the reduction in the preparation time, which results in an increase in the overall yield, and a simplification of the automated equipment necessary for the synthesis of a radiopharmaceutical product. In particular, the removal of any purification step by FIPLC facilitates the automation of the synthesis.
    The solid support of the second purification has the characteristic of retaining the quaternization products and non-polar products (such as the precursor), but to pass the choline analogs marked with [18F] in an aqueous solution.
    In certain preferred embodiments of the invention, the solid support is obtained perfunctionalization of the surface of preformed beads consisting of (co) polymers of divinylbenzene and / or styrene by copolymerization with a vinylic comonomer compound.
    Suitable vinyl compounds used for the copolymerization or surface functionalization include vinylpyrrolidone, vinyl acetate, (methacryloyloxymethyl) naphthalene, 4,4'-bis (maleimido) diphenylmethane, ester ρ, ρ'-diglycidylmethacrylic acid dihydroxydiphenylmethane, p-dihydroxydiphenylpropane diglycidyl methacryl ester, 2-hydroxyethyl methacrylate (HEMA), 2,2-dimethylaminoethyl methacrylate (DMAEMA), glycidyl ethylenedimethacrylate methacrylate, N-vinylcarbazole, acrylonitrile, vinylpyridine, N-methyl-N-vinylacetamide, aminostyrene, methyl acrylate, ethyl acrylate, methyl methacrylate, N-vinylcaprolactam, N-methyl-N-vinylacetamide. Trademark names for these solid media are Waters Oasis® HLB, Mallinckrodt ™ JBBaker® H20-philic DVB, Phoeomenex® Waters Porapak ™ RDX, Strata-X ™ and Synergi ™ Polar-RP, etc.
    [0021] Trademark names for solid supports having a graphite carbon phase are Hypercarb ™ from Thermo Electron Corp and Carbograph from Alltech.
    EXAMPLE
    This example shows how the crude product of a synthesis [18F] -FCH with the synthetic route below can be purified using Strata-X ™ Phenomenex® cartridges, containing a phase-functionalized polymeric sorbent inverted which gives strong retention of neutral, acidic or basic compounds under high aggressive organic washing conditions. This sorbent is based on three retention mechanisms: the pi-pi bond, the hydrogen bond (bipole-bipole interactions) and the hydrophobic interaction.
    [18F] -FCH was prepared in two main chemical steps from the starting reagent, methylene bis (toluene-4-sulfonate). This reagent reacts with [18F] -fluoride to give [18F] -fluoromethylene-toluene-4-sulfonate. This compound is allowed to react with dimethylaminoethanol (DMEA) to give [18F] -FCFI. The crude solution is purified on a cation exchange cartridge on which the [18F] -FCH is trapped. The [18F] -FCH is then eluted from the cartridge and passes through the purification cartridges directly to the vial of the crude product.
    The [18F] -FCH obtained according to the preparation route above shows the presence of an impurity which is a quaternization product resulting from the reaction between the DMEA and methylene bis (toluene-4-sulfonate). The chromatograms obtained before and after the SPE purification (Phenomenex® Strata-X ™) are shown in FIGS. 1 and 2 respectively. This demonstrates the ability of the purification method described in this patent to eliminate these quaternized impurities.
    权利要求:
    Claims (5)
    [1]
    NEW CLAIMS GAME
    A process for the synthesis and purification of [18F] labeled choline analogs for a solution for injection to a patient, prepared using non-gaseous synthetic routes, comprising the following successive steps: - reacting fluoride [ 18F] in a solution of an alkylating agent having a tosylate leaving group to give a tosylate compound [18F]; reacting said tosylate compound [18F] with dimethylethanolamine (DMEA) to give a crude solution of fluorocholine analogues [18F]; performing a first purification of this crude solution of fluorocholine analogues [18F] on a solid cation-exchange support; carry out a second purification on the elution product of this first purification, on a solid support selected from the group consisting of solid phase extraction resins and liquid chromatography resins having a structure offering polar / non-polar properties polar and / or hydrophilic / lipophilic intermediates in order to retain impurities and reagents which are essentially non-polar products, including aromatic quaternization impurities, characterized in that the structure of the solid support of this second purification results from the copolymerization of divinylbenzene and / or styrene with a vinyl comonomer compound, or comprises a graphite carbon phase.
    [2]
    2. The process as claimed in claim 1, in which the vinyl compound used for the copolymerization is chosen from the group consisting of vinylpyrrolidone, vinyl acetate, (methacryloyloxymethyl) naphthalene, 4,4'-bis (maleimido) diphenylmethane, and the ester β'-Diglycidylmethacrylic acid dihydroxydiphenylmethane, diglycidylmethacrylic ester of p, p'-dihydroxydiphenylpropane, 2-hydroxyethyl methacrylate (HEMA), 2,2-dimethylaminoethyl methacrylate (DMAEMA), glycidyl ethylenedimethacrylate methacrylate, N-vinylcarbazole, acrylonitrile, vinylpyridine, N-methyl-N-vinylacetamide, aminostyrene, methyl acrylate, ethyl acrylate, methyl methacrylate, N-vinylcaprolactam and N-methyl-N-vinylacetamide.
    [3]
    3. The method of claim 1, wherein the solid support of the second purification is obtained by functionalization of the surface of preformed beads made of (co) polymers of divinylbenzene and / or styrene by copolymerization with a vinylic comonomer compound.
    [4]
    The process according to claim 1, wherein the alkylating agent having tosylate as the leaving group is methylene bis (toluene-4-sulfonate).
    [5]
    The process according to claim 4, wherein the aromatic quaternization impurity results from the reaction between DMEA and methylene bis (toluene-4-sulfonate).
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    WO2001019484A1|1999-09-13|2001-03-22|Dyax Corporation|Purification device and purification method|
    WO2005009928A2|2003-07-24|2005-02-03|The Queen's Medical Center|Preparation and use of alkylating agents|
    WO2006133732A1|2005-06-17|2006-12-21|Advanced Accelerator Applications|Process for synthesizing labelled compounds|
    EP2121542A1|2007-03-09|2009-11-25|GE Healthcare Limited|Separation process|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US201361830848P| true| 2013-06-04|2013-06-04|
    US61/830848|2013-06-04|
    EP61/830848|2013-06-04|
    EP13183543.1A|EP2845608A1|2013-09-09|2013-09-09|Method for purification of 18F-labeled choline analogues|
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