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    • 专利摘要:
    The present invention relates to a method for the production of radiolabelled nucleoside-based 2-nitroimidazole analogs in a solution, comprising: (i) labeling a nucleoside-protected 2-nitroimidazole precursor compound with a radionuclide of short period by means of nucleophilic substitution; (ii) deprotecting the radiolabelled compound obtained in step (i) by means of alkaline hydrolysis; (iii) purifying the deprotected radiolabelled compound obtained in step (ii) by HPLC chromatographic purification or SPE purification; (iv) the final formulation of the purified deprotected radiolabelled compound obtained in step (iii) in a solution.
    公开号:BE1024388B1
    申请号:E2016/5903
    申请日:2016-12-06
    公开日:2018-02-12
    发明作者:Jean-Luc Morelle；Muhammad Otabashi；Gauthier Philippart；Thomas Vergote
    申请人:Trasis S.A.；
    IPC主号:
    专利说明:

    (73) Holder (s):
    TRASIS S.A. 4000, LIEGE Belgium (72) Inventor (s):
    MORELLE Jean-Luc 4000 LIEGE Belgium
    OTABASHI Muhammad 4000 LIEGE Belgium
    PHILIPPART Gauthier 4280 AVI N Belgium
    VERGOTE Thomas 1350 MARILLES Belgium (54) PROCESS FOR THE PREPARATION OF NITROIMIDAZOLE ANALOGS BASED ON RADIOMARKED NUCLEOSIDE (57) The present invention relates to a process for the production of analogs of 2-nitroimidazole based on radiolabelled nucleoside in a solution, comprising: (i) labeling a nucleoside-based 2-nitroimidazole precursor compound protected with a short-lived radionuclide using nucleophilic substitution; (ii) deprotecting the radiolabelled compound obtained in step (i) by means of alkaline hydrolysis; (iii) purifying the deprotected radiolabelled compound obtained in step (ii) by HPLC chromatographic purification or SPE purification; (iv) the final formulation of the purified deprotected radiolabelled compound obtained in step (iii) in a solution.
    BELGIAN INVENTION PATENT
    FPS Economy, SMEs, Middle Classes & Energy
    Publication number: 1024388 Deposit number: BE2016 / 5903
    Intellectual Property Office International Classification: A61K 51/04 C07B 59/00 A61K 101/02 Date of issue: 12/02/2018
    The Minister of the Economy,
    Having regard to the Paris Convention of March 20, 1883 for the Protection of Industrial Property;
    Considering the law of March 28, 1984 on patents for invention, article 22, for patent applications introduced before September 22, 2014;
    Given Title 1 “Patents for invention” of Book XI of the Code of Economic Law, article XI.24, for patent applications introduced from September 22, 2014;
    Having regard to the Royal Decree of 2 December 1986 relating to the request, the issue and the maintenance in force of invention patents, article 28;
    Given the patent application received by the Intellectual Property Office on 06/12/2016.
    Whereas for patent applications falling within the scope of Title 1, Book XI of the Code of Economic Law (hereinafter CDE), in accordance with article XI. 19, §4, paragraph 2, of the CDE, if the patent application has been the subject of a search report mentioning a lack of unity of invention within the meaning of the §ler of article XI.19 cited above and in the event that the applicant does not limit or file a divisional application in accordance with the results of the search report, the granted patent will be limited to the claims for which the search report has been drawn up.
    Stopped :
    First article. - It is issued to
    TRASIS S.A., Allée du VI Août, Bâtiment B6a, 4000 LIEGE Belgium;
    represented by
    PRONOVEM - Office Van Malderen, Zénobe Gramme business park (building K) - Square des Conduites d'eau 1-2, 4020, LIEGE;
    a Belgian invention patent with a duration of 20 years, subject to payment of the annual fees referred to in article XI.48, §1 of the Code of Economic Law, for: PROCESS FOR PREPARATION
    OF NITROIMIDAZOLE ANALOGS BASED ON RADIOMARKED NUCLEOSIDE.
    INVENTOR (S):
    MORELLE Jean-Luc, Avenue des Ormes 15, 4000, LIEGE;
    OTABASHI Muhammad, Rue Georges Antoine 12, 4000, LIEGE;
    PHILIPPART Gauthier, Rue d'Atrive 49, 4280, AVIN;
    VERGOTE Thomas, Rue du Village 87, 1350, MARILLES;
    PRIORITY (S):
    12/07/2015 EP 15198187.5;
    DIVISION:
    divided from the basic application: filing date of the basic application:
    Article 2. - This patent is granted without prior examination of the patentability of the invention, without guarantee of the merit of the invention or of the accuracy of the description thereof and at the risk and peril of the applicant (s) ( s).
    Brussels, 02/02/2018, By special delegation:
    BE2016 / 5903
    PROCESS FOR THE PREPARATION OF NITROIMIDAZOLE A ANALOGS
    RADSOMARKED NUCLEOSIDE BASE
    Field of the Invention The present invention relates to a process for the production of 2-nitroimidazoI analogs based on radiolabelled nucleosides in an injectable solution.
    Background of the technique Positron emission tomography Positron emission tomography (PET) is an imaging process for obtaining quantitative molecular and biochemical information relating to physiological processes in the body. The most commonly used radiopharmaceutical for PET today is [18F] -fluorodeoxyglucose ([18F] -FDG), a radiolabelled glucose molecule. PET imaging with [18Fj-FDG makes it possible to visualize glucose metabolism and has a wide range of clinical indications. Among the positron emitters, 18F is the most widely used today in clinical environment. Due to the increasing pressure of regulations, radiopharmaceuticals are nowadays usually prepared on single-use components assembled in ready-to-use cassettes.
    Hypoxia of a tumor [0003] In certain cancers, cell growth can develop in poorly vascularized environments. These environments which are isolated from the vasculature or which are poorly vascularized can become hypoxic, being characterized by low levels of tissue pO2. Hypoxia of a tumor has long been considered an important prognostic factor in oncology (J.
    Dunst et al., Tumor Volume and tumor hypoxia in head and neck cancers. The amount of the hypoxic volume is important. Strahlenther Onkol. 2003,179: 521-526; P. Vaupei,
    Hypoxia in cancer: significance and impact on clinical outcome. Metastasis Cancer
    Rev. 2007; 26: 225-239).
    Experimental and clinical evidence has demonstrated a relationship between this phenomenon and the probability of malignant progression, local recurrence and distant metastases (EK. Rofstad, Microenvironment-induced cancer metastasis, tnt J Radiai Biol. 2000 ; 76: 589-605; M. Nordsmark et al., Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy. An international multi-center study. Radioether Oncot. 2005; 77: 18-24).
    BE2016 / 5903 [0005] In addition, hypoxic tumors are clinically problematic since they are usually resistant to both radiotherapy and / or cytotoxic therapy, which can lead to treatment failure and poor results ( LB Harrison et al., Impact of tumor hypoxia and anemia on radiation therapy outcomes. Oncologist 2005, 77: 18-24; J. Overgaard, Hypoxic radiosensitization: adored and ignored. J Clin Oncol. 2007; 25: 4066-4074).
    [0006] Distribution and quantitative information of the oxygen concentration would be a precious tool for improving the treatment methods in order to kill the maximum number of tumor cells with minimal side effects. Given the importance of this aspect, many techniques have been reported to be useful for the detection of hypoxia in tumors (B, Gailez et al ,, Assessment of tumor oxygenation by electron paramagnetic resonance: principles and applications, NMR Biomed. 2004: 17: 240-262; JL. Tatum et al., Hypoxia: importance in tumor biology, noninvasive measurement by imaging, and value of its measurement in the management of cancer therapy, Int J radiai Biol. 2006; 86: 699-757); however, a limited number of procedures have been implemented in clinical practice.
    PET for diagnosing tumor hypoxia [0007] Positron emission tomography (PET) is one of the methods currently available for application to humans. For PET hypoxia imaging, it is recognized that 2-nitroimidazoles are specific for hypoxic cells (A. Nunn et ai., Nitroimidazoles and imaging hypoxia. Eur J Nucl Med. 1995; 22: 265-280) .
    These compounds enter the cells and undergo a succession of reduction steps. In the presence of oxygen, the first step is reversible; therefore, the reduced nitroimidazole is immediately reoxidized and eluted out of the tissue. Under hypoxic conditions, reoxidation is slow, allowing further reduction to occur; ie the compound can thus bind covalently to intracellular macromoiecules and be retained inside the cells. Since it is necessary for the enzyme system to reduce and bind nitroimidazole, these tracers only selectively accumulate in viable hypoxic cells.
    The other advantages of PET are its non-invasive and non-toxic nature; its ability to perform repeated measurements, and the resulting global hypoxia images in three dimensions (IN Fleming et ai ,, imaging tumor hypoxia with positron emission tomography. British J Cane. 2015; 112: 238-250).
    Various first generation 2-nitroimidazole derivatives, including
    BE2016 / 5903 [18F] FMiSO, [18F] FRP-170, (18F] FETNIM, [18F] FETA, and [18F] EF5, have been developed (Fig.1) (Oh et al ·, Fully automated of [18F ] fluoromisonidazole using a conventional [18F] FDG module. Nuc! Med Biol. 2005; 32: 899: 905; Ishikawa et al., Automated preparation of hypoxic cell marker [18F] FRP-170 by on-column hydrolysis. Appl Radiat isot . 2005; 62: 705-710; Gronroos et al., Pharmacokinetics of [18F] FETNIM: a potential marker for PET. J Nuci Med. 2001; 42: 1397-1404; Tewson et al., Synthesis of [18F] fluoroetanidazole : a potential new tracer for imaging hypoxia. Nucl Med Biol. 1997; 24: 755-760; Dolbieretal., [18F] -EF5, a marker for PET detection of hypoxia: synthesis of precursor and a new fluorination procedure. Isot. 2001; 54: 73-80).
    [18F] FMISO was the first PET tracer specific for hypoxia and, although it may be the most frequently used tracer for this purpose, its suitability is limited due to slow tumor-specific accumulation and a non-specific elution (Krohn et al., Molecular imaging of hypoxia. J Nuci Med. 2008; 49 (suppl2): 129S-148S). [ÖÖ11] Second generation 2-nitroimidazole tracers, having different clearance and hydrophilic characteristics, have been developed in an attempt to overcome these drawbacks, among which [18F] HX4 and ie very promising 1 - (5 - [18F] fluoro-5-deoxy-aD-arabinofuranosyi) -2-nitroimidazole, [18F] FAZA (Fig.1) (Dubois et al., Preclinical evaluation and validation of [18F] -HX4, a promising hypoxia marker for PET imaging. Prod Natl Acad Sci USA 2011; 108: 146202 0 14625; Kumar et al., Microwaved assisted (radio) halogenation of nitroimidazole-based hypoxia marker. Appl Radiat isot. 2002; 57: 697-703; Piert et al. , Hypoxia-specific tumor imaging with [18F] -fluoroazomycin arabinose. J Nucl Med. 2005; 46: 106-113; Postema etal., Initial results of hypoxia imaging using [18F) FAZA. Eur J Nucl Med. 2009; 36: 1565-1573). Compared to [18FJFMISO, [18F] FAZA has more favorable tumor / background ratios due to its rapid clearance from the blood and non-target tissues.
    Consequently, high-contrast PET images of a specific uptake of hypoxia have been obtained with this radiopharmaceutical (Reischl et al., Imaging of tumor hypoxia with [124IJIAZA in comparison with [18F] FMISO and [18F] FAZA-first small animal PET results. J Pharm Pharm Sci. 2007; 10: 203-211). [18F] FAZA is currently used clinically in human cancer patients as a PET radiodiagnostic agent to determine the level of hypoxia in solid tumors and develop better treatment plans {Postema et al ·, Hypoxia imaging using [18FJFAZA : the initial results of Phase i / ll study. Eur J Nuci Med Mol
    Imaging 2009; 36: 1565-1573; Lopci et al., PET radiopharmaceuticals for imaging of tumor hypoxia: a review of the evidence. Am J Nucl Med Mol imaging 2014; 4: 3654
    BE2016 / 5903
    384) Structurally, [18F] FAZA is a nucleoside-based 2-nitroimidazole (ie carrying a monosaccharide fragment covalently linked to the 2nitroimidazole fragment, FIG. 1),
    Synthesis process [8813] [18F] FAZA is generally synthesized from the commercially available precursor of 2 ', 3'-diaceiyl-AZA S'-toylate in two stages (Fig. 2). In a first step, [18F] F _ displaces the tosylate leaving group in a nucleophilic substitution reaction at an elevated temperature, ranging from 90 to 120 ° C, for 5 to 10 minutes. Then, the acetylated protecting group is removed from the radiofluoric intermediate by alkaline hydrolysis using a 0.1 N NaOH solution for 3-5 minutes at a temperature ranging from 25 to 5G ° C.
    The pH of the reaction mixture is then neutralized by adding 0.4-0.6 M NahkPO or 0.1 N HCl, and the whole mixture is introduced into a purification system by HPLC for a final chromatographic purification.
    The reported radochemical purity is usually greater than 90% and the radiochemical yields (corrected for decay) for synthesis and purification are approximately 5 to 20% (reaction time approximately 50 minutes, including purification) (Patt et al., Preparation of [18F] fluoromisonidazo! E by nucleophilic
    0 substitution on THP-protected precursor: yield dependence on reaction parameters. J Radioanal Nucl Chem. 1999; 240: 925-927; Nandy et al., Simple, column purification technique for the fully automated radiosynthesis of [18F] fluoroazomycinarabinoside ([18F] FAZA). Applied Radia losot. 2010; 68: 1944-1949; Sorger et al., [18F] Fluoroazomycinarabinofuranoside (18FAZA) and [18F] Fluoromisonidazole (18FMISO): a comparative study of their selective uptake in hypoxic cells and PET imaging in experimental rat tumors. Nucl Med Biol. 2003; 30: 317-326).
    The increasing clinical demands for [18FjFAZA (Beck et al., Pretreatment18F-FAZA PET predicts success of hypoxia-directed radiochemotherapy using tirapazamine. J Nucl Med. 2007; 48: 973-980) require the development of a method of improved and easy manufacturing which can give this product and other products of this class at low cost and without much complication in the synthesis. To achieve these goals, a usual production of high volume radiopharmaceutical requires minimum reproducible yields of 65% (corrected for decay here on a reaction time scale of 50 minutes, or uncorrected for decay of 47%). This objective is currently not achieved.
    [8017] Thermal and chemical degradation (to bases) (mainly by
    BE2016 / 5903 deacetylation (i.e. removal of protective groups) leading to unwanted side reactions) of nucleosides is a common phenomenon (Kumar et al., US 8,969,546 B2). It can lead to poor fluorination during the first stage of the synthesis, but also to degradation of the fluorinated intermediate during the hydrolysis stage, explaining the low yield obtained so far.
    [8818] [18F] F is usually proposed in water enriched in [180] ([IBOjHiO) directly from the cyclotron. The use of an anion exchange cartridge (commonly of the QMA type) to trap [18F] F and separate [ISOjFLO requires an excess amount of base (usually K2CO3) to elute [18F] F ~ from the cartridge to the reactor. This leads to a low precursor to base ratio (P / B) and therefore to low fluorination yields (Suehiro et ai., Investigation of the role of the base in the synthesis of [18F] FLT. Appl Radiai isot . 2007; 65: 1350-1358). Hayashi et al. studied the role of the base in the synthesis of [18F] FAZA focusing only on the first step of the synthesis, and found a report
    Optimal P / B of 1.0, reporting better, but still too low, corrected yields for decay, from 40 to 45% (Hayashi et al., High-yield automated synthesis of [18F] fluoroazomycin arabinoside ([18F] FAZA) for hypoxia-specific tumor imaging. Applied Radiai isot. 2011; 69: 1007-1013). The work did not attempt to optimize the second stage of the reaction, that is to say the alkaline hydrolysis of the intermediate
    0 radio frequency in the presence of a base.
    Problem to be solved FAZA has proven to be one of the most promising tracers for imaging hypoxia of a tumor. In addition, the analog [1241] ([124I] IAZA) is easily accessible by the same route from the same precursor as for the synthesis of [18F] FAZA, giving the therapeutic solution. However, the most widely used synthesis path for the [18F] FAZA tracer is characterized by yields that are too low to offer viable and inexpensive high-yield productions. Therefore, alternative or optimized synthesis methods are highly desired.
    The proposed optimization aims to avoid degradation of both the precursor and the fluorinated intermediate. This can be obtained by combining an optimal P / B ratio during the first synthesis step with an optimization of the reaction conditions of the second step.
    3.5
    BE2016 / 5903
    OBJECT OF THE INVENTION The present invention aims to implement high-yield syntheses of analogs of 2-nitroimidazoie based on radiolabelled nuciéoside, and in particular of [18F] FAZA, in two stages of synthesis from of an available precursor. In other words, the invention aims to stabilize the radiochemical yields here radiochemical synthesis of analogues of 2-nitroimidazole based on 13F-labeled nuciezoside, easily automated by allowing a monotope synthesis with a high yield.
    Summary of the Invention [6022] The present invention relates to a process for the production of 2-nitroimidazole analogs based on radiolabelled nuciéoside, in a ready-to-inject solution, comprising the steps consisting in:
    i. labeling a 2-nitroimidazoy precursor compound based on nuciéoside protected with a short-lived radionuclide by means of a nuciéophie substitution;
    ii. deprotecting the radiolabelled compound obtained in step (i) by means of alkaline hydrolysis;
    iii. purifying the deprotected radiolabelled compound obtained in step {ii);
    iv. formulating the ready-to-inject solution by adding the purified deprotected radiolabelled compound obtained in step (iii) in an injectable solution (for example in 0.9% saline solution);
    characterized in that the alkaline hydrolysis is carried out by addition of a strong base in aqueous solution followed by neutralization by means of an acid solution, the time between the addition of the strong base and the neutralization being between 30 seconds and 90 seconds.
    In accordance with particularly preferred embodiments, the method of the invention comprises one, or a suitable combination of several, of the following characteristics:
    the purification step is carried out by purification by HPLC chromatography or purification by solid phase extraction (SPE);
    - the precursor of 2-nitroimidazoie based on nuciéoside is of formula:
    L
    ΛΛ
    NP.
    * representing chiral centers
    V
    BE2016 / 5903 in which the chiral centers can be of configuration (R) or (S); L is a leaving group such as halogen, alkyl / aryisulfonyloxy, perfluoroalkylsulfonyloxy, substituted alkyl / aryisulfonyloxy, etc. ; R is a protective group such as -acetyl, pivaloyl, -allyl, -aliyloxycarbonyl, -benzyie, -benzyloxycarbonyl, benzyloxymethyl, -tert-butoxycarbonyl, -tert-butyl, -tert-butyldimethylsilyl, -tertbutyldiphenylsilyyl, -tertyl chloroacetyl, -diethylisopropylsilyl, -3,4dimethoxybenzyl, -methylacetyl, -4-methoxybenzy! e, -4methoxybenzyloxymethyl, -2-methoxymethyl, -2-methoxyethoxymethyl, methylthiomethyl, -4-nitrobenzyloxyethylcarbonylethyl , 2,2-trichloroethoxycarbonyl, -triethylsilyl, triisopropylsilyl, -trimethylsilyl, -2- (trimethylsilyl) ethoxycarbonyl, or tripbenylsilyie;
    the nucleoside-based 2-nitroimldazole precursor has the formula:
    the * representing the chiral centers, in which the chiral centers can be of configuration (R) or (S); L is halogen, alkylsulfonyloxy, perfluoroalkylsulfonyloxy, arylsulfonyloxy, substituted alkylsulfonyloxy or substituted arylsulfonyloxy; and R is alkyl, aryl, aralkyl, heteroaryl, heterocyclic;
    - ie precursor of 2-nitroimidazoie based on nucleoside is of formula:
    the * representing the chiral centers, in which the chiral centers can be of configuration (R) or (S); L is halogen, alkylsulfonyloxy, perfluoroalkylsulfonyloxy, arylsulfonyloxy, substituted alkylsulfonyloxy or substituted arylsulfonyloxy; and R is alkyl, aryl, aralkyl, heteroaryl, heterocyclic;
    BE2016 / 5903
    - The short period radionuclide is 18F or ie 123/124/125/131 -iodine, preferably 18F;
    - The ratio of the precursor to the base during here nucleophilia substitution is between 0.8 and 1.2;
    the aqueous solution comprises between 0.01 and 1 mol / i, preferably between 0.1 and 0.5 mol / i, of the strong base, said strong base being of formula X-OH, where X is chosen from group consisting of Li, Na and K, and the hydrolysis is carried out at a temperature between 20 and 40 ° C;
    the ratio of the precursor to the base during the nucleophylization substitution is 1.0, the alkaline hydrolysis step lasts between 45 seconds and 75 seconds, preferably 60 seconds, the aqueous solution comprises 0.1 mol / i of the strong base, said strong base being of formula X-OH where X is chosen from the group consisting of Li, Na and K, and the hydrolysis is carried out at a temperature between 20 and 40 ° C .;
    - the 2-nitroimidazole based on radiolabelled nucleoside is [18F] FAZA.
    Brief Description of the Drawings [8024] Figure 1 shows the structural formula of well-known 18F-labeled tracers of tumor hypoxia, [8825] Figure 2 shows the reaction scheme for the synthesis of [18F] FAZA.
    Description of the Invention [8028] The process of the present invention enables high-yield synthesis of 2-niiroimidazole analogs based on radiolabelled nucleosides, and in particular [18F] FAZA, prepared using a monotope synthesis in two steps optimized from a commercially available nucleoside-based 2-nitroimidazole precursor (Fig. 2), followed by purification, preferably by HPLC or SPE. In addition, the resulting tracer solution is easily injectable into a patient. The radiochemicals produced using the method of the present application can be used in the case of many diseases, including, but not limited to, oncological disorders, ie diabetes, inflammatory disorders, and a stroke.
    BE2016 / 5903 In accordance with the present invention, the synthetic route can involve 2-nitroïmidazoie agents based on nucleoside of formula:
    the * representing the chiral centers, in which the chiral centers can be of configuration (R) or (S); L is a leaving group. The term leaving group as used herein refers to groups which are easily displaced for example by a nucleophile. These leaving groups are well known. Non-limiting examples of L include halogen, alkyl / arylsulfonyloxy, perfluoroaikylsuifonyloxy, aikyl / substituted arylsuifonyloxy, etc .; R is H or a protecting group. The term protecting group refers to a group which is introduced into a molecule by chemical modification of a functional group to obtain chemoselectivity in a subsequent chemical reaction. In a subsequent deprotection step, the protective groups are then removed, for example by basic hydrolysis. These protecting groups are well known. Non-limiting examples of R include -acetyl, -pivaloyl, -allyl, -allyloxycarbonyl, -benzyie, benzyioxycarbonyie, -benzyloxymethyl, -teri-buioxycarbonyie, -iert-butyie, -tertbutyldimethylsilyl, -tert-butyldylmethylsilyl, -chloroacetyl, diethylisopropylsilyl, -3,4-dimethoxybenzyl, -methylaceticy, -4-methoxybenzyl, -4methoxybenzyloxymethyl, -2-methoxymethyl, -2-methoxyethoxymethyl, methylthiomethyl, -4-nitrobenzyloxycarbon , 2,2-trichloroethoxycarbonyl, -triethylsilyy, triisopropylsilyl, -irimethylsilyl, -2- (trimethylsiiyi) ethoxycarbonyie, or -triphenylsilyie, [0029] In certain embodiments, said compound has the formula
    R * representing the chiral centers, in which the chiral centers can be of configuration (R) or (S); L is halogen, alkyisulfonyloxy, perfluoroaikylsulfonyloxy, arylsulfonyloxy, substituted aikylsulfonyloxy or substituted arylsulfonyloxy; and R is H or alkyl, aryl, aralkyie,
    BE2016 / 5903 heteroaryl, heterocyclic.
    In certain embodiments, said compound has the formula:
    • y
    the * representing the chiral centers in which the chiral centers can be of configuration (R) or (S); L is halogen, alkylsulfonyloxy, perfluoroalkylsulfonyloxy, arylsulfonyloxy, substituted aikylsuifonyioxy or substituted arylsulfonyloxy; and R is H or alkyl, aryl, aralkyie, heteroaryl, heterocyclic.
    The precursors mentioned here include fragments substitutable by nuciéophiie which can react chemically to incorporate various short-lived radionuclides such as radioactive halogens, for example 18F, radioactive iodine (1-123 / 124/125 / 131), ie carbon-11, etc.
    The high-yield radiolabelling process for precursors described here involves a two-step monotope synthesis pathway (illustrated in FIG. 2 with the starting precursor 5'-2'-iosylate 3'-3'-diacetyl- AZA). The first stage is a conventional thermal chemical stage during which the fragment which can be substituted with a nucleotide of the precursor is displaced by a short-lived radionuclide. The second step is the elimination of fluorinated intermediate protective R groups by alkaline hydrolysis. This last step is characterized in that the alkaline hydrolysis is carried out by addition of a strong base in aqueous solution followed by neutralization with an acid solution, ie time between the addition of the strong base and the neutralization being between 30 seconds and 90 seconds. The deprotected radiolabelled product is then purified by HPLC or SPE purification and formulated in an injectable solution.
    The proposed method achieves a high yield not yet obtained, avoiding the degradation of both the precursor and the fluorinated intermediate. This is achieved by combining an optimal P / B ratio during the first synthesis step with an optimization of the reaction conditions of the second step.
    [8834] In certain embodiments of the present invention, said radionuclide is fluorine-18 or iodine- (123/124/125/131).
    [8835] In certain preferred embodiments of the present invention, said
    BE2016 / 5903 radionuclide is ie fiuor-18.
    In some embodiments of the present invention, the P / B ratio during the nucleopbile substitution is between 0.8 and 1.2 and the alkaline hydrolysis step lasts 30 seconds to 90 seconds using XOH 0.01 to 1.0 N, where X = Li,
    Na or K, at a temperature ranging from 20 to 40 ° C.
    In some preferred embodiments of the present invention, ie P / B ratio during the nucleophilic substitution is 1.0 and the alkaline hydrolysis step lasts 60 seconds using 0.1 N XOH, where X = Li, Na or K, at a temperature ranging from 20 to 40 ° C.
    Examples
    Example 1 - Automated synthesis of Ï18FJFAZA carried out with a P / B ratio of 1.0 and a duration of aicain hydrolysis of 3 minutes [ÖÖ38] The automated synthesis of [18FJFAZA is carried out as follows. Is isolated from [18O] H2O [18F] F ~ without added support (1.5 GBq) from the cyclotron target by trapping on a QMA cartridge (Sep-Pak Acceil Plus QMA carbonate light mg; Waters , Catalog No. 18600454) previously primed with 8 ml of EtOH and 20 ml of water to remove all traces of carbonate anion. [18F] ~ ballast then fully eluted with a mixture of K.222 (14 pmol, CAS N ° 23978-09-08) and K2CO3 (10 pmol)
    0 in 0.9 mi of 80% MeOH in a reaction vessel under a stream of nitrogen gas. The residue is dried by azeorope evaporation to ensure anhydrous reaction conditions for labeling with fluorine. The AZA precursor (1H-imidazole, 1- [2,3-di-O-acetyl-5-O - [(4-methylphenyl) sulfonyl], 10 pmol) dissolved in 1.1 ml of anhydrous DMSO is added to the reaction vessel and heated to 10G ° C for 5 minutes. An optimal P / B ratio for the fluorination yield is thus respected.
    After bringing the reaction mixture to room temperature, 0.5 ml of 0.1 M NaOH is added to the reaction vessel and it is bubbled with a stream of nitrogen gas at room temperature for 3 minutes. To neutralize the reaction mixture, 0.5 ml of 0.1 M HCl is added to the reaction vessel. Then the solution is transferred to the tank and then injected into the HPLC column (Macherey Nagel VP250 / 10 nucleosil 100-7 C18, eluent: water 95/5 EtOH, flow rate: 5 ml / min). The fraction corresponding to [18F] FAZA (residence time = 12 minutes) is collected and formulated with saline solution (15 ml of final product) passing through a sterile 0.22 μm filter, to give the final product (18FjFAZA ready to be injected.
    3.5 above procedures are performed automatically using an automated synthesizer (AllinOne synthesizer, Trasis, Liège, Belgium), The radiochemical purity is
    BE2016 / 5903 greater than 98% and the radiochemical yield (corrected for the decrease) for the synthesis and the purification is 32.1% (reaction time approximately 45 minutes, including the purification).
    Example 2 - Automated synthesis of Π 8 F JE AZA performed with a P / B ratio of 1.0 and a duration of alkaline hydrolysis of 2 minutes [Ö039] The automated synthesis of [18F] FAZA is carried out as follows. Is isolated from [18O] H2O from [18F] F without added support (1.7 GBq) from the cyclotron target by trapping on a QMA cartridge (Sep-Pak Acceil Plus QMA carbonate light
    46 mg; Waters, Catalog No. 18600454) previously primed with 8 mi of EtOH and 20 mi of water to remove all traces of carbonate anion. [18F] “is then slowly eluted with a mixture of K.222 (14 pmoi) and K2CO3 (10 pmol) in 0.9 mi of 80% MeOH in a reaction vessel under a stream of nitrogen gas. The residue is dried by azeotropic evaporation to ensure anhydrous reaction conditions for labeling with fluorine. The AZA precursor (1H-imidazoie, 1- [2,3-di-O-acety-5-O - [(4methylphenyl) sulfonyl], 10 pmoi) dissolved in 1.1 ml of anhydrous DMSO is added to the reaction vessel and heated at 100 ° C for 5 minutes. An optimal P / B ratio for the fluorination yield is thus respected. After bringing the reaction mixture to room temperature, 0.5 ml of 0.1 M NaOH is added to the
    0 reaction vessel and a stream of nitrogen gas is bubbled through it at room temperature for 2 minutes. To neutralize the reaction mixture, 0.5 ml of 0.1 M HCl is added to the reaction vessel. Then the solution is transferred to the reservoir and then injected into the HPLC column (Macherey Nagel VP250 / 10 nucleosii 100-7 C18, eluent: water 95/5 EtOH, flow rate: 5 ml / min). The fraction corresponding to [18F] FAZA (residence time = 12 minutes) is collected and formulated with saline solution (15 ml of final product) passing through a sterile 0.22 μm filter, to give the final product [18F] FAZA ready to be injected. All of the above procedures are performed automatically using an automated synthesizer (AllinOne, Trasis,
    Liège, Belgium). The radiochemical purity is greater than 98% and the radiochemical yield (corrected for the decrease) for the synthesis and the purification is 42.2% (reaction time approximately 45 minutes, including the purification).
    Example 3 - Automated synthesis of [18FJFAZA carried out with a P / B ratio of 1.0 and a duration of alkaline hydrolysis of 1 minute [0040] The automated synthesis of [18FjFAZA is carried out as follows. Is isolated from [18O] H2O from [18F] F _ without added support (1.5 GBq) from the cyclotron by
    BE2016 / 5903 trapping on a QMÄ cartridge (Sep-Pak Acceli Pius QMA carbonate light 46 mg;
    Waters, Catalog No. 18600454) previously primed with 8 ml of EtOH and 20 ml of water to remove all traces of arsenic carbonate. [18F] is then slowly eluted with a mixture of K.222 (14 pmol) and K2CO3 (10 pmoi) in 0.9 ml of MeOH to
    80% in a reaction vessel under a stream of nitrogen gas. The residue is dried by azeotropic evaporation to ensure anhydrous reaction conditions for labeling with fluorine. The AZA precursor (1H-imidazole, 1- [2,3-di-O-acetyl-5-O - [(4methylphenyl) sulfonyl], 10 pmol) dissolved in 1.1 ml of anhydrous DMSO is added to the reaction vessel and heated at 100 ° C for 5 minutes. An optimal P / B ratio for the fluorination yield is thus respected. After bringing the reaction mixture to room temperature, 0.5 ml of 0.1 M NaOH is added to the reaction vessel and a stream of nitrogen gas is bubbled through it at room temperature for 1 minute instead of 3 to 5 minutes usual. To neutralize the reaction mixture, 0.5 ml of 0.1 M HGI is added to the reaction vessel. Then the solution is transferred to the reservoir and then injected into the HPLG column (Macherey Nagel VP250 / 10 rsucleosii 100-7 C18, eluent: water 95/5 EtOH, flow rate: 5 ml / min). The fraction corresponding to [18F] FAZA (residence time = 12 minutes) is collected and formulated with here saline solution (15 ml of final product) passing through a sterile 0.22 μm filter, to give the final product [18F] FAZA ready to be injected. All ies
    0 above procedures are performed automatically using an automated synthesizer (AllinOne synthesizer, Trasis, Liège, Belgium). The radiochemical purity is greater than 98% and the radiochemical yield (corrected for the decrease) for the synthesis and the purification is 62.0 ± 2.3% (n = 3) with the optimized conditions (reaction time approximately 45 minutes , including purification). As mentioned above, using an optimal P / B ratio makes it possible to achieve a yield of up to 40% (corrected for decay), while minimizing the duration of the hydrolysis provides an additional gain of 20%. The reason is that the radiofluoric intermediate is also susceptible to chemical degradation under basic conditions, it is useful to note that decreasing the concentration of NaOH (i.e. <0.1 N) does not increase not the yield.
    BE2016 / 5903
    权利要求:
    Claims (10)
    [1]
    1. Process for the production of a 2-nitroimidazole compound based on radiolabelled nuciéoside comprising:
    (i) labeling a precursor compound of 2-nitroimidazole based on nuciéoside protected with a short-lived radionuclide by means of a nuciéophie substitution;
    (ii) here deprotection of the radiolabelled compound obtained in step (i) by means of alkaline hydrolysis;
    (iii) neutralizing the mixture of step (ii);
    (iv) purifying the deprotected radiolabelled compound obtained in step (iii);
    (v) ia formulation of the purified deprotected radiolabelled compound obtained in step (iv) in a solution;
    characterized in that the alkaline hydrolysis is carried out by addition of a strong base in aqueous solution followed by neutralization by means of an acid solution, ie the time between the addition of the strong base and the neutralization being between 30 seconds and 90 seconds;
    said precursor of 2-nitroimidazole based on nuciéoside having a structure of formula:
    O-, the * representing the chiral centers,
    - in which the chiral centers can be of configuration (R) or (S);
    - L is a leaving group chosen from the group consisting of a halogen, an alkyl / aryisulfonyloxy, a perfluoroalkylsulfonyioxy, and a substituted alkyl / aryisulfonyloxy;
    - R is a protecting group chosen from the group consisting of -acety, -pivaioyl, allyia, -aiiyloxycarbonyle, -benzyie, -benzyioxycarbonyie, -benzyloxyméthyie, -tertbutoxycarbonyle, -tert-butyle, -tert-butyidiméthyisilyyid, -tertyl, -tertyl -tert-
    butylmethylsilyl, -chloroacétyie, -diéthylisopropylsilyie, -3.4- dimethoxybenzyl, -methyiacétyie, „4. methoxybenzyl, -4-methoxybenzyloxymethyie, -2- methoxymethyl, -2-methoxyethoxymethyl, - methyithiométhyie, -4-nitrobenzyioxycarbonyie, -tétrahydropyran-2-
    BE2016 / 5903 yl, -hexyldimethylsiiyle, -2,2,2-trichloroethoxycarbonyle, -triéthyîsiîyle, triisopropyisilyl, -triméthyisilyie, -2- (triméthylsilyl) éthoxycarbonyle, and —tripbényfsilyl.
    [2]
    2. Method according to ia claim 1, characterized in that the purification step (iv) is carried out by HPLG or SPE.
    5
    [3]
    3. Method according to any one of the preceding claims, characterized in that the short-lived radionuclide is 18F or ie 123/124/125/131-iodine.
    [4]
    4, Process according to any one of the preceding claims, characterized in that the short-lived radionuclide is 18F.
    10
    [5]
    5. Method according to any one of the preceding claims, characterized in that the ratio of the precursor to the base during the substitution of nucleophytes is between 0.8 and 1.2.
    [6]
    6. Method according to any one of the preceding claims, characterized in that the aqueous solution comprises between 0.01 and 1 mol / l of ia base
    15 strong, said strong base being of formula X-OH, where X is chosen from the group consisting of Li, Na and K, and the hydrolysis is carried out at a temperature between 20 and 40 ° C.
    [7]
    7. Method according to any one of the preceding claims, characterized in that the ratio of the precursor to the base here during the nucleophylization is 1.0, the alkaline hydrolysis step lasts between 45 seconds and 75
    20 seconds, preferably 60 seconds, the aqueous solution comprises 0.1 mol / i of the strong base, said strong base being of formula X-OH where X is chosen from the group consisting of Li, Na and K, and l hydrolysis is carried out at a temperature between 20 and 40 ° C.
    [8]
    8. Method according to any one of the preceding claims,
    25 characterized in that the radiolabelled nucleoside 2-nitroimidazole is [18F] FAZA.
    BE2016 / 5903 • X
    irt
    '' Girt
    ZGrt '' rt <
    rt.
    W
    ...--
    ÎSFsPiirt>; ö rtL '</ /
    rtf rt;
    "1
    BE2016 / 5903
    RrécLifSeyr:
    194 ^ 103201,3,1- (2, .3 ^ 1-0-300 ^ 4-5-0 - ((4 :. méthvlpftényl) sdfonde]
    Also indicated -'by 5-fosylate of $ 2 -diâôétÿî-ÂZÂ in the text jnfeïmëdjalie rsdiQfîüôre
    RG, 2
    BE2016 / 5903
    SHORT
    PROCESS FOR THE PREPARATION OF NITROIMIDAZOLE A ANALOGS
    RADIOMARKED NUCLEOSIDE BASE
    The present invention relates to a process for the production of nucleoside-based radiolabelled 2-nitroimidazole analogs in a solution, comprising:
    (i) labeling of a nucleoside-based 2-nitroimidazole precursor compound protected with a short-lived radionuclide by means of a substitution
    [9]
    10 nucleophile;
    (ii) deprotection of the radiolabelled compound obtained in step (i) by means of alkaline hydrolysis;
    (iii) purification of the deprotected radiolabelled compound obtained in step (ii) by HPLG chromatographic purification or SPE purification;
    [10]
    (Iv) ia final formulation of the purified deprotected radiolabelled compound obtained in step (iii) in a solution.
    PATENT COOPERATION TREATY
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    同族专利:
    公开号 | 公开日
    BE1024388A1|2018-02-05|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US20130211066A1|2010-06-24|2013-08-15|Alberta Health Services|Compounds useful in imaging and therapy|
    法律状态:
    2018-03-07| FG| Patent granted|Effective date: 20180212 |
    优先权:
    申请号 | 申请日 | 专利标题
    EP15198187|2015-12-07|
    EP15198187.5|2015-12-07|
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