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    • 专利摘要:
    The invention relates to a new chemical process, a new cassette configuration and new software. The invention enables a single single hot cell synthesizer to sequentially produce two lots of [18F] labeled PET tracers on the same day.
    公开号:BE1022357B1
    申请号:E2014/5062
    申请日:2014-11-12
    公开日:2016-03-24
    发明作者:Xavier Franci
    申请人:Ge Healthcare Limited；
    IPC主号:
    专利说明:

    Dual function cassette
    Technical field of the invention
    The present invention provides devices and methods for the automated synthesis of [18F] labeled compounds, particularly those suitable for use as in vivo imaging agents for positron emission tomography (PET). In particular, the focus of the present invention is on the automated synthesis of more than one lot of a labeled compound [18F] using just a disposable cassette. Description of the Related Art
    Radiolabeled compounds for use as in vivo imaging agents are typically prepared usually by means of an automated synthesis apparatus (also referred to as "radiosynthesizer"). These automated synthesis devices are commercially available from a variety of suppliers including: GE Healthcare; CTI Inc.; Ion Beam
    Applications S.A. (Cyclotron Path 3, B-1348
    Louvain-la-Neuve, Belgium); Raytest (Germany) and Bioscan (USA). The radiochemistry takes place in a "cassette" or "cartridge" designed to fit removably and interchangeably on the apparatus so that a mechanical movement of moving parts of the apparatus controls the operation of the cassette. Suitable cassettes can be provided as a kit of parts which is assembled on the apparatus during a number of steps or can be supplied in one piece which is fixed in a single step, which has the effect of effect of reducing the risk of human error. The one-piece arrangement is generally a single-use disposable cassette that includes all reagents, reaction vessels, and apparatus necessary to perform the preparation of a given batch of radiopharmaceutical.
    The commercially available GE Healthcare FASTlab ™ cassette is an example of a disposable one-piece type of pre-loaded reagent cassette comprising a linear array of valves, each connected to an orifice to which reagents or flasks can be placed. to be fixed. Each valve has a male-female joint that interfaces with a corresponding mobile arm of the automated synthesis apparatus. An external rotation of the arm therefore controls the opening or closing of the valve when the cassette is attached to the apparatus. Additional moving parts of the apparatus are designed to lock onto syringe plunger tips and raise or lower syringe bodies. The FASTlab ™ cassette has 25 identical 3-way valves in a linear array, examples of which are shown in Figs. 1 and 2. FIG. 1 illustrates the commercially available FDG Phosphate FASTlab ™ cassette and FIG. 2 the commercially available FDG Citrate FASTlab ™ cassette.
    The synthesis of [18 F] fluorodeoxyglucose (FDG [18F]) on the cassettes of FIGS. 1 and 2 is carried out by nucleophilic fluorination with [F] fluoride produced by a reaction 0 (p, n) F. The fluoride [18F] thus produced enters the cassette in position 6 and moves in a QMA solid phase extraction (SPE) column (quaternary methylammonium anion exchange) placed in position 4 via the tube in position 5. The fluoride [18F] is retained by an ion exchange reaction and the water 180 can flow through the common path of the cassette to be recovered in position 1. The fluoride [F] retained on the QMA is then eluted with an elution solution (solution of Kryptofix ™ 222 acetonitrile and potassium carbonate in position 2) withdrawn into the syringe in position 3 and into the reaction vessel (connected by three tubes, a tube leading to each of the positions 7, 8 and 25). Water is evaporated and a mannose triflate precursor (from position 12) is added to the reaction vessel. Then, the labeled [18F] mannose triflate (fluorotetracetylglucose [18F], FTAG) is trapped and thus separated from [18 F] fluorides on an environmental SPE tC18 column at position 18 via the tube at position 17 to hydrolyze with NaOH (from the bottle in position 14) to remove acetyl protecting groups. The hydrolysed basic solution obtained is then neutralized in the syringe placed in position 24 with phosphoric acid in the case of the phosphate configuration (Figure 1) or hydrochloric acid present in a citrate buffer in the case of the citrate configuration (Fig. 2). Residual potential [18F] fluoride removal takes place on an alumina SPE column at position 20 via the tube at position 21 and removal of weakly hydrophilic impurities on an SPE HLB column (for the phosphate cassette of FIG. 1) or on an SPE tC18 column (for the citrate cassette of Fig. 2) in position 22 via the tube in position 23. The final purified FDG solution [18F] is transferred to a collection bottle via a long, connected tube in position 19.
    Two positions on the FASTlab cassette are free in the case of each of the known FDG cassettes [18 F] illustrated in FIGS. 1 and 2, i.e. positions 9 and 10. Caps are placed on the valves in these positions.
    A typical FDG [F] production site produces a minimum of two lots of FDG [18F] in one day. However, because of the residual activity on the FASTlab ™ cassette, the transfer line and the shadow due to the waste bottle at the completion of a batch, it is impossible for safety reasons perform operations one after the other of the method described above on the same apparatus. This, combined with the relatively large size of the FASTlab ™ device, means that to produce a second batch of FDG [18F] in the same day using this method, it is necessary to have a second unit in a second hot cell.
    It would be desirable to have a means to produce more than one lot of FDG [18F] using FASTlab ™ during the same day and in only one hot cell. For the two commercially available FDG [18F] FASTlab ™ cassettes described above, 23 of the total 25 positions are used. It is therefore not possible to adapt all dual components for a second batch on the same cassette. Summary of the invention
    In a first aspect, the present invention provides a cassette (1) for the synthesis of a plurality of batches of a positron emission tomography (PET) tracer array labeled [18F], wherein said cassette comprises: ) an anion exchange column (3, 4) for each of said plurality of batches; (ii) a reaction vessel (5); (iii) a vial (2) containing an aliquot of eluent for each of said plurality of batches; (iv) a vial (6) containing an aliquot of a precursor compound for each of said plurality of batches; (v) reagent vials (7, 8, 9), wherein each reagent vial contains an aliquot of reagent for each of said plurality of batches; (vi) optionally, a solid phase extraction (SPE) column for deprotection (10) and / or one or more SPE columns for purification (11, 12); and (vii) means for cleaning said reaction vessel and said SPE columns.
    In another aspect, the present invention is directed to a method for synthesizing a plurality of batches of a labeled PET tracer [18F], wherein said method comprises the steps of: (a) trapping a first aliquot of fluoride [18 F] on a first anion exchange column (3); (b) providing a first aliquot of a precursor compound in a reaction vessel (5); (c) passing a first aliquot of eluent through said first anion exchange column (3) to elute said aliquot of fluoride [18F] into said reaction vessel (5); (d) heating the reaction vessel (5) for a predetermined period of time to obtain a crude [18F] labeled PET tracer; (e) optionally deprotecting said crude labeled [18F] PET tracer on an SPE column (10);
    (f) optionally purifying said labeled PET tracer [18F] on one or more SPE columns (11, 12); (g) cleaning said reaction vessel (5) and said SPE columns (10, 11, 12); and (h) repeating steps (a) to (g) one or more times, each time using a subsequent aliquot of [18F] fluoride, a subsequent anion exchange column (4) and a subsequent aliquot a precursor compound of FDG [18F]; wherein said method is performed on a single cassette (1).
    In another aspect, the present invention is directed to a non-transitory storage means comprising computer readable program code, wherein execution of the computer readable program code causes a processor to perform the steps of the method of the invention such as that they are defined above.
    The present invention allows a synthesizer of a single hot cell to sequentially produce multiple batches of a labeled PET tracer [18 F]. It has been demonstrated that good yields are obtained for each of two FDG lots [18 F] sequential and good trapping and elution of incoming activity. The quality control analyzes of the two lots described in Example 1 below show that each lot meets the requirements of the Pharmacopoeia for FDG [18F].
    Brief description of the figures
    Fig. 1 and FIG. 2 illustrate examples of known cassettes for producing a batch by cassette of a compound mark [F].
    Fig. 3 illustrates a cassette suitable for performing two FDG operations [18F] on FASTlab ™.
    Fig. 4 illustrates the process of producing two batches of FDG [18 F] on FASTlab ™ using a single cassette as illustrated in FIG. 3.
    Detailed Description of the Preferred Embodiments
    The term "cassette" refers to a single-use part of a device designed to fit removably and interchangeably on an automated synthesis apparatus so that a mechanical movement of moving parts of the synthesizer controls the operation of the cassette from outside of it, that is to say externally. The term "single use" as used in the context of a cassette of the present invention means that the cassette is intended to be used only once before discarding for the production of a plurality of lots of a labeled PET tracer [18F]. Suitable cassettes include a linear array of valves, each connected to an orifice where reagents or vials can be attached, by needling perforation of a sealed base-sealed vial or by joining gas-tight connections. In one embodiment, each valve is a 3-way valve. In one embodiment, each valve is a shutoff valve comprising a rotary valve. Each valve has a male-female joint that interfaces with a corresponding mobile arm of the automated synthesis apparatus. An external rotation of the arm therefore controls the opening or closing of the valve when the cassette is attached to the automated synthesis apparatus. Additional moving parts of the automated synthesis apparatus are designed to lock onto syringe plunger tips and raise or lower syringe bodies. The cassette is flexible, typically having several positions where reagents can be attached, and several positions for attaching syringe bottles of reagents or chromatographic columns. The cassette always includes a reaction vessel generally configured such that three or more orifices of the cassette are connected thereto to allow the transfer of reagents or solvents from various ports on the cassette. Cassettes must be designed to be suitable for radiopharmaceutical manufacturing and are therefore made from materials that are pharmaceutical grade and also resistant to radiolysis. In one embodiment of the present invention, the disposable cassette is a FASTlab ™ type cassette, i.e., a cassette that is suitable for use with a FASTlab ™ Automated Synthesis Machine.
    In one embodiment of the present invention, the various elements of the cassette are selectively connected by fluid communication. The expression "selectively connected by fluid communication" means that it is possible to choose whether or not a fluid can pass to the characteristic of the invention and / or the characteristic to another characteristic of the invention, for example by the use of an appropriate valve. In one embodiment of the invention, a suitable valve is a 3-way valve having three orifices and means for placing any two of the three associated orifices in fluid communication with each other while isolating at the fluid the third orifice. In another embodiment of the invention, a suitable valve is a shutoff valve comprising a rotary valve. In one embodiment, the cassette components are selectively connected in fluid communication along a common path. The term "common path" is intended to define a fluid path to which the other components of the system or cassette of the present invention are selectively connected in fluid communication. In one embodiment, the common path is a linear fluid path. In one embodiment, the common path is made of a rigid pharmaceutical grade polymer material that resists radiation. Non-limiting examples of such suitable materials are polypropylene, polyethylene, polysulfone and Ultem®. In one embodiment, said common path is made of polypropylene or polyethylene.
    By the term "automated synthesis apparatus" is meant an automated module based on the principle of unit operations as described by Satyamurthy et al. (1999 Clin Positr Imag; 2 (5): 233-253). The term "unit operations" means that complex processes are reduced to a series of simple operations or reactions that can be applied to a range of materials. These automated synthesizers are preferred for the process of the present invention, particularly where a radiopharmaceutical composition is desired. These are commercially available from a variety of suppliers (Satyamurthy et al., Supra), including: GE Healthcare; CTI Inc; Ion Beam Applications S.A. (Cyclotron Road 3, B-1348 Louvain-la-Neuve, Belgium); Raytest (Germany) and Bioscan (USA). Automated synthesis devices are designed to be used in an appropriately configured radioactive working cell or "hot cell", which provides appropriate radiation protection to protect the operator from a potential radiation dose as well as ventilation to remove chemical and / or radioactive vapors. By using a cassette, the automated synthesis apparatus has the flexibility to produce a variety of different radiopharmaceuticals with minimal risk of cross-contamination simply by changing the cassette. This approach also has the advantages of simplified assembly, ie reduced risk of operator error, improved GMP compliance (good manufacturing practice), capacity multi-plotter, rapid change between production operations, automated pre-cassette and reagent diagnostic control, cross-checking automated barcodes of chemical reagents depending on the synthesis to be performed , a traceability of reagents, a single use and, consequently, no risk of cross-contamination, fraud and resistance to abuse.
    The term "plurality" used in the present application in the context of batches of a labeled PET tracer [18F] is intended to refer to more than one lot, when more than one lot is synthesized on a single use cassette. unique. In a first aspect, the term plurality refers to two batches, i.e., a first batch and a second batch. The terms "first batch" and "second batch" represent two separate consecutive syntheses of labeled PET tracers [18F] produced on the same cassette, the second batch being produced only after production of the first batch has been completed, that is, that is, the product was collected in the product collection bottle. The term "lot" is used to refer to a batch of the final tagged PET tracer labeled [18F] synthesized. It is expected that the plurality of batches can be obtained on the same day and without the need to open the hot cell in which the cassette and the automated synthesizer are present.
    A "labeled PET tracer [18F]" is a chemical compound that includes a 18F atom and is suitable for use as a PET tracer. Nonlimiting examples of labeled PET tracers [18F] include the following: fluorodeoxyglucose [18F] (FDG [18F]), fluoromisonidazole [18F] (FMISO [18F]), fluorothymidine [18F] (FL T [18F]) , fluoroazomycin arabinofuranoside [18F] (FAZA [18F]), fluoroethylcholine [18F] (FECH [18F]), fluoro-cyclobutane-1-carboxylic acid [18F] (FACBC [18F]), flumanezil [18F] (FMZ [18F]), tyrosine [18F], altanaserine [18F], 4-fluoro-3-iodobenzylguanidine [18F] (FIBG [18F]), metafluorobenzylguanidine [18F] (FBGm [18F]) and 5-fluorouracil [18F]. ]. In one embodiment of the present invention, the labeled compound [18 F] is selected from FDG [18F], FMISO [18F], FLT [18F] and FACBC [18F]. In another embodiment of the present invention, the labeled compound [18F] is FDG [18F].
    A "reaction vessel" in the context of the present invention is a container of the cassette of the invention where reagents and reagents necessary for synthesis can be sent and the product (s) removed in an appropriate order. The reaction vessel has an internal volume that is suitable for containing reagents and is made of radiation-resistant pharmaceutical grade materials.
    An "aliquot" in the context of the process of the present invention is a sufficient amount of a particular reagent for use in the synthesis of a batch of a PET tracer.
    A "precursor compound" is meant to be here a non-radioactive derivative of a radiolabeled compound designed so that a chemical reaction with a convenient chemical form of the detectable mark occurs specifically at the site in the minimum number of steps (ideally a single step) to give the desired radiolabelled compound. To ensure site-specific labeling, a precursor compound may have protecting groups. The precursor compounds are synthetic and can conveniently be obtained with good chemical purity. A number of precursor compounds are well known to be suitable for the synthesis of labeled compounds [18 F], as taught for example in Chapter 7 of the "Handbook of Radiopharmaceuticals: Radiochemistry and Applications" (2003 John Wiley & Sons Ltd.). , Wench & Redvanly, Eds.). The term "protecting group" refers to a group which prevents or suppresses undesirable chemical reactions, but which is designed to be sufficiently reactive to be cleavable from the functional group in question in order to obtain the desired product under fairly mild conditions. that do not alter the rest of the molecule. Protecting groups and processes for their removal (i.e. "deprotection") are well known to those skilled in the art and are described in "Protective Groups in Organic Synthesis", Theorodora W. Greene and Peter GM Wuts, (4th Edition, John Wiley & Sons, 2007).
    The term "reagent" as used herein is a term for referring to solvents and reagents used in the synthesis of a particular labeled [18F] PET tracer. Suitably, these are stored in a reagent bottle. The term "reagent bottle" is meant to refer to a vial containing one of the reagents for use in the production of labeled PET tracer [18F], sufficient to produce the desired plurality of batches. The term "sufficient" refers to an appropriate amount of a reagent to ensure that the plurality of batches can be obtained. Generally, this amount is a little larger than the exact amount required. A typical reagent bottle is made of a rigid polymer of radiation-resistant pharmaceutical grade. Suitable reagents contained in said reagent bottles are ethanol, acetonitrile, deprotecting agents and buffers. In one embodiment, said deprotection agent is selected from HCl, NaOH and H3PO4. In one embodiment, said deprotection agent is NaOH. In one embodiment, said buffer is based on a weak acid, for example selected from citrate, phosphate, acetate and ascorbate. For example, when the compound labeled [F] of the present invention is FDG [F], the disposable cassette comprises a reagent vial containing ethanol, one containing acetonitrile, another containing NaOH and another containing a weak acid-based buffer selected from citrate or phosphate. The term "solid phase extraction (SPE)" refers to the sample preparation process by which compounds in solution are separated from each other on the basis of their respective affinities for a solid ("phase"). solid "or the" stationary phase ") through which the sample is sent and the solvent (the" mobile phase "or the" liquid phase ") in which they are dissolved. The result is that an interesting compound is retained on the solid phase or in the mobile phase. The portion that passes through the solid phase is collected or discarded depending on whether or not it contains the compound of interest. If the portion retained on the stationary phase comprises the compound of interest, it may be removed from the stationary phase for collection in an additional step, wherein the stationary phase is rinsed with another solution known as "eluent". For the present invention, the SPE is conveniently implemented using an "SPE column" (also often referred to as an "SPE cartridge"), which is readily available commercially and is typically in the form of a column-shaped form. syringe packed with a solid phase. Most known solid phases are based on silica which has been bound to a specific functional group, for example hydrocarbon chains of varying lengths (suitable for reverse phase SPE), quaternary ammonium or amino groups ( suitable for anion exchange) and sulfonic acid or carboxyl groups (suitable for cation exchange).
    The term "elution" refers to the passage of a solution through an SPE column for the purpose of releasing an interesting compound (s) that has or has been bound to the solid phase.
    The term "eluent" used above in connection with SPE is generally also specifically used in conjunction with the disposable cassette of the present invention to refer to the eluent used to elute the fluoride [18F] entrapped on the the anion exchange column. [18 F] fluoride suitable for use in the synthesis of a labeled compound [18F] is normally obtained in the form of an aqueous solution from the nuclear reaction 0 (p, n) F. To increase reactivity fluoride [F] and reduce or minimize hydroxylated byproducts resulting from the presence of water, water is typically removed from fluoride [F] before the reaction and fluorination reactions are carried out using anhydrous reaction solvents (Aigbirhio et al, 1995 J Fluor Chem, 70: 279-87). Another step that is used to improve the reactivity of fluoride [18 F] for radiofluorination reactions is to add a cationic counterion prior to removal of the water. The cationic counterion is dissolved in an aqueous organic solution and this solution is used as an eluent to elute [18 F] fluoride from an anion exchange column on which fluoride [18F] has been trapped. In one embodiment, said aqueous organic solution is an aqueous solution of acetonitrile or methanol. In one embodiment, said aqueous organic solution is an aqueous solution of acetonitrile. Conveniently, the counterion will have sufficient solubility in the anhydrous reaction solvent to maintain the solubility of fluoride [18F]. Accordingly, counterions which are typically used include large, but soft, metal ions such as rubidium or cesium, potassium complexed with a cryptande, such as Kryptofix ™ 22, or tetraalkylammonium salts, where Potassium complexed with a cryptande such as Kryptofix ™ 222 or tetraalkylammonium salts is preferred. The term Kryptofix ™ 222 (or K222) refers herein to a commercial preparation of the compound 4,7,13,16,21,24-hexaoxa-l, 10-diazabicyclo [8.8.8] -hexacosane.
    An "SPE column for deprotection" in the context of the present invention is an SPE column having a solid phase on which a precursor compound having protecting groups is retained after the labeling reaction [18F] in order to eliminate the protective groups and obtain the desired labeled PET tracer [18F]. In one embodiment, the SPE column for deprotection is a reverse phase SPE column as defined herein.
    A "reversed-phase SPE" makes use of a modified non-polar solid phase and a polar mobile phase. The compounds are retained by hydrophobic interactions and eluted using a nonpolar elution solvent to destroy the forces that bind the compound to the solid phase. As non-limiting examples of reverse phase SPE columns, there will be C18, tC18, C8, CN, Diol, HLB, Porapak, RDX and NH2 SPE in column form. In one embodiment of the present invention, the inverted phase SPE column is a tC18 column or SPE HLB column. In one embodiment, said reverse phase SPE column is an SPE HLB column. In another embodiment of the present invention, the reverse phase SPE column is a tC18 column. In some embodiments of the present invention, the tC18 column is an environmental tC18 column, sometimes referred to as a long tC18 column or tC18 plus column. In one embodiment, the reverse phase SPE column used for deprotection is an environmental tC18 column.
    A "normal phase SPE" makes use of a polar modified solid phase and a nonpolar mobile phase. The compounds are retained by hydrophilic interactions and eluted using a solvent that is more polar than the original mobile phase to break the binding mechanism. Non-limiting examples of normal phase SPE columns include SPE columns of alumina, diol and silica. In one embodiment of the present invention, said normal phase SPE column is an alumina SPE column.
    The "anion exchange SPE" uses the electrostatic attraction of a charged group on a compound to a charged group on the surface of the sorbent and can be used for compounds that are loaded in solution. . The main retention mechanism of the compound is based mainly on the electrostatic attraction of the functional group loaded on the compound with respect to the charged group which is bonded to the silica surface. A solution having a pH that neutralizes the functional group of the compound or the functional group on the surface of the sorbent is used to elute the compound of interest. A non-limiting example of an anion exchange SPE column is a quaternary ammonium anion exchange (QMA) SPE column. The term "cleaning means" refers to a reagent source selectively fluidically connected to the component to be cleaned. The selective fluid connection suitably comprises a valve and a flexible tube section. Suitable reagents for cleaning include ethanol and acetonitrile, their aqueous solutions and water. The term "cleaning" in the context of the present invention refers to the process of passing an appropriate amount of one or more reagents through a component to be cleaned to make it suitable for use in the preparation of a subsequent batch. labeled PET tracer [18F]. In one embodiment, said means for cleaning the reaction vessel and said SPE columns comprises a source of water connected by fluid communication to said reaction vessel and said SPE columns. An appropriate source of water is water for injection. In one embodiment, said water source is a water bag fluidly connected to said cassette. In one embodiment, said means for cleaning said reaction vessel and said SPE columns comprises a source of acetonitrile fluidically connected to said SPE column for deprotection. In one embodiment, said means for cleaning the reaction vessel and said SPE columns comprises a source of ethanol fluidly connected to said SPE columns for purification. Said sources of reagents are, in one embodiment, present in flasks included in the cassette of the invention.
    The term "entrapment" refers to the process in which a particular compound (s) binds to the solid phase of an SPE column.
    The term "passage" refers to the act of allowing a reagent, a solvent or a reaction solution to flow through a particular component through the selective opening of valves.
    The term "heating" used in this application refers to the application of heat to promote a particular chemical reaction. In the context of the [18F] labeling as contemplated herein, the heat is conveniently a temperature in the region of 100 to 150 ° C for a brief period of about 2 to 10 minutes.
    The terms "purifying" or "purifying" as used herein can be taken to refer to a process for obtaining a substantially pure labeled compound [18F]. The term "substantially" refers to the complete or nearly complete degree of an action, characteristic, property, state, structure, article or result. The expression "substantially pure" may be taken to refer to a
    1 R composes brand [F] completely pure which would be ideal,
    1 R but also a compound mark [F] which is sufficiently pure to be suitable for use as a PET tracer. The term "suitable for use as a PET tracer" means that the substantially pure [18F] labeled compound is suitable for intravenous administration to a mammalian subject followed by PET imaging to obtain one or more clinically usable images of the subject. location and / or distribution of the labeled compound [18F]. In one embodiment of the present invention, purification is performed using a reverse phase SPE column and / or a normal phase SPE column, each as defined above.
    The term "cleaning" in the context of the present invention refers to the process of passing an appropriate amount of one or more reagents through a component to be cleaned to make it suitable for use in preparing a batch. subsequent labeling of PET tracer [18F]. In one embodiment, the cleaning step in the context of the process of the present invention comprises rinsing the reaction vessel and SPE columns with water. In another embodiment of the process of the present invention, said cleaning step comprises rinsing the SPE column with acetonitrile prior to rinsing with water. In another embodiment of the method of the present invention, said cleaning step comprises rinsing said SPE columns (11, 12) with ethanol prior to rinsing with water.
    In one embodiment of the method of the present invention, the steps are performed in sequence.
    An illustrative example of the present invention is the synthesis of FDG [18F] on FASTlab ™ (GE Healthcare). The first synthesis of FDG [18F] is similar to the current FDG [18F] process on FASTlab ™. It uses the same amount of reagents. At the end of the first FDG process [18F], the first batch is sent to a first product collection bottle. At this stage, there are enough residual reagents in the different flasks for a second FDG synthesis [18F]. FASTlab ™ remains in standby mode after delivery of the first batch of FDG [18F]. From this point on, FASTlab ™ is ready to receive cyclotron radioactivity for a second FDG synthesis [18F]. Once the fluoride solution [18 F] from the cyclotron arrives on the conical flask of the cassette, the operator can initiate the second FDG elaboration process [18F], which starts with the cleaning of the tC18 column with 1 ml of acetonitrile and rinsing with water for injection purification columns. The reaction vessel was already washed during the first synthesis. A second column of QMA and a second tube are added to the cassette to ensure proper entrapment and elution of fluoride [18F] prior to the drying step. After the elution of the [18F] fluoride in the reactor, the rest of the FDG [18F] preparation process is carried out in the same manner as the first FDG [18F] synthesis. A separate outlet duct is used. The cassette allows the two masses of FDG [18F] to have their own outlet ducts, sterilization filters and product collection flasks, so that the separation of the lot is clear.
    Fig. 3 is a diagram of a non-limiting example of a cassette of the present invention designed for the radiosynthesis of 2 consecutive lots of FDG [18F]. Brief Description of Examples Example 1 describes the synthesis of two batches of FDG [18F] on a single FASTlab ™ cassette.
    List of abbreviations used in FDG [18 F] examples: Fluorodeoxyglucose [18 F] FTAG [18 F]: Fluoro-tetraacetylglucose [18 F] GC: Gas Chromatography HLB: Hydrophilic-Lipophilic Balance IC: Ion Chromatography K222: 4,7,13,16,21,24-hexaoxa-l, 10-diaza-bicyclo [8.8.8] hexacosane
    MeCN: acetonitrile min: minute (s) NCY: uncorrected yield ppm: parts per million QMA: quaternary methylammonium SPE: solid phase extraction
    EXAMPLES EXAMPLE 1 Synthesis of two batches of FDG [18F] on a single FASTlab ™ cassette
    The configuration of the cassette, as illustrated in FIG. 3, was used to produce two consecutive batches of FDG [18F] using the following method (the numbers of this method are reference numerals in Fig. 3, except mentioned as a "position", which is one of positions 1 to 25 running from left to right on the cassette of Fig. 3): (i) 800 μL of MeCN (from vial 7) was used to condition the environmental SPE column of tC18 (10) and mL of H2O were used to condition each of the SPE HLB column (11) and the alumina SPE column (12). (ii) Fluoride [18F] was obtained from the bombardment of [180] -H 2 O with a high energy proton beam extracted from an 18/9 cyclotron cyclone (IBA) and transferred to the cassette via the reservoir conic in position 6. (iii) Fluoride [18F] was trapped on the QMA column (3) and separated from the enriched water which was collected in an outer vial via a path through the 5-4-1 positions . (iv) Eluent (from vial 2) was withdrawn into the syringe at position 3 and passed through the QMA column (3) to release fluoride [F] and send it to the reaction vessel (5). (v) Evaporation of water into the reaction vessel was catalyzed by adding a small amount of 25 mg / mL of mannose triflate precursor (vial 6 at position 12 at 120 ° C). (vi) Mannose triflate precursor (from vial 6) was withdrawn into the syringe at position 11 and transferred to reaction vessel (5) at position 10, where the labeling reaction was performed at 125 ° C for 2 minutes. minutes. (vii) The radiolabeling intermediate obtained FTAG [18F] was trapped and separated from the unreacted fluorides on the upper side of the environmental column of tC18 (10) at position 18. (viii) Hydroxide Sodium (from vial 8) was sent through the column (10) to convert the FTAG [18 F] to FDG [18 F] collected by the syringe at position 24. (ix) The neutralization of the basic solution obtained was was made using phosphoric acid (from vial 9). (x) The final product was sent to a first external collection flask (13) connected to position 21 via the two purification columns (11, 12) of a row (i.e. HLB in position 23 and alumina in position 20). (xi) The tC18 environment was washed with acetonitrile from position 13 (vial 7) and the reactor, purification columns and tube were rinsed with water from the water bag connected to the tip in position 15. (xii) A second batch of fluoride [18 F] from the cyclotron was transferred to the cassette as in step (ii). (xiii) [18 F] fluoride was trapped on a new column of QMA (4) found at position 8 and separated from the enriched water which is collected in an outer flask via a path through the 7-8- 19-1. (xiv) With fluoride [18F] from QMA (4) at position 8, steps (iv) - (ix) were performed as for the first batch. (xv) The second batch of FDG [18F] was purified via the same columns (11, 12) at position 23 (HLB) and (alumina) and then transferred to a new external collection bottle (14) connected to the tube. position 22.
    This cassette configuration has an enriched water recycling path on the left side for the first batch (Fig 4 above) and on the right side for the second batch (Fig 4 below) of the cassette (contamination of the tubing with enriched water is possible with seven positions on the cassette engaged, that is to say the position 6 for the entry of activity, the position 1 for the enriched water bottle connection, the position 4 for QMA 1, position 5 for QMA tube 1, position 7 for QMA 2, position 8 for QMA tube 2 and position 19 for enriched water recovery from batch 2. Starting activity, final activity and residual activities were measured by a VEENSTRA calibrated ionisation chamber (VIK-202).
    To determine the yield, the following yield calculations have been made: - if delta Tf = time elapsed after the start of synthesis in min - if Af = final activity in mCi - cAf = corrected final activity in mCi for the start of synthesis in min = Af. Exp (In (2) * (delta Tf / 110)) where 110 = half-life of fluorine [18F] in minutes - if cAi = corrected initial activity in mCi concerning the initiation of synthesis in mCi-si delta Ts = duration of synthesis - corrected performance (CY) = (cAf / cAi) * 100 - uncorrected yield (NCY) = CY * Exp (In (2) * (-delta Ts / 110))
    The results below for starting activity, final activity, and residual activities were obtained with the following cassette configuration:
    For quality control, measurements of pH, glucose concentration, acetic acid concentration and K222 concentration were performed.
    PH was measured using a pH meter
    Metrohm 744.
    The glucose concentration was determined by ion chromatography (IC) where the analytical conditions were as follows: - Dionex IC system - Carbopak Dionex PAIO column, 4.0 * 250 mm at
    25 ° C - 100 mM KOH solvent at 1 mL / min - electrochemical detector at 30 ° C.
    The composition of the standard for FDG used was as follows:
    - glucose = 25 μg / mL
    - FDM = 50 pg / mL
    - FDG = 50 pg / mL
    - CIDG = 50 pg / mL
    The determination of the amount of acetic acid was evaluated using gas chromatography (GC) performed on a Varian CP-3800 machine equipped with a CP-8400 autosampler and the following parameters: - column: Macherey column -Nagel Optima® 624-LB, 30m * 0.32mm ID, 1.80μm film
    injection: volume 1 μL, scission ratio 1:10, injector at 250 ° C. - carrier gas: helium 10 PSI 5 mL / min - temperature: 80 ° C from 0 to 3 min, 80 to 200 ° C from 3 to 9 min at 20 ° C / min and finally 200 ° C from 9 to 10 min - detector: FID at 250 ° C (He 20 mL / min, H2 30 mL / min and compressed air 260 mL / min) - reference used: acetic acid solution at 500 ppm w / w (which corresponds to one-tenth of the limit, 5000 ppm).
    The amount of K222 in the final product was determined by forming sample spots on a TLC plate which was impregnated with an iodoplatinate revealing solution (0.5 g of hexa-hydrated chloroplatinic acid: H 2 PtCl 6. 6H20 (very hygroscopic!), 9g of potassium iodide: KI, 200 mL of distilled water) and comparing this with standard solutions of K222 1, 5, 10, 50 and 100 ppm). The color intensity of the spots obtained is proportional to the amount of K222 present in the solution.
    The results below were obtained:
    权利要求:
    Claims (40)
    [1]
    1. - Cassette (1) for the synthesis of a plurality of batches of a labeled positron emission tomography (PET) tracer [18F], wherein said cassette comprises: (i) an exchange column of anions (3, 4) for each of said plurality of batches; (ii) a reaction vessel (5); (iii) a vial (2) containing an aliquot fraction of eluent for each of said plurality of batches; (iv) a vial (6) containing an aliquot of a precursor compound for each of said plurality of batches; (v) reagent vials (7, 8, 9), wherein each reagent vial contains an aliquot of reagent for each of said plurality of batches; (vi) a solid phase extraction (SPE) column for deprotection (10) and one or more SPE columns for purification (11, 12); and (vii) means for cleaning said reaction vessel and said SPE columns.
    [2]
    The cassette of claim 1, wherein said anion exchange column (3, 4) is a quaternary ammonium anion exchange column (QMA).
    [3]
    3. Cassette according to any one of claims 1 to 2, wherein said eluent comprises a cationic counterion dissolved in an aqueous organic solution.
    [4]
    4. Cassette according to claim 3, wherein said cationic counterion is selected from rubidium, cesium, potassium complexed with a cryptande and a tetraalkylammonium salt.
    [5]
    5. Cassette according to claim 4, wherein said cationic counterion is potassium complexed with a cryptande.
    [6]
    6. Cassette according to claim 5, wherein said cryptande is, 4, 7,13,16,2.1,24-hexaoxa-1,10-diazabicyclo [8.8.8] hexacosane (Kryptofix 2.2.2).
    [7]
    7. Cassette according to any one of claims 3 to 6, wherein said organic aqueous solution is an aqueous solution of acetonitrile or methanol.
    [8]
    8. Cassette according to claim 7, wherein said organic aqueous solution is an aqueous solution of acetonitrile.
    [9]
    The cassette according to any one of claims 1 to 8, wherein said SPE column (10) for deprotection is a reversed phase SPE column.
    [10]
    The cassette of claim 9 wherein said reverse phase SPE column is a C18 column.
    [11]
    The cassette according to any one of claims 1 to 10, wherein said one or more SPE columns for purification (11, 12) comprises or comprises a normal phase SPE column.
    [12]
    12. The cassette according to claim 11, wherein said normal phase SPE column is an alumina SPE column. 13. The cassette according to any one of claims 1 to 12, wherein said one or more SPE columns for purifying (11, 12) comprises or comprises a reverse phase SPE column.
    [14]
    14. Cassette according to claim 13, wherein said reversed phase column is a column. SPE, ELB ..
    [15]
    15. A cassette according to any one of claims 1 to 14, wherein said means for cleaning said reaction vessel and said SPE columns comprises a source of water in fluid communication with said reaction vessel and said SPE columns.
    [16]
    The cassette of claim 15, wherein said means for cleaning said reaction vessel and said SPE columns comprises a source of acetonitrile in fluid communication with said SPE column for deprotection (10).
    [17]
    A cassette according to claim 15 or claim 16, wherein said means for cleaning said reaction vessel and said SPE columns comprises a source of ethanol in fluid communication with said SPE columns for purification.
    [18]
    18. A method for synthesizing a plurality of batches of a labeled PET tracer [18F], wherein said method comprises the steps of: (a) trapping a first aliquot of fluoride [18F] on a first anion exchange column (3); (b) providing a first aliquot of a precursor compound in a reaction vessel (5); (c) passing a first aliquot of eluent through said first anion exchange column (3) to elute said aliquot of fluoride [18F] into said reaction vessel (5), · (d) heating the reaction vessel (5) for a predetermined period of time to obtain a crude [18F] labeled PET tracer; (e) optionally deprotecting said crude labeled [18F] PET tracer on an SPE column (10); (f) optionally purifying said labeled PET tracer [18F] on one or more SPE columns (11, 12); (g) cleaning said reaction vessel (5) and said SPE columns (10, 11, 12); and (h) repeating steps (a) to (g) one or more times, each time using a subsequent aliquot of [18F] fluoride, a subsequent anion exchange column (4) and a subsequent aliquot a precursor compound of FDG [18F]; wherein said method is performed on a single cassette (1).
    [19]
    19. The process according to claim 18, wherein said PET tracer is chosen from the following: fluorodeoxyglucose [18F] (FDG [18F]), fluoromedonidazole [18F] (FMISO [18F]), fluorothymidine [18F] ( FLT [18F]), fluoroazomycin arabinofuranoside [18F] (FAZA [18F]), fluoroethylcholine [18F] (FECH [18F]), fluoro-cyclobutane-1-carboxylic acid [18F] (FACBC [18F]), flumanezil [18F] ] (FMZ [18F]), tyrosine [1SF], altanaserine [18F], 4-fluoro-3-iodobenzylguanidine [18F] (FIBG [18F]), meta-fluorobenzylguanidine [18F] (FBGm [18F]) and 5- fluorouracil [18F].
    [20]
    20. - The method of claim 19, wherein said PET tracer is selected from the following: .FDG [18F]. FLT [18F.], FMISO. [1SF], and FACBC [18F].
    [21]
    21. The method of claim 20, wherein said PET tracer is FDG [18F].
    [22]
    22. - Method according to any one of claims 18 to 20, wherein each of said first anion exchange column (3) and said subsequent anion exchange (4) is an exchange column. of quaternary ammonium anions (QMA).
    [23]
    23. - Process according to any one of claims 18 to 22, wherein said eluent comprises a cationic counterion dissolved in an aqueous organic solution.
    [24]
    24. - The method of claim 23, wherein said cationic counterion is selected from rubidium, cesium, potassium complexed with a cryptande and a tetraalkylammonium salt.
    [25]
    25. - The method of claim 24, wherein said cationic counterion is potassium complexed with a cryptande.
    [26]
    26. The method of claim 25, wherein said cryptande is 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo [8.8.8] hexacosane (Kryptofix 2.2.2).
    [27]
    27. - Process according to any one of claims 23 to 26, wherein said organic aqueous solution is an aqueous solution of acetonitrile or methanol.
    [28]
    28. - The method of claim 27, wherein said organic aqueous solution is an aqueous solution of acetonitrile.
    [29]
    29 .- Method according to. . . any one of claims 18 to 28, wherein said SPE column for deprotection (10) is a reversed phase SPE column.
    [30]
    30. - The method of claim 29, wherein said inverted phase SPE column is a C18 column.
    [31]
    31. The method according to any one of claims 18 to 30, wherein said one or more SPE columns for purification (11, 12) comprises or comprises a normal phase SPE column.
    [32]
    32. The method according to claim 31, wherein said normal phase SPE column is an alumina SPE column.
    [33]
    The method of any one of claims 18 to 32, wherein said one or more SPE columns for purification (11, 12) comprises or comprises a reverse phase SPE column.
    [34]
    The method of claim 33, wherein said reverse phase column is an SPE HLB column.
    [35]
    The method of any one of claims 18 to 34, wherein said cleaning step comprises rinsing said reaction vessel (5) and said SPE columns (10, 11, 12) with water.
    [36]
    36. The method of claim 35 wherein said cleaning step comprises rinsing said EPS column with acetonitrile prior to rinsing with water.
    [37]
    The method of claim 35 or claim 36, wherein said cleaning step comprises rinsing said SPE columns (11, 12) with ethanol prior to rinsing with water.
    [38]
    A non-transient storage medium comprising a computer readable program code, wherein executing the computer readable program code causes a processor to perform the steps as defined in any one of claims 18 to 37.
    [39]
    39, - Use of a cassette for the synthesis of a plurality of batches of a [18F] labeled positron emission tomography (PET) tracer, characterized in that the synthesized PET tracer is chosen from the following: fluorodeoxyglucose [18F] (FDG [18F]), fluoro-misonidazole [18F] (FMISO [18F]), fluorothymidine [18F] (FLT [18F]), fluoroazomycin arabinofuranoside [18F] (FAZA [18F]), fluoroethylcholine [18F] ] (FECH [1SF]), fluorocyclobutane-1-carboxylic acid [18F] (FACBC [1SF]), flumanezil [18F] (FMZ [18F]), tyrosine [18F], altanaserine [18F] / 4-fluoro-3 -iodobenzylguanidine [18F] (FIBG [18F]), meta-fluorobenzylguanidine [18F] (FBGm [18F]) and 5-fluorouracil [18F].
    [40]
    40. - Use of a cassette according to claim 39, characterized in that said PET tracer is selected from FDG [18F], FLT [1SF], FMISO [18F] and FACBC [18F].
    [41]
    41. - Use of a cassette according to claim 40, characterized in that said PET tracer is FDG [18F].
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    同族专利:
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    JP2017503752A|2017-02-02|
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    KR102335535B1|2021-12-08|
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    JP6496726B2|2019-04-03|
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    WO2015071288A1|2015-05-21|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US201361903486P| true| 2013-11-13|2013-11-13|
    US61/903,486|2013-11-13|
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