Novel formulations and synthesis methods

Abstract

Anti-1-amino-3- 18 F-Fluorocyclyl butyl-1-carboxylic acid ( 18 F-FACBC) AND A COMPOSITION COMPRISING THE COMPOSITION How to do this. anti-1-amino-3-18F-fluorocyclobutyl-1-carboxylic acid ( 18 F-FACBC), dissolved in water. A composition containing aluminum (Al) at 5.0 μg / ml or less, and and a method for obtaining said composition.

Description

[Technical field]

[0001] The present invention relates to pharmaceutical compositions, particularly compositions that include positron emission tomography (PET) tracers. The compositions and methods of synthesis of the present invention offer certain advantages over the prior art. [Background technology]

[0002] Unnatural Amino Acids 18 F-1-amino-3-fluorocyclobutane-1-carboxylic acid ( 18 F -FACBC, 18 F-fluciclovine) is specifically transported by amino acid transporters and shows promise for positron emission tomography (PET) imaging of prostate cancer (N anni et al 2014 Clinical Genitourinary C answer;12(2):106-110).

[0003] 18 The generation of F-FACBC can be achieved by catalyzing the triflate precursor compound as shown below. 18 F-F This involves labelling with a 5'-aminopropyl ether and then removing the two protecting groups.

[0004] [ka]

[0005] [ka]

[0006] After the deprotection step, purification is carried out to remove impurities. is the excess Na remaining from the deprotection step. + and excess Cl - Ion retardation (I) for removing On Retardation) and18 Alumina for removing F-fluoride and 1-amino-3 -Hydroxy-cyclobutane-1-carboxylic acid (Hydroxy-ACBC) and 1-A FACB such as chloro-3-chloro-cyclobutane-1-carboxylic acid (chloro-ACBC) A combination of solid phase with reversed phase to remove C-related impurities has been used.

[0007] Synthesis is currently being undertaken by GE Healthcare, CTI, Ion Beam, and others. Applications, B-1348 Louvain-la-Neuve, Chema, Belgium 3), Raytest (Germany) and Bioscan (USA) To be removable and interchangeable to fit automated synthesis equipment such as those commercially available from For automated radiosynthesis procedures using so-called "cassettes" or "cartridges" designed The cassettes are suitably assembled by methods well known in the art of PET tracer manufacturing. Prepared in 18 After F-fluoride derivatization 18 Required for preparation of F-FACBC Includes all necessary reagents, reaction vessels and equipment.

[0008] 18 The known cassette for F-FACBC synthesis was purchased from GE Healthcare. The cassettes are FASTlab™ cassettes. Each cassette is made of 2 polypropylene The cassette is built around a one-piece manifold with five three-way valves. Cyclic Olefin Methyl Ammonium (QMA) Solid Phase Extraction (SPE) Cartridges, 5ml Copolymer reaction vessel, one 1ml syringe and two 5ml syringes, 5 pre-filled Spikes for connecting with reagent vials A to E, 1 water bag (100ml ), 3 SPE cartridges (tC18, HLB and alumina) and a filter Five FASTlab™ Cassette Reagent Vials are filled as follows: Al A was dissolved in acetonitrile (MeCN) and Kryptofix 2.2.2. Vial B contains an eluent solution containing HCl, vial C contains MeCN, and vial D contains HCl. Vial D contains the dried precursor compound of formula I from the reaction scheme illustrated above, E contains NaOH. This FASTlab™ cassette is used 18 F-FACBC A known method for the preparation of the formulation is described in Example 1 of WO 2013 / 093025. Radiosynthesis is carried out in aqueous 18 By trapping F-fluoride on the QMA The reaction vessel is then eluted with the eluent from vial A, followed by elution with the eluent from vial C. Concentrate to dryness by azeotropic distillation with acetonitrile. Mix the precursor compound of LeD with the dissolved precursor and add it to the reaction vessel and heat it at 85 °C for 3 min. The reaction mixture is then diluted with water and pumped through a tC18 cartridge. Wash with water and send through the tC18 cartridge. The labeled intermediate was washed with water and then incubated with NaOH for 5 min to obtain the ES The deesterified intermediate was eluted from the tC18 cartridge and purified by water. Add HCl to the reaction vessel and heat to 60°C for 5 minutes. The BOC group is then hydrolyzed. 18 F-FACBC is a contaminant related to FACBC. Pass it through an HLB (HLB = hydrophilic lipophilic balance) cartridge for the removal of substances, 18 F- Pass the solution through an alumina cartridge for removal of fluoride, then into a citrate buffer solution The HLB cartridge and alumina cartridge are then poured into a 30 ml product vial. Finally, NaOH and water are added to the product vial. In addition, 18 The final purified preparation of F-FACBC is obtained. Prior to intravenous administration, this preparation is Pass it through a filter.

[0009] Using the known FASTlab™ cassettes and processes described above, the inventors Final result 18 We found that the quality of the F-FACBC preparation may vary slightly. Residual acetonitrile levels ranged from about 100 μg / ml to about 600 μg / ml. Regarding the permissible daily exposure, 18 F-FACBC formulation approved Although acceptable as a standard, this amount and the variability observed are far from ideal. Furthermore, residual aluminum ranged from about 7 μg / ml to almost 20 μg / ml. This was found to be the case for 5 ml 18 F-FACBC can be injected at a dose of 100 μg. This means there is a possibility. 18 If the F-FACBC formulation also contains a citrate buffer, aluminum It is possible that complexes of ninium with citrate exist. Such complexes may cross the blood-brain barrier and This is problematic because it is known that ls;17:669-689).

[0010] Therefore, 18 There is room for improvement in the F-FACBC preparation. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] International Publication No. 2013 / 093025 Brochure Summary of the Invention

[0012] The present invention overcomes the problems found in known compositions. 18 Pharmaceutical composition containing F-FACBC In particular, the compositions of the present invention have an improved impurity profile, which is The composition of the present invention is safer and more effective for imaging than the prior art. The low and predictable levels of acetonitrile and / or aluminum in the formulation are This means that the compositions of the invention can more easily meet the requirements of pharmacopoeias around the world. In addition to significantly reducing the concentration of aluminum, removing the alumina cartridge This allows for a shorter and simplified process, and There is an associated advantage that there are no particles that cause the particles to break down. The child can block the sterile filter used before the injection of the formulation. The obvious advantage is that only minor changes to the known process are required to 18 F-FACBC composition This is achieved without compromising the desired quality. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] In order to more clearly and concisely describe and illustrate the subject matter claimed, the following description and The following definitions are provided for certain terms used in the appended claims. Any instances of particular terms in the specification should be considered as non-limiting examples.

[0014] In one embodiment, the present invention provides a method for preparing a food additive comprising the steps of: The anti-1-amino-3- 18 F-Fluorocyclobutyl-1-carb Phosphoric acid ( 18 Positron Emission Tomography (PET) Tracer Compositions Containing F-FACBC do.

[0015] In one aspect, the present invention provides an anti-1-amino-3- 18 F-Fluorocyclobutyl-1-phenyl Carboxylic acid ( 18 F-FACBC) in a positron emission tomography (PET) tracer composition. Dissolved aluminum (Al) is 5.0μg / ml or less and acetonitrile (MeC N) at 50 μg / ml or less.

[0016] Regarding the present invention, PET Tracer Composition " refers to the use of a PET tracer in a biocompatible carrier. The PET tracer composition of the present invention refers to a composition in a form suitable for administration to a mammal, including the human body. The composition is hereinafter also referred to as the composition of the present invention. PET tracer " in this specification to obtain one or more clinically useful images of the location and / or distribution of a PET tracer. , which is a positron emitter suitable for intravenous administration to mammalian subjects and subsequent PET imaging. As defined herein, a "biologically active molecule" is defined as a molecule that contains an atom that is Biocompatible Carriers " refers to a composition that is physiologically tolerable, i.e., does not cause toxicity or excessive toxicity to the mammalian body. A fluid, especially a liquid, that suspends or dissolves medicines so that they can be administered without discomfort. The biocompatible carrier is preferably a sterile pyrogen-free water for injection or an aqueous solution, e.g. An injectable carrier liquid such as saline.

[0017] Compound “ 18 F -FACBC " is represented by the following chemical structure:

[0018] [ka]

[0019] term" below As used herein, " " means any amount less than or including the recited amount. In an idealized embodiment of the composition of the present invention, 0 μg / ml of each impurity is present. However, in reality, 0 μg / ml of impurities is unlikely and is at least The term "less than" means that trace amounts of one or more impurities are present in the composition. T is permitted to be present in the tracer composition, above which the composition is unacceptable for use. Define the concentration limits that are considered to be

[0020] In one embodiment, the composition of the present invention contains no more than 3.0 μg / ml of dissolved Al, and In an embodiment, it contains no more than 1.5 μg / ml of dissolved Al.

[0021] In one embodiment, the composition of the present invention contains MeCN at a concentration of 20 μg / ml or less. do not have.

[0022] In one embodiment, the composition of the present invention is 95% or more, in another embodiment, 98% or more, and Another embodiment has an end of synthesis (EOS) radiochemical purity (RCP) of 99% or greater.

[0023] term" At the end of synthesis " refers to the time point at which the labeled compound is collected in the product collection vial. say.

[0024] European Patent Application Publication No. 2119458 18 A more stable formulation of F-FACBC is This is achieved when the pH is maintained within the range of 2.0 to 5.9. As discussed in Publication No. 2013 / 093025, the use of a citrate buffer reduces the p This allows H to be maintained within a tighter range, providing resistance to degradation, In one embodiment, the composition of the present invention is capable of being autoclaved. In another embodiment, about 50 to 100 mM citrate buffer is used for the purpose of the present invention, and about 60 to 90 mM citrate buffer is used for the purpose of the present invention. In yet another embodiment, the citrate buffer is about 75-85 mM citrate buffer. "About" in this context means that the exact value of the range is within the skill of the art to achieve the same stabilizing effect. We also incorporate small variations around these values ​​predicted by

[0025] In another aspect, the present invention provides a method for preparing a PET tracer composition of the present invention, comprising the steps of: (a) In a reaction vessel 18 Reacting an F-fluoride source with a precursor compound of formula I: obtaining a reaction mixture comprising a compound of formula II:

[0026] [ka]

[0027] (In the formula, LG is a leaving group, PG 1 is a carboxy protecting group, PG 2 is an amine protecting group.

[0028] [ka]

[0029] (In the formula, PG 1 and P.G. 2 is as defined in formula I. (b)PG 1 and P.G. 2 Removal of 18 Obtaining a reaction mixture containing F-FACBC and, (c) 18 The reaction mixture containing F-FACBC was passed through a hydrophilic lipophilic balance (HLB) solid phase. and purifying the product by The purification process is 18 Passing the reaction mixture containing F-FACBC through an alumina solid phase The present invention provides a method for producing a pharmaceutical composition comprising the steps of:

[0030] In another aspect, the present invention provides a method for preparing a PET tracer composition of the present invention, comprising the steps of: (a) In a reaction vessel 18 Reacting an F-fluoride source with a precursor compound of formula I: obtaining a reaction mixture containing a compound of formula II, the reaction being carried out in acetonitrile; The process to be carried out;

[0031] [ka]

[0032] (In the formula, LG is a leaving group, PG 1 is a carboxy protecting group, PG 2 is an amine protecting group.

[0033] [ka]

[0034] (In the formula, PG 1 and P.G. 2is as defined in formula I. (b) transferring the reaction mixture containing the compound of formula II out of the reaction vessel and 1 Removal of obtaining a reaction mixture comprising a compound of formula III:

[0035] [ka]

[0036] (In the formula, PG 2 is as defined in formula I. (c)PG 1 applying heat to the reaction vessel simultaneously with the removal of (d) returning the reaction mixture containing the compound of formula III to the reaction vessel and reacting with PG 2 Removal of 1 8 obtaining a reaction mixture comprising F-FACBC; (e) 18 The reaction mixture containing F-FACBC was passed through a hydrophilic lipophilic balance (HLB) solid phase. and purifying the product by It contains 18 The reaction mixture containing F-FACBC was passed through an alumina solid phase. The present invention provides a method for the prevention of a catalysis comprising the steps of:

[0037] "Suitable for use in step (a) of the method of the present invention 18 F-Fluoride Source " is usually a nuclear reaction 18 O(p,n) 18 It is obtained as an aqueous solution from F. It increases the reactivity of fluoride and is produced in the presence of water. Water is generally not added to the reaction to reduce or minimize the hydroxylated by-products that occur. in front of 18 F-fluoride is removed and the fluorination reaction is carried out using anhydrous reaction solvents ( Aigbirhio et al 1995 J Fluor Chem;70:279 -87) Radioactive fluorination reactions 18 Additional fluoride used to improve reactivity The step of adding is the step of adding a cationic counterion prior to the removal of water. On is 18 To maintain the solubility of F-fluoride, a compound with sufficient solubility in anhydrous reaction solvents must be used. Therefore, commonly used counterions include rubidium or cesium. Large but soft metal ions such as Kryptofix™ or tetraalkanes. Examples of potassium complexes with cryptands such as potassium ammonium salts include Kryptofi x or potassium complexed with a cryptand such as a tetraalkylammonium salt. preferable.

[0038] For step (a) of the method of the present invention precursor compound " is a desired radiolabeled compound. To obtain a detectable label, a chemical reaction is carried out site-specifically with a convenient chemical form, can be carried out in a few steps (ideally in a single step) and does not require significant purification Non-radioactive derivatization of radiolabeled compounds, designed to be ideally not further purified Such precursor compounds are synthetic and conveniently available in good chemical purity. can be obtained.

[0039] In the context of the compound of formula I in step (a) of the method of the present invention, leaving group " is a fluoride These are chemical groups that can be displaced by nucleophilic substitution reactions with protons. In some embodiments, the leaving groups of the present invention are linear or branched C 1-10 Ha alkylsulfonic acid substituents, linear or branched C 1-10 Alkyl sulfonic acid substituent, fluoro In another embodiment of the present invention, The leaving groups are methanesulfonic acid, toluenesulfonic acid, nitrobenzenesulfonic acid, benzene sulfonic acid, trifluoromethanesulfonic acid, fluorosulfonic acid, and perfluoro In some embodiments, the leaving group is selected from methanesulfonic acid. , trifluoromethanesulfonic acid or toluenesulfonic acid; In this embodiment, the leaving group is trifluoromethanesulfonic acid.

[0040] Substituent PG 1 and P.G. 2 The term " protecting group " means an undesirable chemical reaction The desired product is obtained under mild conditions that inhibit or suppress the reaction but do not alter the remaining molecules. The functional group is designed to be sufficiently reactive that it can be cleaved from the functional group in question in order to Protective groups are well known to those skilled in the art and are described in the "Protective Groups in Organic Synthesis”, Theorodora W.Greene a ndPeter GMWuts,(Fourth Edition,John Wi Ley & Sons, 2007).

[0041] PG 1 " Carboxy Protecting Group " as used herein preferably means linear or branched C 1-10 The term "alkyl" refers to an alkyl chain or an aryl substituent. Alkyl " means any linear, branched or cyclic, saturated or unsaturated C n H 2n+1 The group is defined as The term " Aryl" means a monocyclic or polycyclic aromatic hydrocarbon or a monocyclic or polycyclic Any C derived from heteroaromatic hydrocarbons 6-14 The present invention relates to a method for producing a compound comprising the steps of: In one embodiment, PG 1 is selected from methyl, ethyl, t-butyl and phenyl. In another embodiment of the present invention, 1 is methyl or ethyl, and In terms of form, PG 1 is ethyl.

[0042] PG 2 " Amine Protecting Groups " refers herein to a process for providing a compound of formula II Leave 18 A chemical group that preferably prevents the reaction of F with an amino group. Examples of suitable amine protecting groups are Various carbamate substituents, various amide substituents, various imide substituents, and various Preferably, the amine protecting group is a linear or branched C 2-7 Al C 3-7 Alkenyloxycarbonyl Substituent , C which may have a modifying group 7-12 Benzyloxycarbonyl Substituent, C 2-7 Alkyldithiox Carbonyl substituent, linear or branched 1-6 Alkyl amide substituent, linear or branched C 2-6 Alkenyl amide substituent, C which may have a modifying group 6-11 Benzamide Substituent, C 4-10 Cyclic Immune C, which may have a substituent 6-11 Aromatic imine substituents, linear or branched C 1-6 Alkyl Amine Substituent, Linear or Branched C 2-6 C6, which may have an alkenylamine substituent and a modifying group -11In some embodiments of the present invention, P is selected from the group consisting of benzylamine substituents. G 2 are t-butoxycarbonyl, allyloxycarbonyl, phthalimide, and N-phenyl In another embodiment, PG is selected from the group consisting of phenylalanine, ... 2 is t-butoxyl In one embodiment of the present invention, the PG is selected from the group consisting of PG, ... 2 t-Butoxy It is carbonyl.

[0043] As is well known to those skilled in the art, in step (a) of the method of the present invention, the term " To react " is, Two or more chemical substances (commonly referred to in the art as "reactants" or "reagents") are brought together This refers to the process of bringing about a chemical change in one or both / all of the chemicals.

[0044] In step (b) of the method of the present invention, PG 1 Removal of " refers to the reaction mixture obtained in step (a) This is preferably achieved by contacting a compound of formula II contained in Suitable carboxy deprotecting agents are either acidic or alkaline solutions, as known to those skilled in the art. (See Greene and Wuts, supra.) The concentration is a concentration that is just enough to adequately remove the carboxy protecting group. In certain embodiments, the carboxy deprotection agent is an alkaline solution. In a preferred embodiment, the hydroxide is, for example, 0.5 The temperature and duration used for deprotection were: In some embodiments, PG 1 For example, in certain embodiments, In one embodiment, the reaction step is carried out at room temperature for a duration of about 1 to 5 minutes. 1 The removal of is carried out by passing the reaction mixture containing the compound of formula II through a solid phase extraction (SPE) column. The method is carried out by binding the compound of formula II to a solid phase. The SPE column is then loaded with carboxy deprotecting agent so that the carboxy deprotecting agent is retained therein for a predetermined period of time. The outlet is closed. A suitable solid phase for use in this method is a reverse phase solid phase, for example tC18.

[0045] Step (c) can be carried out by, for example, placing a reaction vessel therein for radiosynthesis using methods well known to those skilled in the art. This involves applying heat to the reaction vessel using a dedicated heating device for a sustained period of time. The application of must be such that the reaction vessel can be used for the subsequent step (d). i.e. the reaction vessel must be intact and undamaged and the residual This step (c) must be such that the remaining solvent is effectively removed. 1 Simultaneously with the removal of, i.e., the reaction mixture containing the compound of formula II was transferred from the reaction vessel. The temperature suitable for this heating step is within the limits of the reaction vessel, e.g. The reactor is made of polyether ether copolymer (COC) and the temperature is below 130°C. For polyether ether ketone (PEEK) reactors, the temperature should be about 200° C. or less. The temperature used to heat the reaction vessel in step (c) is the same as that used during the labeling step (a). Suitable temperatures for the radiolabeling step (a) may be selected to be as close as possible to the temperature at which the reaction is carried out. In another embodiment, the temperature is within the range of about 80 to 140°C, and in another embodiment, 85 to 130°C.

[0046] In step (d) of the method of the present invention, PG2 Removal of " is a compound of formula III and an amine deprotection Suitable amine deprotection agents are known to those skilled in the art. The solution may be either an acid or an alkaline solution (see Greene and Wuts, supra). The concentration of the amine deprotecting agent is preferably PG 2 The concentration is just enough to remove the Alternatively, the amine deprotecting agent is an acidic solution. Suitable acids include inorganic acids, such as hydrochloric acid (HCl). , sulfuric acid (H2SO4) and nitric acid (HNO3), as well as organic acids, such as perfluoroalkanes. The acid is selected from alkyl carboxylic acids, such as trifluoroacetic acid (CF3CO2H). In certain embodiments, the amine deprotecting agent is, for example, HCl at a concentration of 1.0 to 4.0 M. Yes. PG 2 The removal of the aryl group is, in one embodiment, carried out using heat to proceed faster than the deprotection. The time depends on the reaction temperature and other conditions. For example, in one embodiment, 2 The removal is carried out at 60° C. with a reaction time of 5 minutes.

[0047] " purification The objective of step (e) is to obtain a substantially pure 18 The aim is to obtain F-FACBC. word" In effect " means the complete or nearly complete extent or degree of action, characteristic, property, condition, structure, As used herein, the term "measurement," "item," or "result" refers to a measurement, item, or result. 18 The term "F-FACBC" used in the context of Virtually pure " is completely pure 18 Use as F-FACBC or PET tracer Pure enough to be suitable for 18 F-FACBC. As a PET tracer Suitable for use in " means refined18 The F-FACBC product is 18 F-FACBC Intravenous administration to a mammalian subject to obtain one or more clinically useful images of location and / or distribution. This means that it is suitable for administration and subsequent PET imaging.

[0048] " HLB solid phase " is a reversed phase solid phase with hydrophilic and lipophilic components suitable for a variety of purposes. The HLB solid phase can be used in an SPE cartridge suitable for use in the method of the invention, e.g., Oasi s Commercially available as HLB SPE cartridges.

[0049] " Alumina Solid Phase " is a free 18 Removes F-fluoride and optimizes the radiochemical purity of the final product As a means of 18 Aluminum oxide normal phase solid phase routinely used in F labeling methods The alumina solid phase can be used in the methods of the invention in SPE cartridges, e.g. It is sold commercially as rs Alumina N Light.

[0050] In the method of the present invention, steps (a) to (c) or (a) to (e) are carried out in sequence.

[0051] In one embodiment of the method of the present invention, the substituent LG in the compound of formula I is a linear or branched C 1- 10 Haloalkylsulfonic acid substituents, linear or branched C 1-10 Alkyl sulfonic acid substituent, Examples of LG include fluorosulfonic acid substituents, or aromatic sulfonic acid substituents. benzenesulfonic acid, toluenesulfonic acid, nitrobenzenesulfonic acid, benzenesulfonic acid, Trifluoromethanesulfonic acid, fluorosulfonic acid, and perfluoroalkylsulfonic acid In one embodiment, LG is trifluoromethanesulfonic acid.

[0052] In one embodiment of the method of the present invention, the substituent PG in the compounds of formula I and II 1 is linear or Branch C 1-10 It is an alkyl chain or an aryl substituent. For example, PG 1 is methyl, ethyl, It may be t-butyl or phenyl. In one embodiment, PG 1 is methyl or ethyl In another embodiment, PG 1 is ethyl.

[0053] In one embodiment of the method of the present invention, the substituent PG in the compounds of formula I-III 2 Carbami The substituents are phosphate, amide, imide or amine. Examples include t- Butoxycarbonyl, allyloxycarbonyl, phthalimide, and N-benzylidene In one embodiment, PG 2 is t-butoxycarbonyl.

[0054] The method of the present invention further comprises the step of combining the purified reaction mixture obtained in step (e) with a citrate buffer. In one embodiment, the compounding step may further include a 50 to 100 mM concentration of chloramphenicol. In another embodiment, a 60 to 90 mM citrate buffer; in yet another embodiment, This gives a 75-85 mM citrate buffer.

[0055] In one embodiment, the methods of the invention are automated, for example, performed on an automated synthesizer. 18 F-labeled PET tracers are often conveniently prepared in an automated radiosynthesizer. word" automatic radiosynthesizer ” means Satyamurthy et al (1999 Cl The principle of the unit operation described in (in Positr Imag;2(5):233-253) The term "means an automated module based on Unit Operations " is a complex process This means that the process becomes a series of simple operations or reactions that can be applied to a variety of materials. Suitable automated synthesizers are commercially available from a variety of suppliers, including: GE H Healthcare (Chalfont St. Giles, UK); CTI (Northampton, USA) Ion Beam Applications (Belgium, B-13 48 Levain-la-Neuve, Chemin du Cyclotron 3), Raytest (D Examples include Sigma-Aldrich (St. Ill., Strabenhardt) and Bioscan (Washington, DC, USA).

[0056] Commercial automated radiosynthesizers also produce liquid radioactive materials as a result of radiopharmaceutical preparation. Suitable containers for radioactive waste are also provided. Because they are designed for use in industrial cells, they generally do not have radiation shielding. The hazardous work cells, also known as hot cells, protect operators from potential radiation doses as well as chemical vapors. and / or provide suitable radiation shielding to protect against ventilation to remove radioactive vapours. Provide.

[0057] The preferred automated radiosynthesizer of the present invention performs the preparation of a given batch of radiopharmaceuticals. Disposable or single-use " cassette " The cassette is a synthesis device that interacts with a chromatographic cassette (commonly called a "cartridge"). The automated radiosynthesizer minimizes the risk of cross-contamination by simply exchanging cassettes. This means that it has the flexibility to manufacture various radiopharmaceuticals while keeping costs down. The following are the advantages of the system: simplification of the equipment configuration and the associated reduction in the risk of operator error; Improved manufacturing practice compliance, multi-tracer capabilities, and Rapid change of cassettes, automatic pre-operation diagnostic testing of cassettes and reagents, and the relationship between the synthesis to be performed and the chemical reagents Automatic barcode cross-checking, traceability of reagents, disposable and therefore The advantages are that there is no risk of cross-contamination and tampering and misuse are prevented. The cassette was simplified by removing the alumina cartridge. The cartridge is free 18 F-fluoride residues from inadequate purification and / or radiolysis However, the inventors have decided to use an alumina cartridge to remove the The rest activity in the tracheid was very low (0.1-0.3%), and the purified These data show both alumina radiolysis and a low degree of radiolysis. This suggests that the cartridge is redundant and can be omitted. The risk of any particles from the alumina cartridge being present in the drug product poses a risk to has the added benefit of not having

[0058] This process removes residual acetone while the deesterification step proceeds on the tC18 cartridge. This was improved by adding a parallel step to remove the nitrile from the reaction vessel. and more predictable residual acetonitrile concentrations than obtained using prior art methods. This results in a final formulation that can be used. [Brief description of the drawings]

[0059] [Figure 1] FIG. 1 shows an exemplary cassette for carrying out the methods of the present invention.

[0060] Brief description of the embodiment The following non-limiting examples serve to illustrate specific embodiments of the inventive subject matter.

[0061] Abbreviations used in the examples BOC tert-Butyloxycarbonyl DP Pharmaceuticals HLB Hydrophobic Lipophilic Balance K 222 Kryptofix 222 MeCN Acetonitrile QMA Quaternary Methyl Ammonium RAC radioactivity concentration RCP radiochemical purity. EXAMPLES

[0062] Comparative Example 1: Prior Art 18 Synthesis of F-FACBC 1(i) FASTlab Cassette Commercially available GE FASTlab™ single-use cartridges All radiochemistry was carried out using the set. Each cassette was made of polypropylene. It is built around a one-piece manifold with 25 three-way valves. The kit contains a 5 ml reaction vessel (cyclic olefin copolymer), one 1 ml syringe and two 5 ml syringes, spikes for connecting 5 pre-filled reagent vials, 1 Includes water bags (100ml) and various SPE cartridges and filters The flow path is controlled by nitrogen purge, vacuum and three syringes. Fully automated system. was produced by a cyclotron. 18 Designed for single-step fluorination with F-fluoride FASTlab is a software package that allows you to control syringe movement, nitrogen gas injection, and Events such as heating, vacuuming, and temperature adjustments are programmed in a step-by-step, time-dependent sequence. Vial A contained 1105 μl of 79.5% (v / v) MeCN aqueous solution of K 222 (58.8mg, 156μmol), K2CO3 (8.1mg, 60.8μmol) Vial B contained 4M HCl (2.0 ml). Vial C contained MeCN (4.1 ml). Vial D contained the precursor (48.4 mg, 123.5 μmol ) in its dried form (stored at -20°C until cassette assembly). Vial E contained 2 A 30 ml product collection glass vial contained 20 M NaOH (4.1 ml). The tube was filled with 10 mM trisodium citrate (10 ml).

[0063] 1(ii) 18 F-Fluoride Production No carrier added 18 F-fluoride, 18 O(p,n) 18 F nuclear reaction GEPETt Race 6 Cyclotron (Norwegian Cyclotron Centre The device was fabricated at the National Institute of Informatics (NII) in Oslo, Norway. It was equipped with a dual beam, HAVAR foil, and a current of 30 μA. Two identical Ag targets were irradiated with 16.5 MeV protons. Each target had a ≥96% 18 O] Water (Marshall Isotope After irradiation and delivery to the hot cell, each target was 16 O ] and washed with water (Merck, water for GR analysis). 18 The F-fluoride solution was passed through the QMA.18 The QMA was then flushed with MeCN and sent to waste. Ta.

[0064] 1(iii) 18 F-Fluoride labeling Captured 18 F-fluoride is eluted into the reaction vessel using the eluent from vial A, then The mixture was concentrated to dryness by azeotropic distillation with acetonitrile (vial C). The precursor was mixed with the precursor in solution D, and the dissolved precursor was added to a reaction vessel and heated to 85°C. Ta.

[0065] 1(iv) Removal of Ester Protecting Group The reaction mixture was diluted with water and sent through a tC18 cartridge. The reaction vessel was diluted with water. The cartridge was then sent through the tC18 cartridge. The interstitial tissue was washed with water and then incubated with 2M NaOH, followed by 2M Na The OH was sent to waste.

[0066] 1(v) Removal of BOC protecting group The labeled intermediate (without the ester group) was then reacted from the tC18 cartridge with water. The BOC group was hydrolyzed by adding 4M HCl, and the reaction The reaction vessel was heated.

[0067] 1(vi) Purification Coarse 18 The contents of the reaction vessel containing F-FACBC were passed through HLB and alumina cartridges. The HLB and alumina cartridges were washed with water and transferred to a 30 ml product vial. and collected in a product vial.

[0068] 1(vii) combination 2M NaOH and water were added to the product vial to obtain a total of 26 ml of purified formulation (DP). Got it at l. ( 1viii) Acetonitrile concentration Acetonitrile (MeCN) concentration was measured using an FID, automatic liquid injector, and USP stationary phase G Fused silica containing 43 (6% cyanopropylphenyl-94% dimethylpolysiloxane) Capillary column and reporting integrator A gas chromatograph equipped with a data system with reintegration capability. The pH was determined using the Fischer system. 1000 μg / ml MeCN was used as the standard solution. The ink was prepared by transferring 1 ml of purified water into a 2 ml GC crimp-cap vial. 1 ml of the standard solution was placed in a 2 ml GC crimp cap vial. The 0.20 ml sample was transferred to a low volume insert (0. The solution was transferred to a 2 ml GC crimp-cap vial equipped with a 25 ml centrifuge tube and immediately capped. The experimental conditions for the C instrument were as follows: Carrier gas flow, helium: 2.0 ml / min Oven temperature program: 40°C for 6 min, then 20°C / min to 240°C for 4 min. Injector temperature: 225℃ Split ratio: 10:1 Detector: FID Detector temperature: 250℃ Hydrogen flow rate: 30ml / min Air flow rate: 400ml / min Make-up gas flow rate (He): 25ml / min.

[0069] The experimental conditions for the automatic liquid injector were as follows: Solvent pre-wash: 3 Sample pump: 3 Solvent post-wash: 3 Injection volume: 1ml.

[0070] The column was conditioned at 250° C. for at least 1 hour before use.

[0071] One injection of each standard solution and two replicate injections of the sample solution were performed in addition to a blank injection. , was carried out in the following order: 1. Blank 2.Calibration standard solution 3.Calibration standard solution 4. Blank 5. Sample, iteration 1 6. Sample, iteration 2 7. Blank.

[0072] The concentration of each analyte, C sample was calculated in μg / ml using the following formula:

[0073]

number

[0074] (In the formula, A sample : Peak area of ​​the analyte in the sample C std : concentration of analyte in calibration standard (μg / ml) A std : Peak area of ​​analyte in calibration standard, average of duplicate injections. ( 1ix) Aluminum concentration Aluminum concentrations were determined by inductively coupled plasma atomic emission spectrometry (ICP-AES). He asked. ( 1x) Radiochemical parameters 18 The radiochemical purity (RCP) and radioactivity concentration (RAC) of F-FACBC were measured.

[0075] RCP was determined by thin layer chromatography (TLC). TLC strip analysis was performed using a mobile phase consisting of ethanol:water:acetic acid, 20:5:5:1 v / v. RCP and 18 All radiochemical impurities, including F-fluoride, The results are reported as a percentage of the net sum of the peaks. ( 1xi) Results The following results were obtained.

[0076] [Table 1]

[0077] Example 2: Using the method of the present invention 18 Synthesis of F-FACBC 2(i) Changes in Order A modified FASTlab™ cassette was used, as shown in Figure 1. The sequence described in Example 1 was used, except that extra heating / purging of the vessel was included. The hydrolysis step is replaced by two steps, the first of which involves the addition of Heat the reaction vessel at 85° C., purge the reaction vessel with nitrogen (600 mbar HF) and evacuate (-600 mbar). The second step also involved hydrolysis, but at 100°C. Heating was stopped. Nitrogen purge (600 mbar HF) and vacuum (-600 mbar) were applied. It was used to cool the reaction vessel. In addition, the alumina SPE was removed and the arrangement was changed to HLB After the cartridge step the product was transferred directly into the formulation buffer vial.

[0078] 2(ii) Analysis The analytical method described in Example 1 was used.

[0079] [Table 2] The present invention includes the following aspects. <1> anti-1-amino-3- 18 F-Fluorocyclobutyl-1-carboxylic acid ( 18 1. A positron emission tomography (PET) tracer composition comprising F-FACBC, the composition containing no more than 5.0 μg / ml of dissolved aluminum (Al). <2> The composition contains acetonitrile (MeCN) at 50 μg / ml or less; <1> PET tracer composition according to claim 1. <3> the composition contains no more than 3.0 μg / ml of dissolved Al; <1> or <2> PET tracer composition according to claim 1. <4> the composition contains no more than 1.5 μg / ml of dissolved Al; <3> PET tracer composition according to claim 1. <5> With an end of synthesis (EOS) radiochemical purity (RCP) of 95% or more, <1> ~ <4> PET tracer composition according to any one of claims 1 to 5. <6> With EOS RCP of 98% or more, <5> PET tracer composition according to claim 1. <7> With EOS RCP of 99% or more, <6> PET tracer composition according to claim 1. <8> Contains 50-100mM citrate buffer, <1> ~ <7> PET tracer composition according to any one of claims 1 to 5. <9> 1. A method for preparing a PET tracer composition, the method comprising: (a) In a reaction vessel 18 reacting a F-fluoride source with a precursor compound of formula I to obtain a reaction mixture comprising a compound of formula II:

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Claims

1. anti-1-amino-3- 18 F-fluorocyclobutyl-1-carboxylic acid ( 18 1. A pharmaceutical composition for positron emission tomography (PET) comprising F-FACBC, said pharmaceutical composition containing no more than 5.0 μg / ml of dissolved aluminum (Al) and no more than 50 μg / ml of acetonitrile (MeCN).

2. 2. The pharmaceutical composition of claim 1, containing no more than 25 μg / ml of acetonitrile (MeCN).

3. The pharmaceutical composition of claim 1 or 2 for use in imaging of prostate cancer.

4. 4. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition contains less than 3.0 μg / ml of dissolved Al.

5. 5. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition contains no more than 1.5 μg / ml of dissolved Al.

6. 6. The pharmaceutical composition of claim 1, having an end of synthesis (EOS) radiochemical purity (RCP) of 95% or more.

7. 7. The pharmaceutical composition of claim 6 having an EOS RCP of 98% or greater.

8. The pharmaceutical composition according to any one of claims 1 to 7, comprising 50 to 100 mM citrate buffer.

9. anti-1-amino-3- 18 F-fluorocyclobutyl-1-carboxylic acid ( 18 F-FACBC) for use in positron emission tomography (PET), comprising: the pharmaceutical composition contains no more than 5.0 μg / ml of dissolved aluminum (Al) and no more than 50 μg / ml of acetonitrile (MeCN); The method further comprising: (a) In a reaction vessel 18 reacting a F-fluoride source with a precursor compound of formula I below to obtain a reaction mixture comprising a compound of formula II below, wherein the reacting step is carried out in acetonitrile; 【Chemistry 3】 (In the formula, LG is trifluoromethanesulfonic acid; P.G. 1 is ethyl, P.G. 2 is t-butoxycarbonyl. 【Chemistry 4】 (In the formula, PG 1 and P.G. 2 is as defined in formula I. (b) The reaction mixture containing the compound of formula II is transferred outside the reaction vessel, and PG is removed using an alkaline solution. 1 to obtain a reaction mixture comprising a compound of formula III: 【Chemistry 5】 (In the formula, PG 2 is as defined in formula I. (c) PG 1 applying heat to the reaction vessel simultaneously with the removal of (d) Return the reaction mixture containing the compound of Formula III to the reaction vessel and remove PG using an acid solution. 2 Removal of 18 obtaining a reaction mixture comprising F-FACBC; (e) 18 purifying the reaction mixture containing F-FACBC by passing it through a hydrophilic lipophilic balance (HLB) solid phase, 18 and a step not including passing a reaction mixture containing F-FACBC through an alumina solid phase. A method comprising:

10. 10. The method of claim 9, wherein the pharmaceutical composition contains no more than 25 μg / ml of acetonitrile (MeCN).

11. 11. The method of claim 9 or claim 10, wherein the preparation of the pharmaceutical composition is carried out using an automated radiosynthesizer.

12. The method of claim 11 , wherein the automated radiosynthesizer does not include an alumina cartridge.

13. 13. The process of any one of claims 9 to 12, wherein the temperature used to apply heat to the reaction vessel in step (c) is from 80°C to 140°C.

14. 13. The process of any one of claims 9 to 12, wherein the temperature used to apply heat to the reaction vessel in step (c) is from 85°C to 130°C.

15. 13. The process of any one of claims 9 to 12, wherein the temperature used to apply heat to the reaction vessel in step (c) is from 80°C to 85°C.

16. anti-1-amino-3- 18 F-fluorocyclobutyl-1-carboxylic acid ( 18 F-FACBC), the pharmaceutical composition comprising 60-90 mM citrate buffer, containing no more than 5.0 μg / ml dissolved aluminum (Al), and no more than 50 μg / ml acetonitrile (MeCN).

17. 17. The pharmaceutical composition of claim 16, wherein the pharmaceutical composition contains no more than 25 μg / ml of acetonitrile (MeCN).

18. 18. The pharmaceutical composition according to claim 16 or 17, comprising 75 to 85 mM citrate buffer.

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