Method for preparing a composition containing dissolved [18F]fluoride and compositions obtainable thereby

Abstract

Dissolved [ 18 A method for preparing a composition suitable for radiofluorination comprising: - water and [F] fluoride ion. 18 providing an aqueous solution containing [F] fluoride ions; and passing the aqueous solution through a solid phase extraction device containing an anion exchange resin to deposit [F] fluoride ions on the anion exchange resin. 18 [F] fluoride ions captured on the anion exchange resin 18 [F] fluoride ions from the water; and [F] fluoride ions from the anion exchange resin by passing an elution composition comprising an organic solvent and a salt of an alkanoic acid through a solid phase extraction device. 18 and eluting the [F] fluoride ions dissolved in an organic solvent and a salt of an alkanoic acid. 18 and obtaining as an eluate a composition comprising dissolved [F] fluoride ions. 18 A composition comprising [F] fluoride ions, and a dissolved [ 18 A method for preparing a radiofluorinated organic compound is provided that involves preparing a composition containing [F] fluoride ion.

Description

[Technical field]

[0001] The present invention provides a method for the efficient radiofluorination of organic compounds, such as compounds containing silicon-based fluoride acceptor (SiFA) groups, by the synthesis of dissolved [ 18 The present invention relates to a method for the preparation of a composition comprising [F] fluoride, and to a composition obtainable by the method according to the invention. Furthermore, a method for the preparation of a radioactive fluorinated organic compound is provided. [Background technology]

[0002] In Nuclear Medicine 18 F During the last few decades, positron emission tomography (PET) has emerged as an established diagnostic procedure with ever-increasing importance in nuclear medicine. 11 C. 13 N, 15 O. 64 Cu, and 68 In contrast to other common PET radionuclides such as Ga, 18 F has always attracted great interest, mainly due to its favorable physical properties (Non-Patent Document 1). Among them, its favorable half-life (109.7 min) is notable for being long enough to allow the radiosynthesis of even complex tracers and to allow the delivery of these tracers to small facilities that do not have their own manufacturing facilities (Non-Patent Documents 1 and 2). Furthermore, 18 The decay of F occurs primarily by positron emission (97%) at relatively low energy (649 keV), making this isotope an ideal candidate for high-resolution PET imaging (Non-Patent Documents 1 and 3). Despite these remarkable properties, 18 While the rather difficult radiochemistry of F has always been a crucial limitation to its widespread use, 68 Ga-labeled radiopharmaceuticals were pioneered by simple kit-like radiolabeling methods, but a variety of exciting new approaches are beginning to transition radiofluorinated tracers to more widespread use in nuclear medicine.

[0003] New18 Silicon-based fluoride acceptors as a F-labeling technique To radioactive tracers 18 The introduction of F usually occurs via nucleophilic substitution reactions in electron-deficient aromatic and aliphatic systems bearing suitable leaving groups. 18 Due to the low reactivity of [F] fluoride, 18 Harsh reaction conditions are usually required to generate [F] fluorine-carbon bonds (Non-Patent Document 4), which lead to undesirable by-products and, as a result, laborious purification of the tracer (Non-Patent Document 4). Such harsh labeling conditions also preclude the direct radiofluorination of complex biomolecules, which are usually only accessible by the use of prosthetic groups (Non-Patent Document 5). For these reasons, novel 18 Intense research efforts have been directed towards the development of F-labeling methods. In 2006, Schirrmacher et al. reported the use of natural F-labeling at the silicon atom of so-called silicon-based fluoride acceptors, as shown in the following scheme: 19 F and radioactivity 18 An alternative approach based on isotopic exchange with F 18 reported a F labeling technique (Non-patent Documents 6 and 7).

[0004] [ka]

[0005] The main advantage of this method is that no special activation reagents or elevated reaction temperatures are required for labeling, and 18 Radiochemical yield (RCY) and molar radioactivity (A m This relies on the fact that it eliminates the need for subsequent high performance liquid chromatography (HPLC) purification, which would reduce the amount of chromatographic conversion required. 8 In recent years, this method has been gaining popularity due to its high RCY and A m In 18 It has been developed into a rapid and efficient method for the preparation of F-labeled PET ligands (Non-Patent Documents 5 and 9).

[0006] Radiofluorination of silicon-based fluoride acceptors Initial attempts to radiolabel compounds with silicon-based fluoride acceptors consisted of azeotropically dried [ 18 Radiofluorination was carried out using [F] fluoride (Non-Patent Document 8). It was soon recognized that partial neutralization of the base required during the preparation of the radioactivity was a prerequisite for efficient radiofluorination (Non-Patent Document 8). Unfortunately, due to the variability in the adsorption of the base to the walls of the drying vessel, it was difficult to determine the exact amount of acid required for the neutralization reaction (Non-Patent Document 8). As a result, the RCY in the radiofluorination of compounds with silicon-based fluoride acceptors was reproducible only to a limited extent (Non-Patent Document 8). The so-called Munich Method [ 18 It was later realized that the preparation of [F] fluoride would be the preferred technique from this point of view (Non-Patent Document 8). The Munich process, first developed by Wessmann et al., involves the deposition of aqueous [ 18 F]fluoride capture followed by drying the activity on the cartridge using anhydrous solvents and [K + ⊂ 2.2.2] OH - The dried [ 18 The application of this technology to the radiofluorination of silicon-based fluoride acceptors has made it possible to achieve two goals at once. On the one hand, the dried [F] fluoride is extracted by solid-phase extraction, and then the [F] fluoride is recovered (Non-Patent Document 10 and Patent Document 1). 18 The preparation of [F] fluorides avoided the laborious and time-consuming azeotropic distillation procedure (Non-Patent Document 10). On the other hand, partial neutralization of the eluate could be achieved more easily due to the absence of adsorption (Non-Patent Document 8). Wangler et al. were the first to precisely quantify the effect of neutralization of the eluate on the subsequent radiofluorination of silicon-based fluoride acceptors (Non-Patent Document 8). This group demonstrated that the addition of oxalic acid resulted in the formation of hydroxide-containing [ 18 Adjust the [F]fluoride eluate and [K + ⊂ 2.2.2] OH -The highest radiochemical conversion rate (RCC) of somatostatin ligands bearing silicon-based fluoride acceptors was determined using a molar ratio of 4:1 and 4:1 (Non-Patent Document 8). Similar observations were made with PSMA ligands bearing silicon-based fluoride acceptors using the same labeling method. nat This was done by Wurzer et al., who studied the isotope exchange reaction with Ga-rhPSMA-7 (Non-Patent Document 11). + ⊂ 2.2.2] OH - Only when the molar ratio of oxalic acid to acetic acid was 3.3 to 6.7, sufficient 18 The incorporation of F has been reported (Non-Patent Document 11). Their detailed radioactive fluorination protocol is shown in Figure 1. 18 This includes preparation of [F]fluoride, neutralization of the eluate with oxalic acid, optimized reaction conditions for isotope exchange, and final radiotracer workup by solid-phase extraction.

[0007] In detail, the optimized radiofluorination procedure for silicon-based fluoride acceptors established by Wurzer et al. 18 [F] fluoride was dissolved in Sep-Pak® QMA Carbonate (sorbent weight 46 mg, ion exchange capacity 230 μeq g -1 ), and then drying the activity by washing the cartridge with air, MeCN (10 mL), and air (Non-Patent Document 16). 18Recovery of [F]fluoride is achieved by purging the cartridge in the reverse direction with an elution cocktail containing a solution of KOH (83 μmol) and Kryptofix® 222 (91 μmol) in MeCN (500 μL) (Non-Patent Document 16). The eluate is then partially neutralized by adding oxalic acid (1 M in MeCN, 30 μL, 30 μmol) and subsequently diluted with a compound with a silicon-based fluoride acceptor (1 mM in DMSO, 10-150 μL, 10-150 nmol) (Non-Patent Document 16). Labeling is continued for 5 min at room temperature, followed by dilution of the reaction mixture with an acidic buffer (PBS, pH=3, 9 mL) (Non-Patent Documents 12 and 16). Unincorporated [F]fluoride is then recovered by purging the cartridge in the reverse direction with an elution cocktail containing KOH (83 μmol) and Kryptofix® 222 (91 μmol) in MeCN (Non-Patent Document 16). 18 As [F]fluoride is the only impurity requiring separation, purification is then performed by simple solid-phase extraction. Thus, the radioactive fluorinated compound is retained on an Oasis® HLB Plus Light cartridge (sorbent weight 30 mg) and flushed with PBS (10 mL) and air (12). Finally, the purified tracer is eluted with a mixture of ethanol and water (1:1, v / v, 300 μL) (12).

[0008] Dried by the Munich process 18 Although the use of [F]fluoride has emerged as the preferred method for radiofluorination of silicon-based fluoride acceptors, certain drawbacks remain. Most notably, the precise addition of oxalic acid for partial neutralization of the eluate remains a weak point affecting the efficiency of radiolabeling (Non-Patent Documents 8 and 11). Furthermore, the prepared eluate still exhibits alkaline properties, so radiofluorination of base-labile precursors seems impossible. Another aspect is the lack of feasibility of using [F]fluoride dried by the Munich method in clinical practice. 18F] fluoride. Due to its toxicity, the concentration of Kryptofix® 222 must be determined in the final product of the radiotracer before administration (Non-Patent Document 13). In addition, oxalic acid is not listed in the US and European Pharmacopoeias, so additional toxicological evaluation and quality control procedures of the final product are required before the corresponding manufacturing procedures can be recognized as GMP manufacturing of radiopharmaceuticals in terms of clinical trials. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] WO2011 / 141410 [Patent Document 2] WO2020 / 157177A1 [Patent Document 3] WO2020 / 157128A1 [Non-patent literature]

[0010] [Non-Patent Document 1] Schirrmacher, R.; Wangler, C.; Schirrmacher, E., Fluorine-18 Radiochemistry: Theroy and Practice. Pharmaceutical Radiochemistry (I) 2010, 1, 5-73. [Non-Patent Document 2] Tredwell, M.; Gouverneur, V., 18F labeling of arenes. Angewandte Chemie International Edition 2012, 51 (46), 11426-11437 [Non-Patent Document 3] Jadvar, H.; Parker, JA, Clinical PET and PET / CT. Springer Science & Business Media: 2006. [Non-Patent Document 4] Bernard-Gauthier, V.; Bailey , JJ ; Liu , ZB ; Wangler , B. ; Wangler , C. ; Jurkschat , K. ; Perrin , DM ; Schirrmacher, R., From Unorthodox to Established: The Current Status of F-18-Trifluoroborate- and F-18-SiFA-Based Radiopharmaceuticals in PET Nuclear Imaging. Bioconjugate Chemistry 2016, 27(2), 267-279.

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[0011] In this context, we have developed a method for the preparation of soluble [ 18 It was an object of the present invention to provide an efficient method for the preparation of compositions containing [F] fluoride, and the compositions obtainable by this method.

[0012] Specifically, the related objects of the present invention can be summarized as follows: From anion exchange resin 18 [F] to provide a method that helps avoid the need for a subsequent evaporation step after fluoride elution; [ 18 reducing the overall time for preparation of compositions containing [F] fluoride, leading to improved RCY in subsequent radiofluorination reactions; in a form that is readily applicable to the radiofluorination of compounds with silicon-based fluoride acceptors without the need for further additives, 18 providing a composition comprising [F] fluoride; To provide a composition which allows particularly efficient radiofluorination of compounds having silicon-based fluoride acceptors by heating the reaction mixture; To provide a composition that allows for the radiofluorination of base-sensitive compounds having silicon-based fluoride acceptors. [Means for solving the problem]

[0013] To that extent, the present invention relates to a method for producing a soluble 18 A method for preparing a composition containing [F] fluoride ions, comprising the steps of: - Water and 18 providing an aqueous solution containing [F] fluoride ions; - The aqueous solution is passed through a solid phase extraction device containing an anion exchange resin, and [ 18 [F] fluoride ions captured on the anion exchange resin 18 F] fluoride ions from the water; - By passing an elution composition comprising an organic solvent and a salt of an alkanoic acid through a solid phase extraction device, 18 and eluting [F] fluoride ions. - An organic solvent, a salt of an alkanoic acid, and a dissolved 18 and obtaining as an eluate a composition comprising [F] fluoride ions.

[0014] A second aspect of the present invention is a method for preparing a radiofluorinated organic compound, comprising the steps of: - by the process according to the first aspect of the present invention, an organic solvent, a salt of an alkanoic acid and a dissolved 18 F] fluoride ions; - The composition thus prepared is contacted with an organic compound to be radioactively fluorinated, so that the organic compound is converted into the [ 18 and causing a radiofluorination reaction with [F] fluoride ion. As a variant of the process for preparing a radiofluorinated organic compound according to the second embodiment, the radiofluorinated organic compound can also be added to the elution composition comprising an organic solvent and a salt of an alkanoic acid used in the process according to the first embodiment of the invention. According to this variant, 18 [F]fluoride ions can be eluted from the anion exchange resin in the presence of a radiofluorinated organic compound.

[0015] According to another aspect, the present invention provides a method for the preparation of a soluble soluble cellulose derivative comprising the steps of: 18 [F] fluoride ions. It will be appreciated that such a composition may be advantageously obtained as a product in the process according to the first aspect of the present invention. Effect of the Invention

[0016] By using the elution composition defined herein, it is possible to obtain a soluble eluent without relying on water as a (co)solvent. 18 It has been found by the inventors that [F]fluoride can be efficiently eluted from anion exchange resins. Additional steps to remove water or other solvents, such as evaporation steps, that may interfere with the subsequent radiofluorination reaction, can be omitted. Furthermore, the presence of cations in the form of cryptates is not required.

[0017] Moreover, compared to the hydroxides used in the Munich process, the anions of alkanoic acids have a much lower basicity, which is a major advantage. In particular, partial neutralization of the eluate prior to any radiofluorination reaction by the addition of a certain amount of acid is no longer required. The eluate of the present invention is readily applicable to radiofluorination, in particular to the radiofluorination of compounds with silicon-based fluoride acceptors, and is also useful for the radiofluorination of base-sensitive compounds. 18 The present invention also provides a method for the preparation of a soluble [ 18A further advantage of the [F]fluoride-containing eluate composition is that the eluate can be heated to increase the reaction rate, and therefore the RCY, of the subsequent radiofluorination reaction without affecting the structural integrity of the fluoride-reactive compounds contained in the eluate. [Brief description of the drawings]

[0018] [Figure 1] FIG. 1 shows a general scheme of the preparation of [18F]fluoride according to the Munich procedure (steps 1–3), its subsequent use in the radiofluorination of compounds bearing silicon-based fluoride acceptors (steps 4–5), and purification of the final radiotracer by solid-phase extraction (steps 6–9). [Diagram 2] FIG. 1 shows a scheme for the preparation of preferred [F]fluorides according to the present invention (steps 1-3), their subsequent use in the radiofluorination of compounds bearing silicon-based fluoride acceptors (steps 4-5), and purification of the final radiotracer by solid phase extraction (steps 6-9). [Diagram 3] Radio-reversed-phase HPLC chromatograms of a compound with a 18F-labeled base-sensitive silicon-based fluoride acceptor purified by solid-phase extraction (column I, 10→70% B in A, 15 min, 95% B in A, 5 min, tR=9.6 min). A) Preparation of [18F]fluoride by the Munich method and subsequent partial neutralization. B) Preparation of [18F]fluoride according to the present invention. [Figure 4]Radio-reversed-phase HPLC chromatograms of folate receptor alpha ligand with 18F-labeled silicon-based fluoride acceptor purified by solid-phase extraction (column II, 10->70% B in A, 15 min, 95% B in A, 5 min, tR=13.0 min). A) Preparation of [18F]fluoride according to the invention and radiofluorination at room temperature. B) Preparation of [18F]fluoride according to the invention and radiofluorination at 95°C. C) Preparation of [18F]fluoride according to the Munich method, followed by partial neutralization of the eluate and radiofluorination at room temperature. D) Preparation of [18F]fluoride according to the Munich method, followed by partial neutralization of the eluate and radiofluorination at 95°C. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] The following items provide an overview of aspects of the invention, as well as an overview of preferred embodiments thereof. 1. Dissolved 18 A method for preparing a composition containing [F] fluoride ions, comprising the steps of: - Water and 18 providing an aqueous solution containing [F] fluoride ions; - passing the aqueous solution through a solid phase extraction device containing an anion exchange resin to deposit on the anion exchange resin [ 18 [F] fluoride ions captured on the anion exchange resin 18 F] fluoride ions from the water; - By passing an elution composition comprising an organic solvent and a salt of an alkanoic acid through a solid phase extraction device, 18 and eluting [F] fluoride ions. - An organic solvent, a salt of an alkanoic acid, and a dissolved 18 and obtaining as an eluate a composition comprising:

[0020] 2. The method according to item 1, wherein the solid phase extraction device is a solid phase extraction column or a solid phase extraction cartridge.

[0021] 3. The method according to item 1 or 2, wherein the anion exchange resin is a resin containing quaternary ammonium groups.

[0022] 4. After the aqueous solution passes through the device, the [ 18 4. The method of any one of items 1 to 3, further comprising purging the solid phase extraction device containing the [F] fluoride ions with a gas.

[0023] 5. The method according to item 4, wherein the gas is selected from air, nitrogen, helium, and argon, or from a mixture of two or more thereof.

[0024] 6. From anion exchange resin [ 18 Before eluting the [F] fluoride ion, the trapped [ 18 The method according to any one of items 1 to 5, further comprising the step of washing the anion exchange resin containing the [F] fluoride ions with an organic solvent.

[0025] 7. The method according to item 6, wherein the organic solvent used to wash the anion exchange resin is an anhydrous solvent.

[0026] 8. The method according to item 6 or 7, wherein the organic solvent used to wash the anion exchange resin comprises or consists of a polar aprotic solvent, preferably comprises or consists of a solvent selected from dimethylsulfoxide (DMSO) and acetonitrile (MeCN), more preferably comprises or consists of dimethylsulfoxide (DMSO).

[0027] 9. [ 18 [F] fluoride ion elution step, and after the anion exchange resin is washed with an organic solvent, [ 18 9. The method of any one of items 6 to 8, further comprising purging the solid phase extraction device containing the [F] fluoride ions with a gas.

[0028] 10. The method according to item 9, wherein the gas is selected from air, nitrogen, helium, and argon, or from a mixture of two or more thereof.

[0029] 11. The elution composition comprises a compound represented by formula (A-1):

[0030] [ka]

[0031] [In the formula, -X + is selected from the cryptates of ammonium cation, alkylammonium cation and alkali or alkaline earth metal cation; preferably from the ammonium cation or the sodium cryptate of 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (2,2,2-Cryptand, Kryptofix® 222), more preferably from the ammonium cation, - R is H, a linear or branched C1-C20 alkyl group; preferably H or methyl, more preferably H. 11. The method according to any one of the preceding claims, comprising a salt of an alkanoic acid represented by the formula:

[0032] 12. The method according to any one of the preceding claims, wherein the salt of the alkanoic acid comprises or consists of a formate salt.

[0033] 13. The method of claim 12, wherein the salt of an alkanoic acid comprises or consists of ammonium formate.

[0034] 14. The method according to any one of items 1 to 13, wherein the concentration of the salt of alkanoic acid in the elution composition is in the range of 0.1 to 1.5 mol / L, preferably in the range of 0.5 to 1.3 mol / L.

[0035] 15. The method according to any one of items 1 to 14, wherein the organic solvent contained in the elution composition comprises or consists of a polar aprotic organic solvent, preferably comprises or consists of a solvent selected from dimethylsulfoxide (DMSO) and acetonitrile (MeCN), more preferably comprises or consists of dimethylsulfoxide (DMSO).

[0036] 16. [ 18 16. The method according to any one of items 1 to 15, wherein during the step of eluting the [F] fluoride ions, the elution composition or the anion exchange resin has a temperature above room temperature, preferably in the range of 25°C to below the boiling point of the organic solvent contained in the elution composition, more preferably in the range of 25°C to 120°C.

[0037] 17. The method according to any one of items 1 to 16, wherein the ratio of the volume of the elution composition passed through the solid phase extraction device to the mass of the anion exchange resin in the solid phase extraction device, in μL / mg, is in the range of 2:1 to 40:1, preferably 5:1 to 20:1, more preferably 5:1 to 15:1.

[0038] 18. The method according to any one of items 1 to 17, wherein the volume of the elution composition passed through the solid phase extraction device is in the range of 100 to 2000 μL, preferably 300 to 1000 μL, more preferably 400 to 600 μL.

[0039] 19. The method according to any one of items 1 to 18, wherein the water content of the composition obtained as the eluate is in the range of 0 to 5% (vol. / vol.), preferably 0 to 2% (vol. / vol.), based on the total volume of the eluate composition.

[0040] 20. The method according to any one of the preceding claims, wherein each organic solvent used in the method is an anhydrous organic solvent.

[0041] 21. The method according to any one of items 1 to 20, wherein the composition obtained as eluate is essentially free of water.

[0042] 22. The method according to any one of the preceding claims, which does not include any step in which water is removed by evaporation.

[0043] 23. The method according to any one of items 1 to 22, wherein the elution composition further comprises a radiofluorinated organic compound.

[0044] 24. A method for preparing a radioactive fluorinated organic compound, comprising the steps of: - A method according to any one of items 1 to 22, comprising: 18 F] fluoride ions; - contacting the composition with an organic compound to be radiofluorinated, to cause the organic compound to fluorine-containing 18 and causing a radiofluorination reaction with [F] fluoride ions.

[0045] 25. The organic compound to be radiofluorinated is dissolved in an organic solvent and a salt of an alkanoic acid. 18 25. The method of claim 24, wherein the compound is contacted by dissolving or dispersing in a composition comprising:

[0046] 26. The method according to any one of items 24 or 25, in which the composition obtained as eluate according to the method according to any one of items 1 to 22 is contacted with an organic compound to be radiofluorinated without modifying or removing any components dissolved in the composition obtained as eluate.

[0047] 27. The method according to any one of items 24 to 26, wherein the composition obtained as an eluate according to the method according to any one of items 1 to 22 is diluted with a solvent selected from the group consisting of dimethylsulfoxide (DMSO), acetonitrile (MeCN), or other polar aprotic solvents before being contacted with the organic compound to be radiofluorinated.

[0048] 28. The method according to any one of items 24 to 26, in which the composition obtained as eluate according to the method according to any one of items 1 to 22 is directly contacted with the organic compound to be radiofluorinated without any modification of the composition obtained as eluate.

[0049] 29. A method for preparing a radioactive fluorinated organic compound, comprising the steps of: - The method according to item 23, comprising the steps of: - mixing an organic solvent, a salt of an alkanoic acid, and a dissolved 18 preparing a composition comprising [F] fluoride ions and a radiofluorinated organic compound; - The organic compound contained in the composition 18 and causing a radiofluorination reaction with [F] fluoride ions.

[0050] 30. The organic compound to be radiofluorinated has the formula (S-1):

[0051] [ka]

[0052] [In the formula, X S teeth, 19 F, OH, or H, preferably 19 F, R S1 and R S2 are independently a linear or branched C3 to C10 alkyl group, preferably R S1 and R S2 is independently selected from isopropyl and tert-butyl, more preferably RS1 and R S2 is tert-butyl, the wavy line indicates the bond attaching the functional group to the remainder of the organic compound to be radiofluorinated, The radioactive fluorination reaction is S Base and 18 with the exchange of F. 30. The method according to any one of items 24 to 29, comprising a non-radioactive silicon-based fluoride acceptor (SiFA) moiety having a functional group represented by:

[0053] 31. The method according to item 30, wherein the organic compound to be radiofluorinated comprises a substituted aryl group, the aryl group having a group of formula (S-1) as defined in item 30 as a substituent attached to the aromatic ring, and optionally having one or more further substituents attached to the aromatic ring in addition to the group of formula (S-1).

[0054] 32. The method according to item 31, wherein the substituted aryl group is a substituted phenyl group.

[0055] 33. Radioactive fluorination reaction was carried out at 10°C or higher, and the reaction was carried out with an organic solvent and a salt of an alkanoic acid. 18 33. The method according to any one of items 24 to 32, wherein the method is carried out at a temperature between 0.1 to 1.5° C. and the boiling temperature of the organic solvent contained in the composition comprising [F] fluoride ions.

[0056] 34. Radioactive fluorination reaction is carried out at 20°C or higher, and the organic solvent and salt of alkanoic acid are dissolved [ 18 34. The method according to claim 33, wherein the composition is carried out at a temperature between the boiling temperature of the organic solvent contained in the composition comprising [F] fluoride ion.

[0057] 35. The method of any one of items 24 to 34, further comprising the step of recovering the radiofluorinated organic compound following the radiofluorination reaction.

[0058] 36. A mixture of an organic solvent, a salt of an alkanoic acid, and a dissolved 18 F] fluoride ion.

[0059] 37. The composition according to item 36, further comprising a radiofluorinated organic compound.

[0060] 38. The composition according to item 36 or 37, which is a composition obtainable by the method according to any one of items 1 to 23.

[0061] 39. The composition according to any of items 36 to 38, wherein the organic solvent comprises a polar aprotic organic solvent selected from dimethylsulfoxide (DMSO) and acetonitrile (MeCN), and the salt of the alkanoic acid comprises ammonium formate.

[0062] The present invention will be described in more detail below. It will be understood that the information provided here also applies to the above items and the appended claims. 18 The process for preparing a composition comprising [F]fluoride ions may be referred to hereinafter as a process according to a first aspect of the invention, whereas the process for preparing a radiofluorinated organic compound may be referred to hereinafter as a process according to a second aspect of the invention.

[0063] As a first step in the process according to the first aspect of the present invention, water and [ 18 [F] An aqueous solution containing fluoride ions is provided. As will be appreciated by those skilled in the art, for radiopharmaceutical purposes, 18 F ions, for example, are generated in a cyclotron, 18 O]H 2 It can be produced by bombarding water containing O with protons. In this procedure, [ 18 O]O 2- Part of [ 18 F] fluoride ion ([ 18 F]F - ) is converted into water and [ 18 An aqueous solution containing [F] fluoride ions is typically a solution that contains water as the only solvent.

[0064] [ 18In order to make the [F] fluoride ion available for an efficient radiofluorination reaction, 18 O]O 2- of[ 18 F]F - It may be desirable to reconstitute the aqueous solution resulting from the conversion to provide a composition having a higher concentration of dissolved fluoride ions in a solvent with limited or no water.

[0065] In the method of the first aspect of the present invention, the aqueous solution is passed through a solid phase extraction device containing an anion exchange resin, and [ 18 F] fluoride ions are captured and trapped on the anion exchange resin [ 18 [F] fluoride ions are separated from the water. Suitable solid phase extraction devices, such as solid phase extraction columns or cartridges, are known to those skilled in the art and are commercially available. 18 To retain the [F] fluoride ion, the solid phase extraction device is provided with an anion exchange resin, i.e., a resin having a positively charged ionic functional group, preferably -N(CH 3 ) 3 + The resin contains quaternary ammonium groups such as ammonium phosphate groups. 18 F] the majority of fluoride ions, ideally [ 18 It is desirable to capture most or essentially all of the [F] fluoride ions. This is done by increasing the ion exchange capacity of the extraction device to the amount of [F] fluoride ions supplied by the aqueous solution passed through the device. 18 This can be achieved by adapting the amount of [F] fluoride ion.

[0066] Captured by anion exchange resin 18 The separation of [F] fluoride ions from water is 18 It will be appreciated that this is achieved by passing water through the device while leaving the [F] fluoride ions in the device, thus removing most of the water contained in the aqueous solution.

[0067] Captured by anion exchange resin 18Further reducing the amount of water bound to [F] fluoride ions (i.e., 18 If desired, the resin may be dried further to remove the [F] fluoride ion. 18 Prior to the step in which [F] fluoride ions are eluted, the method of the invention may include one or more additional steps.

[0068] For example, the method of the first aspect includes: (a) capturing a cationically active substance on an anion exchange resin; 18 The method may further include purging the solid phase extraction device containing [F] fluoride ions with a gas after the aqueous solution has been passed through the device, for example, the gas being selected from air, nitrogen, helium, and argon, or a mixture of two or more thereof. It will be appreciated that the gas may be dried before being used for purging.

[0069] Another step that may be included in the method of the first aspect of the invention to dry the fluoride prior to the step in which the fluoride ions are eluted from the resin is (b) eluting [ 18 Before eluting the [F] fluoride ion, the trapped [ 18 [F] washing the anion exchange resin containing fluoride ions with an organic solvent. A single solvent or a mixture of two or more solvents may be used for this step, with a single solvent being preferred. When a mixture of two or more organic solvents is used, it will be understood that the following preferred properties are desired for each solvent in the mixture:

[0070] The organic solvent is preferably an anhydrous organic solvent. Preferably, the organic solvent comprises or consists of a polar aprotic solvent, such as a solvent selected from acetonitrile (MeCN), dimethylsulfoxide (DMSO), dimethylacetamide (DMAA), dimethylformamide (DMF), and tetrahydrofuran (THF). More preferably, the organic solvent comprises or consists of a solvent selected from dimethylsulfoxide (DMSO) and acetonitrile (MeCN), even more preferably, comprises or consists of dimethylsulfoxide (DMSO), and most preferably consists of dimethylsulfoxide.

[0071] Captured [ 18 If the method of the present invention includes the above-mentioned step (b) of washing the anion exchange resin containing the fluoride ions, (c) after the anion exchange resin has been washed with the organic solvent, removing the [ 18 Before the [F] fluoride ions were eluted, the [ 18 This may be followed by a step of purging the solid phase extraction device containing [F] fluoride ions with a gas. Also, in this step, exemplary gases are selected from air, nitrogen, helium, and argon, or a mixture of two or more thereof. It will be understood that the gas may be dried before being used for purging.

[0072] As the skilled reader will appreciate, optional additional drying steps may be included in the method according to the invention as a single step or in a suitable combination. For example, the method may comprise, after passing the aqueous solution through the solid phase extraction device and before eluting fluoride ions from the resin, step (a), or step (b), or step (a) followed by step (b), or step (a) followed by steps (b) and (c), or step (b) followed by step (c), where steps (a), (b), and (c) are defined as above.

[0073] [ 18 After the [F] fluoride ions have been separated from the water to the desired extent, preferably by essentially or completely removing the water, the [ 18 [F] fluoride ions are eluted from the anion exchange resin. In accordance with the present invention, this is accomplished using an elution composition that includes an organic solvent and a salt of an alkanoic acid.

[0074] The elution composition is generally a liquid composition in which the salt of an alkanoic acid is dissolved in an organic solvent. Typically, the organic solvent and the salt of an alkanoic acid contribute at least 90% by weight, preferably at least 95% by weight, of the elution composition, based on 100% by weight of the total weight of the elution composition. The elution composition may consist essentially of the organic solvent and the salt of an alkanoic acid, and more preferably consists of the organic solvent and the salt of an alkanoic acid.

[0075] The elution composition may comprise a single organic solvent or a mixture of two or more organic solvents, with a single solvent being preferred. When a mixture of two or more organic solvents is used, it will be understood that the following preferred properties are desired for each solvent in the mixture:

[0076] Preferably, the organic solvent contained in the elution composition comprises or consists of a polar aprotic solvent, such as a solvent selected from acetonitrile (MeCN), dimethylsulfoxide (DMSO), dimethylacetamide (DMAA), dimethylformamide (DMF), and tetrahydrofuran (THF). More preferably, the organic solvent contained in the elution composition comprises or consists of a solvent selected from dimethylsulfoxide (DMSO) and acetonitrile (MeCN), even more preferably comprises or consists of dimethylsulfoxide (DMSO), and most preferably consists of dimethylsulfoxide.

[0077] The organic solvent is preferably an anhydrous organic solvent. Thus, each organic solvent used in the method according to the invention, for example in the optional anion exchange resin washing step and in the elution composition, is also preferably an anhydrous organic solvent.

[0078] The elution composition may comprise a single salt of an alkanoic acid or a mixture of two or more such salts, with a single salt being preferred. When a mixture of two or more salts of alkanoic acids is included, it will be understood that the following preferred properties are desired for each salt of the mixture:

[0079] The elution composition preferably has the formula (A-1)

[0080] [ka] The present invention includes salts of alkanoic acids represented by the formula:

[0081] In formula (A-1), X + is selected from ammonium cation, alkylammonium cation, and cryptates of alkali or alkaline earth metal cations. It should be noted that cryptates of alkali or alkaline earth metal cations may be used as the cation of the salt of an alkanoic acid, but may lack such cryptates when another cation, such as an ammonium cation, is used. The nitrogen atom of the alkylammonium cation may have 1 to 4 alkyl substituents, preferably C1 to C6 alkyl substituents, more preferably methyl substituents. Preferably, X + is selected from ammonium cation or sodium or potassium cryptate of 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (2,2,2-Cryptand, Kryptofix® 222), more preferably ammonium cation. R in formula (A-1) is selected from H and linear or branched C1-C20 alkyl groups, preferably H and methyl, more preferably H.

[0082] The salt of formula (A-1) preferably provides at least 90% by weight, more preferably at least 95% by weight, of the salt of alkanoic acid, and even more preferably the salt of alkanoic acid contained in the elution composition consists of the salt of formula (A-1).

[0083] As mentioned above, the salt of an alkanoic acid in the elution composition preferably comprises or consists of a formate salt, and more preferably comprises or consists of ammonium formate.

[0084] The concentration of the salt of alkanoic acid in the elution composition is preferably selected so that the salt can be completely dissolved in the organic solvent of the elution composition.Without exceeding this limit, a higher concentration is generally more advantageous.For example, the concentration of the alkanoic acid in the elution composition can be in the range of 0.1-1.5 mol / L, preferably in the range of 0.5-1.3 mol / L.

[0085] As mentioned above, the elution composition may include a radioactive fluorinated organic compound as an optional further component. As the skilled reader will appreciate, to implement this option, the radioactive fluorinated organic compound may be eluted from the anion exchange resin by [ 18 [F] fluoride ions can be added to the elution composition prior to the step of eluting the fluoride ions.

[0086] Furthermore, as mentioned above, it will be appreciated that the elution composition is particularly preferably an elution composition which comprises or consists of MeCN or DMSO as organic solvent, a formate as salt of an alkanoic acid and, as an optional further component, a radiofluorinated organic compound, and even more preferably an elution composition which comprises or consists of DMSO as organic solvent, ammonium formate as salt of an alkanoic acid and, as an optional further component, a radiofluorinated organic compound.

[0087] By passing the elution composition through the solid phase extraction device, [ 18The temperature of the elution composition and the anion exchange resin for the step of eluting the [F] fluoride ion is not particularly limited. For example, the elution composition and the anion exchange resin may have a temperature of about room temperature (e.g., 15 to 25°C). 18 If it is desired to enhance the mobility of [F]fluoride ions, the elution composition and the anion exchange resin may have a temperature ranging from 25° C. to below the boiling point of the organic solvent contained in the elution composition, such as in the range of 25° C. to 120° C. It will be understood that if the elution composition contains more than one organic solvent, the upper limit will generally be determined by the organic solvent having the lower boiling point.

[0088] The volume of the elution composition passed through the solid phase extraction device is not particularly limited, but 18 In order to obtain an eluate with a high concentration of [F] fluoride ions, it is necessary to use the [ 18 It is convenient to use a volume no greater than that required to elute the majority of the [F] fluoride ions.

[0089] In the method according to the first aspect of the present invention, the ratio of the volume of the elution composition passed through the solid-phase extraction device to the mass of the anion exchange resin in the solid-phase extraction device is not particularly limited. The ratio can be conveniently adjusted to a desired range. For example, the ratio of the volume of the elution composition passed through the solid-phase extraction device (expressed in μL) to the mass of the anion exchange resin in the solid-phase extraction device (expressed in mg) can be in the range of 2:1 to 40:1, preferably 5:1 to 20:1, more preferably 5:1 to 15:1.

[0090] For example, the volume of the elution composition passed through the solid phase extraction device can be in the range of 100 to 2000 μL, preferably 300 to 1000 μL, and more preferably 400 to 600 μL.

[0091] Water and [ in the step in which fluoride ions are captured on the anion exchange resin 18It may be advantageous for the efficiency of the elution step if the direction in which the elution composition in the elution step flows through the solid phase extraction device is reversed relative to the direction of flow of the aqueous solution containing [F] fluoride ions.

[0092] According to the method of the first aspect of the present invention, a mixture of an organic solvent, a salt of an alkanoic acid, and a dissolved 18 A composition is obtained as eluate comprising [F] fluoride ions and, as an optional further component, an organic compound to be radiofluorinated. Such a composition obtained as product by the process according to the first aspect of the invention constitutes a further aspect of the invention. The composition prepared by the process according to the first aspect of the invention and obtained as eluate in this process may hereinafter be referred to as "eluate composition" or simply as "eluate".

[0093] As the skilled reader will appreciate, the content of the eluate composition is typically determined by the elution composition used in the method according to the first aspect of the invention. Thus, a portion of the anions of the alkanoate salts of the elution composition may be present in the eluate composition as eluted [ 18 The information provided above regarding the organic solvents and salts of alkanoic acids of the eluent composition continues to apply to the organic solvents and salts of alkanoic acids of the eluent composition, except that fluoride ion is replaced by [F] fluoride ion.

[0094] Thus, the eluate composition typically contains salts of alkanoic acids and 18 A liquid composition in which fluoride ions [F] are dissolved in an organic solvent. The liquid composition comprises an organic solvent, a salt of an alkanoic acid, and dissolved [ 18 The [F] fluoride ions may provide at least 90% by weight, preferably at least 95% by weight, of the eluent composition, based on a total weight of the eluent composition being 100% by weight. The eluent composition comprises an organic solvent, a salt of an alkanoic acid, and a dissolved [ 18 [F] fluoride ions, or more preferably, the method comprises the steps of: 18 F] fluoride ion.

[0095] In the presence of radioactive fluorinated organic compounds [ 18 Since the radiofluorination reaction may proceed to some extent during the step of eluting [F]fluoride ions, according to an alternative embodiment the eluate composition may comprise, as optional further components, a radiofluorinated organic compound, or a radiofluorinated organic compound and a radiofluorinated compound.

[0096] The eluent composition may comprise a single organic solvent or a mixture of two or more organic solvents, with a single solvent being preferred. When a mixture of two or more organic solvents is used, it will be understood that the following preferred properties are desired for each solvent in the mixture:

[0097] Preferably, the organic solvent contained in the eluent composition comprises or consists of a polar aprotic solvent, such as a solvent selected from acetonitrile (MeCN), dimethylsulfoxide (DMSO), dimethylacetamide (DMAA), dimethylformamide (DMF), and tetrahydrofuran (THF). More preferably, the organic solvent contained in the eluent composition comprises or consists of a solvent selected from dimethylsulfoxide (DMSO) and acetonitrile (MeCN), even more preferably comprises or consists of dimethylsulfoxide (DMSO), and most preferably consists of dimethylsulfoxide.

[0098] The organic solvent is preferably an anhydrous organic solvent.

[0099] The eluent composition may comprise a single salt of an alkanoic acid or a mixture of two or more such salts, with a single salt being preferred. When a mixture of two or more salts of alkanoic acids is included, it will be understood that the following preferred properties are desired for each salt of the mixture:

[0100] The eluate composition preferably comprises a compound represented by the formula (A-1):

[0101] [ka] The present invention includes salts of alkanoic acids represented by the formula:

[0102] In formula (A-1), X + is selected from ammonium cation, alkylammonium cation, and cryptates of alkali or alkaline earth metal cations. It should be noted that cryptates of alkali or alkaline earth metal cations may be used as the cation of the salt of an alkanoic acid, but may lack such a cryptate if another cation, such as an ammonium cation, is used. The nitrogen atom of the alkylammonium cation may have 1 to 4 alkyl substituents, preferably C1 to C6 alkyl substituents, more preferably methyl substituents. Preferably, X + is selected from ammonium cation or sodium or potassium cryptate of 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (2,2,2-Cryptand, Kryptofix® 222), more preferably ammonium cation. R in formula (A-1) is selected from H and linear or branched C1-C20 alkyl groups, preferably H and methyl, more preferably H.

[0103] The salt of formula (A-1) preferably accounts for 90% by weight or more, more preferably 95% by weight or more of the salt of alkanoic acid, and even more preferably the salt of alkanoic acid contained in the eluent composition consists of the salt of formula (A-1).

[0104] As mentioned above, the salt of an alkanoic acid in the eluent composition preferably comprises or consists of a formate salt, and more preferably comprises or consists of ammonium formate.

[0105] The concentration of the salt of alkanoic acid in the eluent composition is, for example, in the range of 0.1 to 1.5 mol / L, preferably in the range of 0.5 to 1.3 mol / L. 18Due to the relatively low concentration of [F] fluoride ions, the concentration of the salt usually does not change significantly when the fluoride ions are eluted.

[0106] Furthermore, as described above, the eluent composition contains MeCN or DMSO as an organic solvent, a formate salt as a salt of an alkanoic acid, and a soluble [ 18 It will be appreciated that it is particularly preferred that the eluent composition comprises or consists of [F] fluoride ions and, as optional further components, a radioactively fluorinated organic compound or a radioactively fluorinated organic compound and a radioactively fluorinated organic compound. Even more preferred is an eluent composition comprising DMSO as the organic solvent, ammonium formate as the salt of an alkanoic acid and dissolved [F] fluoride ions and, as optional further components, a radioactively fluorinated organic compound or a radioactively fluorinated organic compound. 18 F] fluoride ions and, as an optional further component, a radioactively fluorinated organic compound, or a radioactively fluorinated organic compound and a radioactively fluorinated organic compound.

[0107] Using the method according to the present invention, 18 The concentration of [F] fluoride ion can be conveniently adjusted as needed. For example, 18 The concentration of [F] fluoride ions may range from 10 MBq to 150 GBq, which is applied to a 500 μL volume of the eluate composition.

[0108] The water content of the eluate composition is preferably in the range of 0 to 5% (vol. / vol.), more preferably 0 to 2% (vol. / vol.), based on the total volume of the eluate composition. It is even more preferable that the eluate composition is essentially free of water, and even more preferably free of water.

[0109] From anion exchange resin 18 while still ensuring efficient recovery of the captured [F] fluoride ion. 18Due to the ability to dry [F]fluoride ions and / or the ability to use anhydrous solvents, the method according to the first aspect of the invention described above does not include any step of removing water by evaporation, and no such step is required either prior to or during use of the eluate composition in the radiofluorination reaction.

[0110] As will be appreciated from the above, the method according to the first aspect of the invention may be advantageously used to extract, for example, 18 F] fluoride ion, 18 F] to concentrate fluoride ions, and / or 18 F] fluoride ions can be reconstituted.

[0111] A method for preparing a radiofluorinated organic compound according to a second aspect of the present invention comprises the steps of: - according to the method of the first aspect of the invention described above, a mixture of an organic solvent, a salt of an alkanoic acid and a dissolved 18 F] fluoride ions; - contacting the composition with an organic compound to be radiofluorinated, to cause the organic compound to fluorine-containing 18 and causing a radiofluorination reaction with [F] fluoride ions, the product of the radiofluorination reaction being a radiofluorinated organic compound.

[0112] The information provided above with respect to the details and preferred embodiments of the process of the first aspect of the invention described above, is intended to provide a method for the preparation of a soluble soluble carboxylic acid salt of an organic solvent, a salt of an alkanoic acid, and a dissolved 18 It will be understood that this also applies fully to the method according to the second aspect of the invention, which comprises the preparation of a composition comprising [F] fluoride ion.

[0113] As generally mentioned above, it is an advantage of the process according to the first aspect of the invention that the eluate composition obtained is immediately applicable to a subsequent radiofluorination reaction, such as that carried out in the process of the second aspect of the invention. For example, it is not necessary to add an acid to the eluate composition in order to adjust its pH value before contacting it with the compound to be subjected to the radiofluorination reaction. For example, it is possible to contact the eluate composition obtained in the process according to the first aspect of the invention with the organic compound to be radiofluorinated without being subjected to any further processing steps.

[0114] Therefore, contacting the composition obtained as eluate according to the method of the first aspect with an organic compound to be radiofluorinated without modifying or removing any components dissolved in said composition obtained as eluate is a preferred variant of the method according to the second aspect of the invention.

[0115] In a more preferred variant, the organic solution obtained as eluate according to the method of the first embodiment is directly contacted with the organic compound to be radiofluorinated, without any modification of the eluate composition.

[0116] However, if desired, the composition obtained as eluate according to the method of the first aspect can be diluted, for example, with a solvent, preferably a polar aprotic solvent, before contacting with the organic compound to be radiofluorinated. Exemplary solvents are selected from the group consisting of dimethylsulfoxide (DMSO) and acetonitrile (MeCN).

[0117] Typically, the organic compound to be radiofluorinated is dissolved in an organic solvent and a salt of an alkanoic acid. 18 F] fluoride ions by dissolving or dispersing in a composition comprising the compound.

[0118] However, as a variant of the method for preparing a radioactively fluorinated organic compound according to the second aspect, the radioactively fluorinated organic compound can also be added to an elution composition comprising an organic solvent and a salt of an alkanoic acid. According to this variant, a method for preparing a radioactively fluorinated organic compound is provided which no longer requires contacting the radioactively fluorinated organic compound with a composition prepared according to the first aspect of the invention. Rather, this method for preparing a radioactively fluorinated organic compound comprises: According to an embodiment of the process of the first aspect of the invention, a mixture of an organic solvent, a salt of an alkanoic acid and a dissolved 18 preparing a composition comprising [F] fluoride ions and a radiofluorinated organic compound, the elution composition further comprising a radiofluorinated organic compound; - The organic compound contained in the composition 18 and causing a radiofluorination reaction with [F] fluoride ions.

[0119] As will be appreciated by the skilled reader, the radioactive fluorinated organic compounds referred to herein are radioactive [ 18 Radiofluorination (or radiofluorination reaction) is therefore the process by which an organic compound is reacted to produce a radioactive [ 18 In the method according to the second aspect of the invention, the radiofluorination or radiofluorination reaction refers to the step of forming a chemical bond, typically a covalent bond, with a fluorine atom [F]. 18 This is achieved by reacting it with [F] fluoride ion.

[0120] The organic compound to be radiofluorinated preferably contains a silicon-based fluoride acceptor (SiFA) moiety that is not radiofluorinated, i.e., a silicon atom that is covalently bonded to the silicon atom during the radiofluorination reaction. 18 It contains a group having a group or atom that can be substituted with F. Preferably, the SiFA portion has the formula (S-1):

[0121] [ka] It is a functional group represented by the formula:

[0122] In formula (S-1), X bonded to a Si atom S The base is 19 F, OH or H, preferably 19 F. R S1 and R S2 are independently a linear or branched C3 to C10 alkyl group, preferably R S1 and R S2 is independently selected from isopropyl and tert-butyl, more preferably R S1 and R S2 is tert-butyl. Thus, particularly preferred SiFA moieties in organic compounds to be radiofluorinated have a functional group of formula (S-1), where X S teeth 19 F and R S1 and R S2 It will be understood that both are tert-butyl. The wavy line in formula (S-1) represents the bond connecting the functional group to the remainder of the organic compound.

[0123] Preferably, the organic compound to be radiofluorinated comprises a substituted aryl group having a group of formula (S-1) as a substituent attached to the aromatic ring, and optionally, in addition to the group of formula (S-1), one or more further substituents, such as 1, 2 or 3, attached to the aromatic ring. More preferably, the organic compound to be radiofluorinated comprises a substituted phenyl group having a group of formula (S-1) as a substituent attached to the phenyl ring, and optionally, in addition to the group of formula (S-1), one or more further substituents, such as 1, 2 or 3, attached to the phenyl ring.

[0124] When the organic compound to be radiofluorinated contains a non-radiofluorinated silicon-based fluoride acceptor (SiFA) moiety having a functional group represented by formula (S-1), the radiofluorination reaction of the organic compound can be carried out by reacting X S Base and18 With the exchange of F. It is further preferred that the SiFA moiety is a group of formula (S-2):

[0125] [ka]

[0126] In the formula, X S , R S1 , and R S2 is defined as in (S-1) above, including preferred embodiments thereof, and R S3 R comprises one or more aromatic and / or aliphatic moieties and is optionally represented by formula (S-2): S3 In addition to the substituent R, R is a divalent C1-C20 hydrocarbon group having one or more, such as 1, 2, or 3, further substituents. Such optional substituents can be, for example, organic functional groups. S3 R comprises an aromatic ring, may comprise one or more aliphatic moieties, and is optionally represented by formula (S-2): S3 In addition to the substituent, X is a divalent C6-C12 hydrocarbon group having one or more further substituents, such as 1, 2, or 3. Such optional substituents can be, for example, organic functional groups, which, when present, are preferably attached to an aromatic ring. The wavy line in formula (S-2) indicates the bond connecting the functional group to the remainder of the organic compound. Radiofluorination reactions of organic compounds containing the (S-2) group also involve the reaction of X with a fluorinating group. S Base and 18 With the exchange of F.

[0127] Even more preferred as the SiFA moiety in the radiofluorinated compound is a group of formula (S-3):

[0128] [ka]

[0129] In the formula, R S1 and R S2is defined as in (S-1) above, including preferred embodiments thereof, and F is 18 Replaced by F 19 F atom, and Phe is a phenylene group optionally having one or more further substituents, such as 1, 2, or 3, in addition to the substituents of Phe shown in formula (S-3). Such optional substituents can be, for example, organic functional groups. y is an integer from 0 to 6, preferably 0 or 1. The wavy line indicates the bond connecting the group to the remainder of the compound. The two substituents of the phenylene group shown in formula (S-3), i.e., (CH 2 ) y group, and the Si-containing group) are preferably in the para position relative to each other. Particularly preferred is when the compound to be radiofluorinated is S1 and R S2 is tert-butyl, y is 0 or 1, and the two substituents of the phenylene group represented by formula (S-3) are in the para position relative to each other.

[0130] Suitable organic functional groups which may be present as optional substituents in the groups of formulae (S-2) and (S-3) are, for example, groups containing one, two or three heteroatoms selected from O, N and S, and including said heteroatoms, C and H, a total of six atoms.

[0131] The radiofluorination reaction is typically carried out at temperatures from 10°C, more preferably from 20°C, in an organic solvent and a salt of an alkanoic acid. 18 [F] fluoride ion and the boiling temperature of the organic solvent contained in the composition. It will be understood that if the composition contains more than one organic solvent, the upper limit will generally be determined by the organic solvent having the lower boiling point. For example, a suitable temperature range may be 10°C to 150°C, more preferably 20°C to 150°C.

[0132] If necessary to accelerate the reaction, the radiofluorination reaction can be carried out at temperatures above room temperature, such as at or above 50° C., at or above 70° C., or at or above 90° C. As noted above, it is an advantage of the eluate compositions provided in accordance with the present invention that elevated temperatures do not affect the structural integrity of the organic compounds being radiofluorinated.

[0133] It will be appreciated that the method according to the second aspect may also include the step of recovering the radiofluorinated organic compound following the radiofluorination reaction.

[0134] In this specification, a number of documents are cited, including patent applications and manufacturer's instructions.The disclosures of these documents are not considered relevant to the patentability of this invention, but are incorporated herein by reference in their entirety.More specifically, all references are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference.

[0135] References Patent Literature P1. H.-J. Wester, G. Henriksen, S. Wesmann, Method for the direct elution of reactive [18F]fluoride from an anion exchange resin in an organic medium suitable for radiolabelling without any evaporation step by the use of alkalimetal and alkaline earth metal cryptates, WO 2011 / 141410. P2. A. Wurzer, H.-J. Wester, M. Eiber, PSMA binding dual mode radiotracer and therapeutic, WO 2020 / 157177 A1. P3. D. Di Carlo, H.-J. Wester, Silicon-fluoride acceptor substituted radiopharmaceuticals and precursors thereof, WO 2020 / 157128 A1. Non-Patent Literature 1. Schirrmacher, R.; Wangler, C.; Schirrmacher, E., Fluorine-18 Radiochemistry: Theroy and Practice. Pharmaceutical Radiochemistry (I) 2010, 1, 5-73. 2. Tredwell, M.; Gouverneur, V., 18F labeling of arenes. Angewandte Chemie International Edition 2012,51 (46), 11426-11437. 3. Jadvar, H.; Parker, J. A., Clinical PET and PET / CT. Springer Science & Business Media: 2006. 4. Bernard-Gauthier, V.; Bailey, J. J.; Liu, Z. B.; Wangler, B.; Wangler, C.; Jurkschat, K.; Perrin, D. M.; Schirrmacher, R., From Unorthodox to Established: The Current Status of F-18-Trifluoroborate- and F-18-SiFA-Based Radiopharmaceuticals in PET Nuclear Imaging. Bioconjugate Chemistry 2016, 27 (2), 267-279. 5. Bernard-Gauthier, V.; Wangler, C.; Schirrmacher, E.; Kostikov, A.; Jurkschat, K.; Wangler, B.; Schirrmacher, R., 18F-Labeled silicon-based fluoride acceptors: Potential opportunities for novel positron emitting radiopharmaceuticals. BioMed research international 2014, 2014. 6. Schirrmacher, R.; Bradtmoller, G.; Schirrmacher, E.; Thews, O.; Tillmanns, J.; Siessmeier, T.; Buchholz, H. G.; Bartenstein, P.; Wangler, B.; Niemeyer, C. M., 18F-Labeling of Peptides by means of an Organosilicon-Based Fluoride Acceptor. Angewandte Chemie International Edition 2006, 45 (36), 6047-6050. 7. Ting, R.; Adam, M. J.; Ruth, T. J.; Perrin, D. M., Arylfluoroborates and alkylfluorosilicates as potential PET imaging agents: high-yielding aqueous biomolecular 18F-labeling. Journal of the American Chemical Society 2005, 127 (38), 13094-13095. 8. Wangler, C.; Niedermoser, S.; Chin, J.; Orchowski, K.; Schirrmacher, E.; Jurkschat, K.; Iovkova-Berends, L.; Kostikov, A. P.; Schirrmacher, R.; Wangler, B., One-step 18 F-labeling of peptides for positron emission tomography imaging using the SiFA methodology. nature protocols 2012, 7 (11), 1946-1955. 9. Bernard-Gauthier, V.; Bailey, J. J.; Liu, Z.; Waengler, B. r.; Waengler, C.; Jurkschat, K.; Perrin, D. M.; Schirrmacher, R., From unorthodox to established: The current status of 18F-trifluoroborate-and 18F-SiFA-based radiopharmaceuticals in PET nuclear imaging. Bioconjugate chemistry 2015, 27 (2), 267-279. 10. Wessmann, S.; Henriksen, G.; Wester, H.-J., Cryptate mediated nucleophilic 18F-fluorination without azeotropic drying. Nuklearmedizin 2012, 51 (01), 1-8. 11. Wurzer, A.; Di Carlo, D.; Schmidt, A.; Beck, R.; Schwaiger, M.; Herz, M.; Eiber, M.; Wester, H., PSMA-targeted 18F-labeled Radiohybrid Inhibitors: Labeling chemistry and automated GMP production of 18F-rhPSMA-7. Journal of Nuclear Medicine 2019, 60 (supplement 1), 342-342. 12. Wurzer, A.; Di Carlo, D.; Schmidt, A.; Beck, R.; Eiber, M.; Schwaiger, M.; Wester, H.-J., Radiohybrid Ligands: A Novel Tracer Concept Exemplified by 18F-or 68Ga-Labeled rhPSMA Inhibitors. Journal of Nuclear Medicine 2020, 61 (5), 735-742. 13. Kuntzsch, M.; Lamparter, D.; Bruggener, N.; Muller, M.; Kienzle, G. J.; Reischl, G., Development and successful validation of simple and fast TLC spot tests for determination of Kryptofix(R) 2.2. 2 and tetrabutylammonium in 18F-labeled radiopharmaceuticals. Pharmaceuticals 2014, 7 (5), 621-633. 14. Brichard, L.; Aigbirhio, FI, An Efficient method for enhancing the reactivity and flexibility of [18F] fluoride towards nucleophilic substitution using tetraethylammonium bicarbonate. European Journal of Organic Chemistry 2014, 2014 (28), 6145-6149. 15. Inkster, J.; Akurathi, V.; Sromek, A.; Chen, Y.; Neumeyer, J.; Packard, A., A non-anhydrous, minimally basic protocol for the simplification of nucleophilic 18 F-fluorination chemistry. Scientific Reports 2020, 10 (1), 1-9. 16. Wurzer, A.; Di Carlo, D.; Herz, M.; Richter, A.; Robu, S.; Schirrmacher, R.; Mascarin, A.; Weber, W.; Eiber, M.; Schwaiger, M. and Wester H.-J., Automated Synthesis of [18F, natGa]rhPSMA-7 / -7.3: Results, Quality Control and Experience from more than 200 Routine Productions. EJNMMI Radiopharmacy and Chemistry, submitted.

[0136] The following examples serve to illustrate the invention. EXAMPLES

[0137] material Aqueous for radiofluorination18 [F] fluoride (approximately 0.6–2.0 GBq / mL) was provided by Klinikum rechts der Isar (Munich, Germany) and produced in an in-house PETtrace™ 880 cyclotron (GE Healthcare GmbH, Solingen, Germany). For radioactivity measurements, a CRC®-55tR dose calibrator from Capintec Inc. (Florham Park, NJ, USA) was used.

[0138] [ 18 Sep-Pak® Accell Plus QMA Carbonate Plus Light cartridges (sorbent weight 46 mg, particle size 40 μm, ion exchange capacity 230 μeqg) for the preparation of [F]fluoride -1 ), and 18 Oasis® HLB Plus Light cartridges (sorbent weight 30 mg, particle size 30 μm) for purification of F-labeled compounds were supplied by Waters GmbH (Eschborn, Germany).

[0139] NBu 4 OTf, NBu 4 I, N.H. 4 I, N.H. 4 OAc, NH 4 HCOO, KOH (quality grade “99.99%, semiconductor grade”), oxalic acid (quality grade “99.999% based on trace metals”) and anhydrous DMSO (quality grade “≥99.9%”) were purchased from Sigma-Aldrich Chemie GmbH (Steinheim, Germany). 4OAc was supplied by TCI Deutschland GmbH (Eschborn, Germany). Kryptofix® 222 (quality grade "for synthesis"), water (quality grade "Tracepur®") and anhydrous EtOH (quality grade "EMPARTA®") were provided by Merck KGaA (Darmstadt, Germany). Anhydrous MeCN (quality grade "≥99.9% for DNA synthesis") was purchased from VWR International GmbH (Darmstadt, Germany). Further reagents, solvents and buffers were purchased from Sigma-Aldrich.

[0140] Delivered by either Chemie GmbH or Merck KGaA. The ligand precursors used in the radiofluorination shown below were synthesized according to procedures reported in the literature (Patent Documents 2 and 3).

[0141] [ka]

[0142] [ka]

[0143] [ka]

[0144] 18 The analytical evaluation of F-labeled compounds was performed using a LB500 HERM radio flow monitor (Berthold) equipped with a gradient pump (two LC-20ADs), an autosampler (SIL-20AHT), a system controller (CBM-20A), a column oven (CTO-10ASVP), a UV / Vis detector (SPD-20A), and a NaI detector.

[0145] The analysis was carried out on column I (MultoKrom® 100-5 C18, 125 × 4.6 mm, 5 μm, 1 mL / min, CS-Chromatographie Service GmbH, Langerweh, Germany) or column II (MultoKrom® 100-5 C18, 150 × 4.6 mm, 5 μm, 1 mL / min, CS-Chromatographie Service GmbH, Langerweh, Germany) of an HPLC system (Shimadzu Deutschland GmbH, Neufahrn bei Freising, Germany) consisting of 100 HPLC units (Shimadzu Technologies GmbH&Co.KG, Bad Wildbad, Germany). Radiolabeled compounds were eluted using different gradients of solvent A (water with 0.1% TFA, v / v) and solvent B (MeCN, with 0.1% TFA, 2% water, v / v / v) at a constant flow rate. LabSolutions 5.92 software from Shimadzu Deutschland GmbH was employed for the analysis of the radiochromatograms.

[0146] method [ 18 General procedure for the preparation of [F]fluoride

[0147] GP1:Aqueous [ 18 [F]Fluoride was captured on a QMA cartridge (male side) that had been preconditioned with water (10 mL). After drying in air (2 × 20 mL, female side), the cartridge was washed slowly with anhydrous DMSO (8 mL, female side) and then air-dried again (2 × 20 mL, female side).

[0148] GP2: Aqueous [ 18 [F]Fluoride was captured on a QMA cartridge (male side) that had been preconditioned with water (10 mL). After drying in air (2 × 20 mL, female side), the cartridge was washed slowly with anhydrous MeCN (10 mL, female side) and then air-dried again (2 × 20 mL, female side).

[0149] [ 18 General procedure for [F]fluoride elution GE1: Dry [ 18 [F] fluoride was dissolved in NH in anhydrous DMSO (500 µL) 4 The QMA cartridge was eluted (female) with an elution cocktail consisting of HCOO (40 mg, 634 μmol), followed by washing the QMA cartridge with air (20 mL, female) and combining the resulting droplets with the previous eluate.

[0150] GE2: (reference procedure for comparison purposes) Dry [ 18 [F]Fluoride was eluted from the QMA cartridge (female side) with an elution cocktail consisting of KOH (4.7 mg, 83 μmol) and Kryptofix® 222 (34 mg, 91 μmol) in anhydrous MeCN (500 μL). The QMA cartridge was then washed with air (20 mL, female side) and the resulting droplets were combined with the previous eluate. The eluate was then partially neutralized with a solution of oxalic acid (1 M, 30 μL, 30 μmol) in anhydrous MeCN.

[0151] General procedure for radiofluorination GR1: [ 18 The [F]fluoride eluate was incubated with precursor compound solution (1 mM, 150 μL, 150 nmol) in anhydrous DMSO for 5 min at room temperature. GR2: [ 18 The [F]fluoride eluate was incubated with a solution of the precursor compound (1 mM, 30 μL, 30 nmol) in anhydrous DMSO for 5 min at room temperature. GR3: [ 18 The [F]fluoride eluate was incubated with a solution of the precursor compound (1 mM, 30 μL, 30 nmol) in anhydrous DMSO for 10 min at room temperature. GR4: [ 18 The [F]fluoride eluate was incubated with a solution of the precursor compound (1 mM, 30 μL, 30 nmol) in anhydrous DMSO for 10 min at 95 °C. GR5: [ 18The [F]fluoride eluate was incubated with a solution of the precursor compound (1 mM, 0.5 μL, 0.5 nmol) in anhydrous DMSO for 8 min at 65 °C. GR6: [ 18 The [F]fluoride eluate was incubated with a solution of the precursor compound (1 mM, 0.5 μL, 0.5 nmol) in anhydrous DMSO for 5 min at 70 °C.

[0152] 18 General procedure for work-up of F-labelled compounds GW1: The reaction mixture was diluted with PBS (1M aqueous HCl, pH = 3, 10 mL) and passed through an HLB cartridge (female side) that had been preconditioned with absolute EtOH (10 mL) and water (10 mL). Finally, the HLB cartridge was washed with PBS (10 mL, female side), air-dried (20 mL, female side) and the radiofluorinated compounds were eluted with a mixture of absolute EtOH and water (1:1, v / v, 300 μL, female side).

[0153] Development of the invention [ 18 The method of drying [F] fluoride on a cartridge has been demonstrated to be more convenient in terms of ease and efficiency compared to typical azeotropic distillation, and therefore this technique has been incorporated into the present invention. 18 [F] fluoride was obtained using Sep-Pak® QMA Carbonate (sorbent weight 46 mg, ion exchange capacity 230 μeq g -1) and dried with air, MeCN (10 mL), and again with air before being eluted in the reverse direction. The first challenge was to find an alternative elution cocktail composition that could efficiently release the dried activity from the anion exchange resin. This step is crucial, as it particularly influences the final RCY and therefore the success of the entire method. In this respect, the elution cocktail used in the Munich method (83 μmol KOH and 91 μmol Kryptofix® 222 in 500 μL MeCN) is an efficient composition, since it allows almost quantitative recovery (98.3 ± 0.6%, n = 9). Small amounts (500-1000 μL) of MeCN and DMSO were added to the dried [ 18 The elution of [F]fluoride was investigated. The choice of subsequent elution salts was limited by their solubility in the dipolar aprotic medium. Ammonium or tetraalkylammonium salts were chosen as salt cations to avoid the need for toxic Kryptofix® 222 for metal ion complexation. Several salts containing triflate, iodide, acetate, and formate as corresponding counterions were successfully eluted from the QMA resin. 18 The ability of the eluate to remove [F] fluoride was investigated (Table 1). Particular attention was paid to the basicity of the anion, which must be significantly lower compared to hydroxide. Such conditions were considered to be the key to omit further neutralization of the eluate before radiolabeling. Nevertheless, the eluate was [ 18 It remains slightly basic due to traces of carbonate that always co-elute from the QMA cartridge along with [F] fluoride. Entries 1-5 are provided as reference examples for comparison purposes in the table below.

[0154] [Table 1]

[0155] Dried 18To promote the release of [F]fluoride, roughly equal high molar concentrations of the salt were used in all entries. However, both solutions containing tetrabutylammonium salts in MeCN investigated (entries 1 and 2) proved to be unsuitable as eluents. For the latter salt, the use of its ammonium analogue in combination with DMSO as solvent (entry 3) significantly improved the elution efficiency to about 47%. A similar effect was observed for the acetate salts evaluated. NMe in DMSO 4 The OAc solution (entry 4) removed very little radioactivity from the QMA resin, while the NH 4 An elution cocktail composed of OAc (entry 5) achieved a recovery of over 77%. Substitution of acetate with formate proved to be even more advantageous. Thus, NH 4 When HCOO was used (entries 6 and 7), the elution efficiency increased to almost 90%. When the volume of DMSO was doubled (entry 7), [ 18 The recovery of [F]fluoride was slightly improved. To slow the concentration-dependent rate of isotope exchange in the subsequent radiofluorination with silicon-based fluoride acceptors, it was not worthwhile to increase the volume of eluent to improve the recovery, so the volume of solvent was kept at 500 μL.

[0156] In further optimization studies, NH in DMSO was used 4 The molar amount of HCOO and each [ 18 A correlation was established between the elution capacity of QMA and the [F] fluoride (Table 2). In this series of experiments, the QMA-bound activity was dried in DMSO (8 mL) to avoid the need for a different solvent. 634 μmol of NH 4 Since dissolving HCOO results in a nearly saturated solution, only lower or equal molar amounts were investigated. Entry 1 is provided as a reference example for comparison purposes.

[0157] [Table 2]

[0158] As the amount of salt increased, the elution efficiency improved, with 634 μmol of NH 4 When HCOO was used (entry 5), the maximum was reached at over 88%. 18 The recovery of [F]fluoride was consistent with that determined previously using an equivalent elution cocktail composition (Table 1, entry 6). Thus, the recovery of [F]fluoride on the previous QMA cartridge was consistent with that determined previously using an equivalent elution cocktail composition (Table 1, entry 6). 18 The choice of dipolar aprotic solvent (10 mL MeCN or 8 mL DMSO) for drying of the [F]fluoride did not appear to affect the elution step.

[0159] [ 18 With the aim of further improving the recovery of [F]fluoride, the effect of a given amount of water in the elution cocktail was investigated (Table 3). The beneficial effect of aprotic eluents with additional water content on the elution efficiency was previously demonstrated by other groups. For example, Brichard and Aigbirhio eluted 78 μmol of NEt in 1 mL of aprotic solvent (MeCN, DMSO or DMF) containing up to 5% water. 4 HCO 3 The authors used an elution cocktail containing 1,2-dichlorophenyl 1,3-dichlorophenyl 2,4-dichlorophenyl 1,5-tetrahydrofuran (1,2-dichlorophenyl 2,4-dichlorophenyl 1,5-tetrahydrofuran) in water (Non-Patent Document 14). 18 A gradual increase in the recovery of [F] fluoride was observed (Non-Patent Document 14). A similar effect was also reported by Inkster et al., who showed that consistently higher elution efficiencies were observable when using various tetraethylammonium salts in MeCN or DMSO solutions with increasing water content (Non-Patent Document 15). However, the addition of water did not result in a significant increase in the recovery of [F] fluoride. 18 It had to be noted that the improvement in [F] fluoride recovery comes at the expense of eluent reactivity. To determine the benefit of a given water content in the elution cocktail, it was crucial to determine the achievable RCY using the resulting eluate. To that end, a clinically established PSMA ligand with a silicon-based fluoride acceptor was used. natGa-rhPSMA-7.3 was used as a model compound.

[0160] [Table 3]

[0161] Consistent with the above observations, it was found that the elution efficiency was further improved by adding water to the elution cocktail. The eluent with 1% water content eluted almost 93% of the [ 18 The most efficient [F]fluoride recovery was observed (entry 2), while the anhydrous analog (entry 1) released about 88% of the trapped radioactivity. 18 The excretion of [F]fluoride (>95%) was measured using an elution cocktail with 10% of its volume equivalent to water (entry 6). nat Ga-rhPSMA-7.3 18 F labeling was carried out for 5 min at room temperature. Interestingly, when eluents with water contents up to 2% were used (entries 1, 2, and 3), the RCYs in the radiofluorination reactions were in a similar range. 18 The recovery of [F]fluoride was consequently relative to the lower reactivity of the eluent due to its amount of water. Furthermore, radiofluorination reactions involving eluents with higher water content tended to give lower RCYs (entries 4 and 6) and were generally less reproducible (entries 5 and 6). Since adding water to the elution cocktail is of no great advantage, it is preferred to keep the eluent at its anhydrous composition (entry 1).

[0162] Preferred [ 18 A method for the preparation of [F]fluorides and subsequent radiofluorination of silicon-based fluoride acceptors. 18 A scheme for the use of a [F] fluoride eluent is provided in Figure 2. Figure 2 illustrates a preferred [F] fluoride eluent according to the present invention. 18We demonstrate the preparation of [F]fluoride (steps 1–3), its subsequent use for the radiofluorination of compounds with silicon-based fluoride acceptors (steps 4–5), and the purification of the final radiotracer by solid-phase extraction (steps 6–9).

[0163] Radiofluorination Methods Direct comparison with the Munich Process nat Radiofluorination of Ga-rhPSMA-7.3 To evaluate the performance of the present invention, the recovery of radioactivity and the subsequent nat A direct comparison of the RCY for radiofluorination of Ga-rhPSMA-7.3 with the established Munich method was performed (Table 4). nat Ga-rhPSMA-7.3 was purified using partially neutralized Munich eluates (GP2 and GE2) 18 F-labeling (GR1) and then purified by solid phase extraction (GW1). nat Ga-rhPSMA-7.3 was prepared according to the present invention. 18 The fluorinated peptides were radiofluorinated (GR1) using [F] fluoride (GP1 and GE1) and subsequently purified by solid phase extraction (GW1). Entry 1 in the table is provided as a reference example for comparison purposes.

[0164] [Table 4]

[0165] In terms of elution efficiency, the Munich elution cocktail (entry 1) was found to be approximately 10% higher than the eluent of the present invention (entry 2). 18 Although the recovery of [F] fluoride was rather low, the [ 18 F] nat The RCY of Ga-rhPSMA-7.3 was also found to be almost the same. Therefore, it is presumed that the labeling environment of the eluate provided by the present invention is favorable for the isotope exchange reaction to such an extent that it compensates for its lower elution efficiency.

[0166] Radiofluorination of base-sensitive compounds containing silicon-based fluoride acceptors Base-sensitive compounds with silicon-based fluoride acceptors were first purified using the partially neutralized Munich eluates (GP2 and GE2). 18 F-labeling (GR2) and then purification by solid-phase extraction (GW1). However, subsequent analysis by radio-reverse-phase HPLC (Radio-RP-HPLC) (Figure 3, A) revealed that the desired product (t R = 9.6 min), as well as the synthesis of radioactive fluorinated impurities (t R On the other hand, the presence of [ 18 Radiofluorination of the same compounds (GR2 and GW1) with [F]fluoride (GP1 and GE1) resulted in pure, unadulterated 18 Only F-labeled products were formed (Figure 3, B). This experiment shows that the labeling environment of the Munich eluate may not be compatible with base-sensitive structures, highlighting the utility of the present invention. Specifically, Figure 3 shows the results of the analysis of 1,2-difluorophenyl ... 18 Radio-reversed-phase HPLC chromatograms of compounds with F-labeled base-sensitive silicon-based fluoride acceptors (column I, 10→70% B in A, 15 min, 95% B in A, 5 min, t R = 9.6 minutes) A) Munich method [ 18 F] fluoride preparation and subsequent partial neutralization. B) The present invention 18 Preparation of [F]fluoride.

[0167] Radiofluorination of folate receptor alpha ligands bearing silicon-based fluoride acceptors under heating Folate receptor alpha ligands with silicon-based fluoride acceptors were radiofluorinated using the partially neutralized Munich eluates (GP2 and GE2) at room temperature (GR3) and 95°C (GR4), and the respective products were subsequently purified by solid phase extraction (GW1). 18The radiofluorination was repeated at the same temperatures (room temperature, GR3, and 95°C, GR4) using [F] fluoride (GP1 and GE1), followed by similar product purification (GW1). The RCYs for the radiofluorination of folate receptor alpha ligands measured under the above conditions are summarized as follows (Table 5).

[0168] [Table 5]

[0169] The present invention is 18 Radiofluorination at room temperature using [F]fluoride resulted in an RCY of approximately 20%. A similar reaction involving a partially neutralized Munich eluate gave a higher RCY (36.0 ± 2.0%). 18 This resulted in F-labeled ligand. However, the situation was reversed when the radiolabeling reaction was carried out at 95 °C. In this case, the partially neutralized Munich eluate was used. 18 While the RCY was reduced with F labeling, radiofluorination of the eluate produced by the present invention under heating was found to be highly efficient (54.1 ± 9.6%). To explain these results, comparative radio-reversed-phase HPLC analysis of the final products was performed (Figure 4, A-D). Specifically, Figure 4 shows the results of the fluorination of the eluate purified by solid-phase extraction, 18 Radio-reversed-phase HPLC chromatogram of folate receptor alpha ligand with F-labeled silicon-based fluoride acceptor (column II, 10→70% B in A, 15 min, 95% B in A, 5 min, t R = 13.0 minutes) according to the present invention. 18 B) Preparation of [F]fluoride and radiofluorination at room temperature according to the present invention. 18 C) Preparation of [F] fluoride and radiofluorination at 95°C. 18 F] Preparation of fluoride, followed by partial neutralization of the eluate and radiofluorination at room temperature. D) According to the Munich procedure [ 18 F]fluoride preparation, followed by partial neutralization of the eluate and radiofluorination at 95 °C.

[0170] Folate receptor alpha ligands were radiofluorinated at room temperature (Figure 4, A) or at 95°C (Figure 4, B) using the eluate produced by the present invention, and were free of impurities after solid phase extraction. 18 F-labeled product was obtained. Repeating the experiment with the partially neutralized Munich eluate gave the same results when radiofluorination occurred at room temperature (Figure 4, C). On the other hand, purification of the radioligand afforded by the partially neutralized Munich eluate heated to 95 °C yielded only an unknown by-product (t R = 12.4 min) (Fig. 4, D). This finding indicates that the Munich process eluate is not compatible with higher temperatures, probably due to the concomitant increased reactivity of its basic environment. As a result, heating the reaction mixture as a means to increase the RCY is only applicable to eluates prepared according to the present invention. This allows for generally higher RCYs to be obtained in the radiofluorination of heat-insensitive silicon-based fluoride acceptors.

[0171] Radiofluorination of various siPSMA ligands using minimal amounts of precursors According to GP1 and GE1, 215MBq of aqueous [ 18 [F] fluoride was captured on a QMA cartridge, dried, and eluted, and the eluate was used for radiofluorination of siPSMA-01 according to GR5 and GW1. 18 F-siPSMA-01 had an RCY of 11.1% and an A of 47.8 GBq / μmol. m was prepared.

[0172] According to GP1 and GE1, 145MBq of aqueous [ 18 [F] fluoride was captured on a QMA cartridge, dried, and eluted, and the eluate was used for radiofluorination of siPSMA-02 according to GR6 and GW1. 18 F-siPSMA-02 had an RCY of 9.6% and an A of 27.9 GBq / μmol. m was prepared.

[0173] According to GP1 and GE1, 142 MBq of aqueous [ 18 [F] fluoride was captured on a QMA cartridge, dried, and eluted, and the eluate was used for radiofluorination of siPSMA-03 according to GR6 and GW1. 18 F-siPSMA-03 had an RCY of 8.5% and an A of 24.2 GBq / μmol. m was prepared.

[0174] According to GP1 and GE1, 125MBq of aqueous [ 18 [F] fluoride was captured on a QMA cartridge, dried, and eluted, and the eluate was used for radiofluorination of siPSMA-04 according to GR6 and GW1. 18 F-siPSMA-04 had an RCY of 10.9% and an A of 27.1 GBq / μmol. m was prepared.

[0175] According to GP1 and GE1, 169 MBq of aqueous [ 18 [F] fluoride was captured on a QMA cartridge, dried, and eluted, and the eluate was used for radiofluorination of siPSMA-05 according to GR6 and GW1. 18 F-siPSMA-05 had an RCY of 8.5% and an A of 28.7 GBq / μmol. m was prepared.

[0176] According to GP1 and GE1, 148 MBq of aqueous [ 18 [F] fluoride was captured on a QMA cartridge, dried, and eluted, and the eluate was used for radiofluorination of siPSMA-06 according to GR6 and GW1. 18 F-siPSMA-06 had an RCY of 12.1% and an A of 35.9 GBq / μmol. m was prepared.

[0177] According to GP1 and GE1, 180MBq of aqueous [ 18[F] fluoride was captured on a QMA cartridge, dried, and eluted, and the eluate was used for radiofluorination of siPSMA-07 according to GR6 and GW1. 18 F-siPSMA-07 had an RCY of 10.5% and an A of 37.9 GBq / μmol. m was prepared.

[0178] According to GP1 and GE1, 161 MBq of aqueous [ 18 [F] fluoride was captured on a QMA cartridge, dried, and eluted, and the eluate was used for radiofluorination of siPSMA-08 according to GR5 and GW1. 18 F-siPSMA-08 had an RCY of 12.1% and an A of 38.9 GBq / μmol. m was prepared.

[0179] According to GP1 and GE1, 168 MBq of aqueous [ 18 [F] fluoride was captured on a QMA cartridge, dried, and eluted, and the eluate was used for radiofluorination of siPSMA-09 according to GR6 and GW1. 18 F-siPSMA-09 had an RCY of 7.9% and an A of 26.6 GBq / μmol. m was prepared.

[0180] According to GP1 and GE1, 279 MBq of aqueous [ 18 [F] fluoride was captured on a QMA cartridge, dried, and eluted, and the eluate was used for radiofluorination of siPSMA-11 according to GR5 and GW1. 18 F-siPSMA-11 had an RCY of 11.2% and an A of 62.5 GBq / μmol. m was prepared.

[0181] According to GP1 and GE1, 161 MBq of aqueous [ 18 [F] fluoride was captured on a QMA cartridge, dried, and eluted, and the eluate was used for radiofluorination of siPSMA-12D according to GR6 and GW1. 18F-siPSMA-12D had an RCY of 8.6% and an A of 27.7 GBq / μmol. m was prepared.

[0182] According to GP1 and GE1, 205MBq of aqueous [ 18 [F] fluoride was captured on a QMA cartridge, dried, and eluted, and the eluate was used for radiofluorination of siPSMA-12L according to GR5 and GW1. 18 F-siPSMA-12L had an RCY of 11.0% and an A of 45.2 GBq / μmol. m was prepared.

[0183] According to GP1 and GE1, 200MBq of aqueous [ 18 [F] fluoride was captured on a QMA cartridge, dried, and eluted, and the eluate was used for radiofluorination of siPSMA-13 ​​according to GR6 and GW1. 18 F-siPSMA-13 ​​had an RCY of 8.5% and an A of 33.8 GBq / μmol. m was prepared.

[0184] According to GP1 and GE1, 230MBq of aqueous [ 18 [F] fluoride was captured on a QMA cartridge, dried, and eluted, and the eluate was used for radiofluorination of siPSMA-14 according to GR5 and GW1. 18 F-siPSMA-14 had an RCY of 5.5% and an A of 25.2 GBq / μmol. m was prepared.

[0185] According to GP1 and GE1, 160MBq of aqueous [ 18 [F] fluoride was captured on a QMA cartridge, dried, and eluted, and the eluate was used for radiofluorination of siPSMA-15 according to GR6 and GW1. 18 F-siPSMA-15 had an RCY of 6.6% and an A of 21.2 GBq / μmol. m was prepared.

[0186] According to GP1 and GE1, 171 MBq of aqueous [ 18 [F] fluoride was captured on a QMA cartridge, dried, and eluted, and the eluate was used for radiofluorination of siPSMA-16 according to GR6 and GW1. 18 F-siPSMA-16 had an RCY of 5.3% and an A of 18.2 GBq / μmol. m was prepared. According to GP1 and GE1, 273 MBq of aqueous [ 18 [F] fluoride was captured on a QMA cartridge, dried, and eluted, and the eluate was used for radiofluorination of siPSMA-17 according to GR5 and GW1. 18 F-siPSMA-17 had an RCY of 12.4% and an A of 58.8 GBq / μmol. m was prepared.

[0187] According to GP1 and GE1, 206 MBq of aqueous [ 18 [F] fluoride was captured on a QMA cartridge, dried, and eluted, and the eluate was used for radiofluorination of siPSMA-18D according to GR5 and GW1. 18 F-siPSMA-18D had an RCY of 13.9% and an A of 57.3 GBq / μmol. m was prepared.

[0188] According to GP1 and GE1, 193 MBq of aqueous [ 18 [F] fluoride was captured on a QMA cartridge, dried, and eluted, and the eluate was used for radiofluorination of siPSMA-18L according to GR5 and GW1. 18 F-siPSMA-18L had an RCY of 12.9% and an A of 49.8 GBq / μmol. m was prepared.

[0189] According to GP1 and GE1, 250MBq of aqueous [ 18 [F] fluoride was captured on a QMA cartridge, dried, and eluted, and the eluate was used for radiofluorination of siPSMA-19 according to GR6 and GW1. 18F-siPSMA-19 had an RCY of 7.9% and an A of 39.7 GBq / μmol. m was prepared.

[0190] According to GP1 and GE1, 257 MBq of aqueous [ 18 [F] fluoride was captured on a QMA cartridge, dried, and eluted, and the eluate was used for radiofluorination of siPSMA-20 according to GR5 and GW1. 18 F-siPSMA-20 had an RCY of 8.3% and an A of 42.5 GBq / μmol. m was prepared.

[0191] According to GP1 and GE1, 223 MBq of aqueous [ 18 [F] fluoride was captured on a QMA cartridge, dried, and eluted, and the eluate was used for radiofluorination of siPSMA-21 according to GR5 and GW1. 18 F-siPSMA-21 had an RCY of 11.2% and an A of 50.1 GBq / μmol. m was prepared.

[0192] Terms and Abbreviations

[0193] [Table 6]

Claims

1. Dissolved [ １８ A method for preparing a composition containing [F] fluoride ions, comprising the steps of: - Water and [ １８ providing an aqueous solution containing [F] fluoride ions; - passing the aqueous solution through a solid phase extraction device containing an anion exchange resin to deposit [ １８ F] fluoride ions are captured on the anion exchange resin, and the [ １８ F] fluoride ions from the water; - passing an elution composition comprising an organic solvent and a salt of an alkanoic acid through the solid phase extraction device to remove [ １８ F] fluoride ions; - the organic solvent, the salt of the alkanoic acid and the dissolved [ １８ and obtaining as an eluate a composition comprising [F] fluoride ions.

2. The method according to claim 1, further comprising the step of: １８ The method further comprises purging the solid phase extraction device containing [F] fluoride ions with a gas.

3. 3. The method according to claim 1 or 2, further comprising: １８ Before eluting the [F] fluoride ion, the captured [ １８ F] the anion exchange resin containing fluoride ions is washed with an organic solvent.

4. The method according to claim 1 or 2, wherein the elution composition has the formula (A-1): 【Chemistry 1】 [In the formula, -X ＋ is selected from cryptates of ammonium cations, alkylammonium cations, and alkali or alkaline earth metal cations; R is H, a linear or branched C1-C20 alkyl group. The method further comprises the step of:

5. The method of claim 1 or 2, wherein the salt of the alkanoic acid comprises a formate salt.

6. The method according to claim 1 or 2, wherein the concentration of the salt of alkanoic acid in the elution composition is in the range of 0.1 to 1.5 mol / L.

7. 3. The method according to claim 1 or 2, wherein the organic solvent contained in the elution composition comprises a polar aprotic organic solvent, preferably a solvent selected from dimethylsulfoxide and acetonitrile.

8. 3. The method of claim 1 or 2, wherein each organic solvent used in the method is an anhydrous organic solvent.

9. The method of claim 1 or 2, wherein the elution composition further comprises a radiofluorinated organic compound.

10. 1. A method for preparing a radiofluorinated organic compound, comprising the steps of: - preparing a composition according to the method of claim 1, the composition comprising an organic solvent, a salt of an alkanoic acid and dissolved [ １８ F] fluoride ions; - contacting said composition with an organic compound to be radiofluorinated, so that said organic compound is fluorinated with the [ １８ and causing a radiofluorination reaction with [F] fluoride ion.

11. 11. The method according to claim 10, wherein the composition obtained as an eluate according to the method of claim 1 is directly contacted with the organic compound to be radiofluorinated without any compositional modification.

12. 1. A method for preparing a radiofluorinated organic compound, comprising the steps of: - preparing a composition according to the method of claim 1, wherein the elution composition further comprises an organic compound to be radiofluorinated, the composition comprising an organic solvent, a salt of an alkanoic acid and dissolved [ １８ F] fluoride ions and an organic compound to be radiofluorinated; - the organic compound is １８ and causing a radiofluorination reaction with [F] fluoride ion.

13. 13. The method according to any one of claims 10 to 12, wherein the organic compound to be radiofluorinated has the formula (S-1): 【Chemistry 2】 [In the formula, X Ｓ teeth, １９ F, OH, or H; R Ｓ１ and R Ｓ２ are independently a straight or branched C3 to C10 alkyl group; the wavy line represents the bond connecting the functional group to the remainder of the organic compound; The radiofluorination reaction is Ｓ Base and １８ With the exchange of F. The method further comprises the step of:

14. An organic solvent, a salt of an alkanoic acid, and a dissolved １８ F] fluoride ion.

15. 15. The composition of claim 14, wherein the organic solvent comprises a polar aprotic organic solvent selected from dimethylsulfoxide and acetonitrile, and the salt of an alkanoic acid comprises ammonium formate.

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