Method for preparing [18F] radiolabeled compounds having low water content during the labeling step

Abstract

The present invention relates to a method for producing a composition having a controlled moisture content, 18 F] Controlling the water content and source of water within a reaction process has a significant effect on both the yield and purity of the product of the radiolabeling process.

Description

[Technical field]

[0001] The present invention relates generally to methods for preparing radiolabeled compounds. It has been found that the water content and source of water within a reaction process has a significant effect on both the yield and purity of the product of the radiolabeling process. [Background technology]

[0002] A radiopharmaceutical is a compound labeled with a radioactive element suitable for administration to a mammal in vivo for use in the fields of medical imaging, diagnosis or therapy. A radiopharmaceutical composition comprises a radiolabeled compound or a pharma- ceutical acceptable salt thereof, a solvent, and one or more stabilizers.

[0003] Fluorine- 18 ([ 18 F) is a radioactive fluorine isotope commonly used in radiopharmaceuticals suitable for use in diagnostics. 18 Decay occurs by positron emission (97%) and electron capture (3%). 18 As [F] decays, the emitted positrons are exploited for positron emission tomography (PET) imaging, an in vivo imaging method used for cardiac imaging, tumor imaging, and brain imaging, among others.

[0004] Automated synthesis systems are important for the production of radiopharmaceuticals. Prior art synthesis modules are described in WO 2007 / 042781 and WO 2011 / 097649. Synthesis modules such as FASTlab® (GE Healthcare) result in the production of radiopharmaceutical doses for clinical use. The FASTlab synthesis module accepts and runs instrumental methods for producing radiopharmaceuticals.

[0005] In the process of preparing radiolabeled compounds, radiochemical impurities and unreacted [ 18[F] fluoride is an undesirable by-product. It is advantageous to minimize these by-products. Summary of the Invention

[0006] The present invention relates to 18 The present invention relates to an improved method for preparing [F] fluoride radiolabeled compounds.

[0007] One aspect of the present invention is 18 F] A method for preparing a radiolabeled compound comprising: (a) 18 an initial drying step comprising evaporating water and acetonitrile from a solution containing [F] fluoride; (b) Acetonitrile, 18 a further drying step (fluoride activation drying step) comprising azeotropic distillation of water from said solution containing [F] fluoride, and (c) The result from step (b), 18 [F] from a solution containing fluoride 18 Label the precursor compound with [F] fluoride to 18 F] Obtaining the radiolabeled compound Including, After the drying step (b), 18 the water content in the labeling step (c) originating from a solution containing [F] is less than 500 ppm, The water content during the labeling step (c) of the precursor compound is less than 2000 ppm; It concerns the method.

[0008] Preferably, at least two cycles of azeotropic distillation with acetonitrile are carried out, more preferably three cycles of azeotropic distillation with acetonitrile are carried out.

[0009] In one embodiment of the present invention, after the drying step (b), 18 The water content during the labeling step, originating from the solution containing [F], is less than 400 ppm. Preferably, after the drying step (b), 18The water content during the labeling step originating from the solution containing [F] is less than 350 ppm. In one embodiment of the invention, the water content during the labeling step originating from the precursor compound is less than 1500 ppm. Preferably, the water content during the labeling step originating from the precursor compound is between 500 ppm and 1000 ppm. In one embodiment of the invention, the total water content during the labeling step is less than 2500 ppm, for example less than 1000 ppm.

[0010] In another embodiment of the present invention, the step (a) before (at the start of synthesis) 18 The radioactivity of [F] is up to about 500 GBq, for example up to about 450 GBq, up to about 400 GBq, up to about 350 GBq, up to about 300 GBq, or for example, 50 GBq to 250 GBq. By using the process of the present invention, 18 High yields of fluorinated product and low levels of radiochemical impurities are obtained even when the radioactivity (starting activity) of [F]fluoride is greater than 100 GBq. The ability to achieve high yields and low levels of radiochemical impurities while still using higher starting activities allows for larger product doses to be prepared in a single batch.

[0011] In another embodiment of the invention, the radiolabeled compound is 18 F] fluoride-labeled radiopharmaceutical, or a pharma- ceutical acceptable salt thereof. [Brief description of the drawings]

[0012] [Figure 1] 1 is a flow chart of the current process steps for preparing a radiolabeled product. [Diagram 2] 1 is a flow chart for a process of the present invention for preparing a radiolabeled product. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] The term "radiopharmaceutical" has its conventional meaning and refers to a radioactive compound suitable for administration to a mammal in vivo for use in diagnosis or therapy. A radiopharmaceutical, as referred to herein, may be a positron emission tomography (PET) tracer.

[0014] Before a radiopharmaceutical composition, or "drug product," can be administered to a patient, it must be subjected to a thorough quality control (QC) process to ensure that it meets requirements such as purity.

[0015] Radiochemical purity (RCP) may be determined using radio-TLC or HPLC and defined as the ratio of the (radiolabeled) drug substance peak to the total (radiolabeled) peak in a chromatogram. When radiopharmaceuticals with a high radioactivity concentration (RAC) are manufactured, the decrease in RCP during storage is likely to be greater than that of a lower RAC due to increased radiolysis. High radioactivity concentrations result in the destruction (i.e., radiolysis) of the drug substance itself.

[0016] The term "comprising" has its conventional meaning throughout this application to indicate that a method, system, product, etc. must have the recited components, but in addition, other, unspecified components may be present.

[0017] Radiolabeled compounds may contain various radioisotopes. For example, radiolabeled compounds include 18 The radiolabeled compound may be a F-labeled radiopharmaceutical, or a pharma- ceutical acceptable salt thereof. 18 It may be an F-labeled radiopharmaceutical, or a pharma- ceutically acceptable salt thereof.

[0018] The radiolabeled compound is 18 F-labeled radiopharmaceuticals or pharma- ceutical acceptable salts thereof. 18 Examples of F-labeled radiopharmaceuticals are 18 F]FDG(2-deoxy-2-[18 F]fluoro-D-glucose), [ 18 F]FMAU(2'-deoxy-2'-[ 18 F]fluoro-5-methyl-1-beta-D-arabinofuranosyluracil), [ 18 F]FMISO( 18 F fluoromisonidazole), [ 18 F]FHBG(9-(4-[ 18 F]fluoro-3-[hydroxymethyl]butyl)guanine), 18 F]FES(16a-[ 18 F]fluoro-17b-estradiol)[ 18 F]AV-45, [ 18 F]AV-19, 18 F]AV-1, 18 F]Flutemetamol, 18 F]Furupiridazu, [ 18 F]K5,[ 18 F]HX4,[ 18 F]W372,[ 18 F]VM4-037,[ 18 F]CP 18 , [ 18 F]ML-10, [ 18 F]T808,[ 18 F]T807, 2-[ 18 F]Fluoromethyl-L-phenylalanine, GE-135[ 18 F] fluciclatide, GE-212, GE-226, or a combination thereof.

[0019] The radiolabeled compound has the formula (I):

[0020] [ka] (Wherein, A is N(R 7 ), S, O, C(=O), C(=O)O, NHCH 2 CH 2 O, bond, or C(=O)N(R 7 ), When present, B is hydrogen, alkoxyalkyl, alkyloxy, aryl, C optionally substituted with an imaging moiety.1 ~C 6 selected from alkyl, heteroaryl, and imaging moieties; When present, C is hydrogen, alkoxyalkyl, alkyloxy, aryl, C optionally substituted with an imaging moiety. 1 ~C 6 selected from alkyl, heteroaryl, and imaging moieties; D is hydrogen, alkoxyalkyl, alkyloxy, aryl, C optionally substituted with an imaging moiety; 1 ~C 6 selected from alkyl, heteroaryl, and imaging moieties; or C and D together with the atoms to which they are attached form a three- or four-membered carbocyclic ring; G is halo or haloalkyl; n is 0, 1, 2, or 3; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 is hydrogen, C optionally substituted with an imaging moiety 1 ~C 6 alkyl, and an imaging moiety; R 8 is optionally replaced with an imaging moiety, 1 ~C 6 is alkyl, E is selected from a bond, carbon, and oxygen, provided that when E is a bond, B and C are absent, and D is selected from aryl and heteroaryl, provided that when E is oxygen, B and C are absent, and D is selected from hydrogen, alkoxyalkyl, aryl, C optionally substituted with an imaging moiety. 1 ~C 6 alkyl, and heteroaryl; provided that at least one imaging moiety is present in formula (I). The compound may be:

[0021] The substituent A in formula (I) may be O.8 can be tert-butyl. G can be chloro. The imaging moiety can be any radioisotope mentioned herein, for example, [ 18 F] may be used.

[0022] The radiolabeled compound is 18 F]flurpiridaz, which has the following structure:

[0023] [ka]

[0024] Description of the production process The methods of the invention may be carried out on an automated synthesis system such as the FASTlab® system (GE Healthcare) which results in the production of radiopharmaceutical doses for clinical use.

[0025] In the following description, reference is made to the FASTlab® system, however this is not limiting on the invention and another suitable system may be used.

[0026] term[ 18 F] is used to encompass both the non-ionic and anionic forms. 18 F] Fluorine is in anionic form, hence the term [ 18 [F] fluoride is commonly used. 18 A measure of F]PET tracer production is the radioactivity ("activity") used at the start of synthesis ("SOS"), also referred to herein as "start activity" or "start radioactivity." 100 GBq of activity is calculated using 14.2 ng of [ 18 F]. Generally, the greater the radioactivity, the greater the degree of radiolysis.

[0027] FIG. 1 shows a flow chart of part of the radiopharmaceutical production process.

[0028] In step A, 18F] fluoride, 18 O](p,n)[ 18 The [F] nuclear reaction is generated using a GE Medical Systems PETtrace cyclotron with a silver target. A total target volume of 3-5 mL is used. In step B, [ 18 The [F] may be transferred from a temporary storage location or directly from the cyclotron to the FASTlab system, or another suitable system. The use of a temporary storage location is preferred, as it allows the amount of radioactivity transferred to the FASTlab to be measured and controlled. Once transferred to the FASTlab, the [F] may be transferred to the FASTlab system, or another suitable system. 18 F] is captured on an anion solid phase extraction (SPE) cartridge, e.g., a QMA cartridge (preconditioned with carbonate) (Waters Corporation). The activity transferred to the FASTlab is also measured in-line by a calibrated radiodetector placed next to the QMA cartridge. In step C, [ 18 [F] is eluted from the QMA cartridge, for example, with a solution of tetrabutylammonium bicarbonate (e.g., 400 μL) in water and acetonitrile. Nitrogen is used to flush the solution from the QMA cartridge and transfer it to a FASTlab reactor (reaction vessel, RV). In step D, an initial evaporation of water and acetonitrile is carried out at elevated temperature, for example, 120° C., under vacuum and a constant flow of nitrogen. In step F, the compound to be radiolabeled (also referred to herein as “precursor”, or “final intermediate”), dissolved in acetonitrile, is added to the reaction vessel. The precursor can be, for example, 18 The fluorination step may carry a tosyl group (tosylate) that is replaced by the F-radiolabel. This fluorination step results in a crude product. Subsequent purification steps are performed to obtain the pure radiolabeled compound (pure drug substance) and, after sterile filtration, the drug product.

[0029] Several experiments were performed to investigate the effect that increasing the level of water in the precursor vial has on the radiolabeling process.

[0030] Water content during the radiolabeling reaction in Step F was found to be a significant variable in the amount of radioactive impurity (e.g., radiochemical impurity B, depicted below) formed in the crude product.

[0031] The structure of radioactive impurity B is:

[0032] [ka]

[0033] The experimental results support the hypothesis that radiochemical impurities (e.g., radiochemical impurity B) are formed by a free radical radiolysis mechanism. Water is a potential source of free radicals and is responsible for the large amounts of [ 18 [O] analogs were observed in the LC-MS analysis of the crude product. We believe that the relationship between the amount of free or hydroxyl radicals formed during drying (step D) and the water content present during the labeling reaction is important. More free radicals are generated during the drying process with higher RAC, higher temperature and longer process time. We have determined that water needs to be minimized during this part of the process to suppress the formation of free radicals, including hydroxyl free radicals.

[0034] The water content during the radiolabeling step (Step F) is composed of: a) water carried over from the drying step, and b) water in the vial containing the precursor from the solid material and the acetonitrile used for dissolution. It has been determined that the improved drying process of the present invention reduces the number of free radicals that enter the labeling reaction.

[0035] Figure 2 shows a process flow chart including further process steps of the present invention. Steps A to D and F are as previously described in relation to Figure 1. In a new step E (following from step D), a further drying procedure is carried out, also referred to herein as a fluoride activation (drying) step. In step E, 18 The drying procedure for solutions containing [F] involves the addition of acetonitrile followed by azeotropic distillation of water / acetonitrile by evaporation at elevated temperature under vacuum. In the enhanced drying procedure of the present invention, this step is repeated at least twice. Preferably, three azeotropic drying cycles (3 x 0.5 mL acetonitrile) are performed. Step E is followed by step F, which is the fluorination (radiolabeling) step described above in connection with FIG. 1.

[0036] The water content of radiolabeling reactions was investigated by a series of non-radioactive experiments using a Karl Fischer apparatus to measure water content. For each experiment summarized in Table 1, three or four samples were analyzed for water content: (i) the acetonitrile used to dissolve the precursor, (ii) the acetonitrile used for azeotropic drying, (iii) the dissolved precursor, (iv) carryover from the drying process, and (v) the labeling solution itself.

[0037] [Table 1] Experiments 1, 2 and 6 are control examples.

[0038] The structure of the precursor is as follows:

[0039] [ka]

[0040] This precursor is particularly susceptible to radiolytic decomposition.

[0041] The total water content during the labeling reaction (last column) is the sum of the water content originating from the precursor vial and the [ 18 F] is composed of the water content present in solutions containing fluoride.

[0042] The moisture content in the initial high activity run was about 2500 ppm (Table 1, Run 1). The drying schedule for this sequence was about 8.5 minutes at 120° C. ("Original Sequence").

[0043] In run 2, a commonly used drying sequence is applied. Compared to the drying sequence of run 1, in run 2 the temperature is maintained at 120° C. for about 1.5 more minutes, with a slight difference in the inert gas flow rate into the reaction vessel during the early evaporation step. The total drying time was therefore about 10 minutes. The longer drying time had no significant effect on the water content during the labeling reaction, which was 2665 ppm in run 2 compared to 2469 ppm in run 1. The further drying sequences detailed below are based on the drying sequence described for run 2.

[0044] In runs 3 and 4, azeotropic drying (3 × 0.5 mL acetonitrile) was added to the drying sequence of run 2. The total drying time was approximately 15 min at 120 °C, meaning that the addition of three azeotropic drying cycles added approximately 5-6 min to the total drying time. In run 3, the water content in the label was determined to be 605 ppm, of which 375 ppm was carryover water from the drying step and 230 ppm originated from the precursor vial.

[0045] In run 5, an alternative azeotropic drying sequence was run at 110°C instead of 120°C, with a smaller vacuum setting and three azeotropic drying cycles (3 x 0.5 mL acetonitrile). The total drying time was 12.8 min. This sequence has the advantage of not requiring a temperature reduction (cooling step) before the precursor is added to the reactor. Furthermore, the total drying time is shorter than the drying sequences in runs 3 and 4 (12.8 min vs. 15 min). The water content was 605 ppm, which was the same as the sequence with the more stringent conditions (run 3). The enhanced drying procedure in run 5 resulted in a [ 18 The water content in the solution containing the [F] component was reduced from 2238 ppm to 323 ppm (compare experiments 1 and 5).

[0046] [ 18 It was also hypothesized that rinsing the QMA cartridge with acetonitrile after [F]fluoride was captured (and before it was eluted into the reaction vessel) would reduce the amount of water entering the reaction vessel, as residual water in the QMA cartridge would be replaced with acetonitrile. Thus, in experiment 6, a rinse of the QMA cartridge with acetonitrile via syringe S1 was performed, and [ 18 [F]fluoride was dried using the drying process of experiment 2. The amount of water in the labeling reaction in experiment 6 was 1155 ppm, suggesting that rinsing the QMA cartridge resulted in an improvement (i.e., a reduction) in water content compared to the simple drying procedure used in experiment 2. However, in experiment 7, which combined the azeotropic drying sequence of experiments 3 and 4 with rinsing the QMA cartridge, the water content was measured to be 718 ppm, which is greater than without rinsing (compare experiments 6 and 7). This suggests that the water content of the [F]fluoride labeling reaction was 1155 ppm, suggesting that rinsing the QMA cartridge resulted in an improvement (i.e., a reduction) in water content compared to the simple drying procedure used in experiment 2. 18 We have shown that rinsing of the QMA with acetonitrile is unnecessary when solutions containing [F] fluoride are dried azeotropically.

[0047] In conclusion, the enhanced [ 18The [F]fluoride drying process involved azeotropic drying with three portions of acetonitrile (fluoride-activated drying step). The total drying time was just under 13 minutes at 110°C, which is also the temperature required for the subsequent labeling step.

[0048] Preferably, at least two cycles of azeotropic distillation with acetonitrile are carried out. More preferably, at least three cycles of azeotropic distillation with acetonitrile may be carried out. Most preferably, three cycles of azeotropic distillation with acetonitrile are carried out.

[0049] Preferably, the water content during the radiolabeling step is less than 1000 ppm. More preferably, the water content during the radiolabeling step is less than 700 ppm.

[0050] Preferably, after the drying step (including the fluoride activation drying step), 18 The water content during the radiolabeling step, originating from a solution containing [F], is less than 500 ppm. More preferably, after the drying step (including the fluoride activation drying step), 18 The water content during the radiolabeling step, originating from a solution containing [F], is less than 400 ppm. Even more preferably, after the drying step (including the fluoride activation drying step), 18 The water content during the radiolabeling step, originating from a solution containing [F], is less than 350 ppm.

[0051] The enhanced drying step is also believed to lead to the removal or reduction of water molecules associated with the fluoride ion, allowing fluoride to more readily participate in the radiolabeling reaction. That is, by liberating fluoride from its solvent cage of water molecules, fluoride becomes available for reaction with electrophiles, for example by forming a complex with Kryptofix-222 (Sigma Aldrich; Merck KGaA, Germany) or tetrabutylammonium salts (ABX advanced biochemical compounds GmbH, Germany). This drying step is sometimes referred to herein as the "fluoride activation step" or "fluoride activation drying step."

[0052] The reduction of water content after drying (e.g., as described for step E of FIG. 2) allows the radiolabeling step to be optimized. The main radiochemical impurity is reduced to a level that allows efficient purification using SPE, reducing the amount of this impurity to less than 2% of the product, which is the specification limit. This is true even for a starting radioactivity of up to 350 GBq. As mentioned above, higher radioactivity levels lead to higher levels of radiolysis and therefore radiochemical impurities. In other words, the greater the radioactivity, the greater the effect that will be countered. At a radioactivity level of 350 GBq, it was expected that the impurities would be obtained at even higher levels than the target compound. This would reduce the radiochemical yield and reduce the number of resulting drug product doses to unacceptable levels, regardless of which product purification method is used. However, by using the process of the present invention, a high yield of fluorinated product and a low amount of radiochemical impurity were obtained. This high yield of fluorinated product and a low amount of radiochemical impurity B are due to the [ 18This is even possible with radioactivity (starting activity) of [F] fluoride of more than 100 GBq. The ability to achieve high yields and low levels of radiochemical impurities while still using higher starting activities allows for a larger number of product doses (also called "patient doses") to be prepared from a single batch. With a starting activity of 250 GBq, more than 20 patient doses can be prepared from a single batch. 18 The radioactivity (starting activity) of [F]fluoride may be up to about 500 GBq, e.g., up to about 450 GBq, up to about 400 GBq, up to about 350 GBq, up to about 300 GBq, or, for example, at least 100 GBq, 50 GBq to 250 GBq, 100 GBq to 350 GBq, 200 GBq to 300 GBq, 200 GBq to 350 GBq, or 250 GBq to 350 GBq.

[0053] The amount of radioactive impurity B in the product obtained by the process of the present invention is less than 3.5%, such as less than 3%, less than 2.5%, less than 2%, or less than 1.5%.

[0054] Water content of acetonitrile vials To determine the effect of the moisture content of the 100% acetonitrile vials used in the azeotropic drying process, the enhanced drying process of the present invention (i.e., including a fluoride-activated drying step) was performed with acetonitrile having two different moisture levels. For the vials, there are two useful shelf-life moisture content specifications: 750 ppm and 2000 ppm. A comparison of the moisture content carried over to the radiolabeling step from azeotropic drying performed with acetonitrile vials containing 60 ppm or 2016 ppm water is summarized in Table 2.

[0055] [Table 2]

[0056] When acetonitrile containing 60 or 2016 ppm water was used in the azeotropic drying, there was no significant difference in the water content carried over from the drying step, therefore, the inventors found that water added at this stage of the process does not affect the final result.

[0057] High activity testing with enhanced drying process Table 3 compares the results of the radiolabeling step resulting in a crude product using the fluoride drying process of the present invention and a standard drying process.

[0058] [ 18 O](p,n)[ 18 The GE Medical Systems PETtrace cyclotron with a silver target was used to measure the [F] nuclear reaction. 18 [F]fluoride was generated. A total target volume of 3-5 mL was used. Radioactive fluoride was trapped on a Waters QMA cartridge (preconditioned with carbonate) and fluoride was eluted with a solution of tetrabutylammonium bicarbonate (22.8 mg) in water (100 μL) and acetonitrile (400 μL). Nitrogen was used to flush the solution from the QMA cartridge into the reaction vessel. 18 The [F]fluoride was dried at 110 °C for approximately 20 min, including an azeotropic drying step with 3 × 0.5 mL acetonitrile, under vacuum under a constant flow of nitrogen. The precursor (10.2 mg) in acetonitrile (1.7 mL) was dried [ 18 F] fluoride was added and the reaction mixture was heated at 110 °C for 3 min.

[0059] Radiolabeling was significantly improved by the drying process of the present invention: the yield of radiolabeled crude product increased from 72% to 81%, and the amount of unreacted [ 18 The amount of [F] fluoride was reduced from 5% to 1%, and the amount of radiochemical impurity B was reduced from 22% to 13%.

[0060] [Table 3] Experiment 10 is a reference example.

[0061] These results demonstrate the significant advantages achieved by the drying process of the present invention.

[0062] Confirmation of the water content range of precursors in 6 mg / mL vials of acetonitrile It has been found that the water content carried over from the drying step to the radiolabeling step is a key variable in the amount of radiochemical impurity B formed in the crude product. Using the drying procedure of the present invention, the water content during the radiolabeling reaction is about 600 ppm (see Table 1). However, this poses a problem for the useful shelf life of the precursor vials. The water content of the acetonitrile used to dissolve the precursor is 500 ppm, and the water content of the precursor vials is expected to increase by approximately 15 ppm per month due to natural water infiltration into the vials over time. This limits the useful shelf life of the precursor vials to less than 7 months (i.e. (600-500) / 15 ppm=6.7 months) to remain at the desired low water content in the labeling reaction. Ideally, the useful shelf life of the precursor vials is a minimum of 24 months. After 24 months, the precursor dissolved in acetonitrile has a water content of over 860 ppm (i.e., 15 ppm * 24 months + 500 ppm). Therefore, the radiolabeling process was challenged with higher levels of water in the precursor vials. Water was added to the precursor vials and the water content was measured using a Karl Fischer apparatus. The results of these experiments are shown in Table 4. For each of experiments 12-18, the optimized drying sequence of experiment 5 in Table 1 was used (i.e., the water content carried over from the drying sequence is less than 500 ppm).

[0063] [Table 4] Experiments 12-18 use the optimized drying process of the present invention.

[0064] Radiochemical yield refers to the total amount of radioactivity obtained after purification, related to the starting amount of radioactivity (e.g., from a cyclotron or previous reaction step). Note that radiochemical yields can be either decay corrected or non-decay corrected (NDCY).

[0065] Lower yields and higher amounts of radiochemical impurity B are expected with higher water content. However, surprisingly, the results in Table 4 show that increasing the water content of the precursor vials from 250 ppm to 2000 ppm had no noticeable effect on the radiolabeling process. This is a very surprising result, as it shows that the water present in the precursor vials during the radiolabeling reaction does not increase the [ 18 F], indicating that the eluent behaves differently from water derived from an eluent solution containing fluoride.

[0066] Table 5 shows a comparison of two experiments showing improved results with an optimized drying sequence, even at approximately 2-fold greater starting activity. The SPE-purified product has higher purity and lower amounts of radioactive impurity B.

[0067] [Table 5]

[0068] To meet the product specifications, one of the requirements is that the amount of radioactive impurity B must be less than 3.5%. Using the original process without the optimized drying according to the invention, it can be seen that the amount of radioactive impurity B is 5.6% when a starting radioactivity of 125 GBq is used. In contrast, using the optimized process of the invention, the amount of radioactive impurity B is 1.5%, even when a much higher starting radioactivity of 249 GBq is used. In other words, the invention allows the reaction to be scaled up more than two or three times.

[0069] The effect of starting radioactivity is further illustrated in Table 6 below.

[0070] [Table 6]

[0071] The experiments in Table 6 carried out using the optimized drying process of the present invention all have starting activities of over 300 GBq and achieve high product purity (RCP) (over 97%) and low amounts of radioactive impurity B (less than 2%), which are within the product specification requirements for the product.

[0072] In contrast, as shown by experiment 19 in Table 5, using the original drying process only achieved a lower RCP (90%) and an unacceptably high amount of radioactive impurity B (5.6%). To produce less radioactive impurity B (less than 3.5% to meet product specification requirements), the original process required a much smaller starting activity, thereby resulting in the production of a lower patient dose per batch.

[0073] Thus, the optimized drying process of the present invention allows for the use of greater starting activity, producing more patient doses per batch with high yield, high RCP and low levels of radioactive B impurity.

[0074] This can be explained by the relationship between the amount of free or hydroxyl radicals formed during the drying process and the water content present during the labeling reaction. More free radicals are generated during the drying process due to higher RAC, higher temperature and longer process time. The inventors believe that the improved drying process of the present invention reduces the number of free radicals entering the labeling reaction.

[0075] Taken together, these results confirm that the moisture content specification for the precursor vials can be up to 2000 ppm, which should be sufficient to provide a good shelf life (2000 ppm-500 ppm / 15=100 months, or more than 8 years). In addition to a longer shelf life, this tolerance for higher moisture content in the precursor vials allows for easier manufacturing of the precursor vials.

[0076] The present invention shows that water present in the FASTlab process behaves differently depending on when it is introduced into the process: Water added at the beginning of the process has a greater effect on the process than water introduced at the radiolabeling step (i.e., residual water present from the precursor and the solvent used to dissolve it).

[0077] Captured [ 18 [F]fluoride is released from the ion exchange resin with acetonitrile and water. 18 F], water and acetonitrile. Due to the high radioactivity levels, there will be a larger number of hydroxyl free radicals unless the water is removed prior to the radiolabeling (fluorination) step. Current methods evaporate some of the water and acetonitrile prior to the radiolabeling step. However, following the enhanced drying step of the present invention, [ 18 F] eluent ([ 18 It has been found that if a solution containing [F] is dried prior to the radiolabeling step, the presence of fewer free radicals leads to a higher yield of purer product with fewer radiochemical impurities. 18 F] The lower the amount of residual water from the eluent, the fewer radioactive impurities will be generated in the radiolabeling reaction step. 18 F] The effect of the presence of hydroxyl free radicals of water in the eluent is reduced or avoided.

[0078] The subsequent addition of fresh water, which has not been exposed to radioactivity / radiolysis, to the radiolabeling step has no negative impact on the yield of the crude product and does not increase the impurities present.

[0079] The present invention also shows that the origin of water content in the FASTlab process is more important in earlier steps than in later steps. It was found that the water still present after fluoride drying has a greater impact than the water present in the precursor solution. This was unexpected since water was expected to behave similarly in each step. A further advantage of the present invention is that the increased water content of the precursor vials allows for a longer useful shelf life of the vials. This also allows for the production of a larger number of vials in a single production batch.

[0080] Radiostabilisers protect the radiolabelled compound from radiolysis and therefore reduce or prevent loss of purity of the radiolabelled compound over the useful shelf life. Although radiostabilisers may be included to inhibit decomposition reactions, e.g. redox processes, by scavenging highly reactive free radicals, e.g. oxygen-containing free radicals resulting from the radiolysis of water, the enhanced drying step of the present invention has been found to be highly effective and has no effect on the resulting products in quantitative analysis.

[0081] Thus, the present invention allows reactions to be run at higher starting activities, thereby enabling the production of more patient doses per batch with lower levels of radioactive impurities, e.g., radioactive impurity B. Prior to the present invention, reactions had to be run at lower starting activities to control the amount of radioactive impurities generated, resulting in lower product doses per batch.

[0082] It should be readily understood by those skilled in the art that the embodiments of the present invention described herein are widely applicable and applicable. Thus, although the present invention is described in detail herein in connection with exemplary embodiments, it should be understood that the disclosure is illustrative and exemplary of the embodiments and is made to provide an enabling disclosure of the exemplary embodiments. The disclosure is not intended to limit the embodiments of the present invention or to be otherwise construed as excluding any other such embodiments, adaptations, changes, modifications, and equivalent arrangements. The scope of the present invention is defined by the appended claims.

Claims

1. [[]] １８ A method for preparing a composition comprising a (a) [[]] １８ An initial drying step comprising evaporating water and acetonitrile from a solution containing [[]] (b) Further drying step (fluoride activation step) comprising azeotropic distillation of water from the said solution containing [[]] １８ fluoride with acetonitrile, and (c) Labeling a precursor compound with [[]] １８ fluoride derived from the said solution containing [[]] １８ fluoride obtained from step (b) to obtain a composition containing a １８ radioactively labeled compound, comprising, After the drying step (b), the water content during the labeling step (c) originating from the said solution containing [[]] １８ fluoride is less than 500 ppm, The water content during the labeling step (c) originating from the said precursor compound is 2000 ppm or less, The said [[18F]] radioactively labeled compound is a [[18F]] fluorine-labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, The said [[18F]] fluorine-labeled radiopharmaceutical is [[18F]] flurpiridaz or a pharmaceutically acceptable salt thereof, 【Chemical Formula 1】 method.

2. The method according to claim 1, wherein at least two cycles of said azeotropic distillation with acetonitrile are carried out.

3. The method according to claim 1, wherein three cycles of azeotropic distillation with acetonitrile are carried out.

4. After the drying step (b) (said fluoride activation step), [[]] １８The method according to claim 1, wherein the water content during the labeling step of the solution origin containing [F] is less than 400 ppm.

5. After the drying step (b) (the fluoride activation step), １８ The method according to claim 1, wherein the water content during the labeling step of the solution origin containing [F] is less than 350 ppm.

6. The method according to claim 1, wherein the water content during the labeling step of the precursor compound origin is 1500 ppm or less.

7. The method according to claim 1, wherein the water content during the labeling step of the precursor compound origin is 500 ppm to 1000 ppm.

8. The method according to claim 1, wherein the total water content during the labeling step is less than 2500 ppm.

9. The method according to claim 1, wherein the total water content during the labeling step is less than 1000 ppm.

10. [ １８ The method according to claim 1, wherein the solution containing [F] fluoride is an eluent from an ion exchange resin, for example, an anion solid phase extraction cartridge.

11. The [ １８ The method according to claim 1, wherein the composition containing the [F] radiolabeled compound obtained in step (c) is subsequently subjected to a purification step.

12. The initial activity is (i) more than 100 GBq, (ii) 200 - 350 GBq, or (iii) more than 300 GBq, The method according to any one of claims 1 to 11.

13. The method according to claim 12, which is carried out in an automated synthesis system.

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