An automated method and system for the synthesis of radiotracers targeting SV2A

Abstract

This invention relates to an automated synthesis method and system for a radioactive tracer targeting SV2A, belonging to the field of radioactive tracer synthesis technology. The system includes: a gas supply circuit for supplying gas to the system; a cyclotron for bombarding deoxygenated water in a first reaction flask to generate a liquid target; a first reaction flask for generating the liquid target; and an anion exchange column for collecting the liquid target. 18 F ‑ The second reaction flask is used to make... 18 F ‑ Fluorination reaction with precursor produces a product containing [ 18 The first mixture of F]BIBD-181 products; a transfer bottle for terminating the fluorination reaction and transferring the first mixture; a reversed-phase polymer solid-phase extraction column for washing the first mixture to obtain a product containing [ 18 The second mixture of F]BIBD-181 products; high performance liquid chromatography was used to separate and purify the second mixture to obtain [ 18 F]BIBD-181 crude product; rotary flask used to remove [[] by rotary evaporation. 18 The solvent in the crude product F]BIBD-181 was used to obtain [ 18 F]BIBD-181 product.

Description

Technical Field

[0001] This invention belongs to the field of radioactive tracer synthesis technology, specifically relating to an automated synthesis method and system for a radioactive tracer targeting SV2A. Background Technology

[0002] SV2A is a membrane protein distributed on synaptic vesicles, a member of the synaptic vesicle protein 2 family, mainly distributed in brain tissue, including the cerebral cortex, hippocampus, and cerebellum. It regulates action potential-dependent neurotransmitter release, maintains synaptic vesicle homeostasis, and participates in vesicle exocytosis. Abnormal expression of SV2A in synaptic structures can affect the physiological function of synaptic vesicles and cause abnormal postsynaptic membrane potentials, participating in the pathogenesis of various neurodegenerative diseases and epilepsy. 18 F]BIBD181 can target synaptic vesicle glycoprotein 2A (SV2A) for synaptic density imaging, reflecting the characteristics and extent of synaptic loss, thereby assessing the disease progression of AD patients and predicting the therapeutic potential of drugs targeting synapses. Synaptic density imaging is expected to become a novel biomarker assessment method for AD and can be used as an effective means of diagnosis, disease assessment, treatment prediction, and monitoring in AD clinical trials.

[0003] A novel SV2A tracer developed by the Beijing Institute of Brain Diseases, Capital Medical University. 18 F]BIBD-181, validated by in vitro binding experiments and mouse in vivo models, exhibits high affinity, specific targeting, and excellent brain uptake characteristics, demonstrating significant potential for clinical translation. However, this tracer currently relies on manual labeling processes, which suffer from technical bottlenecks such as low synthesis efficiency, large batch-to-batch product variability, and high risk of radiation exposure during operation, severely restricting its clinical application. Summary of the Invention

[0004] To address the problems in existing technologies, this invention provides an automated synthesis method and system for radioactive tracers targeting SV2A, enabling automated, high-dose, and high-purity synthesis. 18 F]BIBD-181; This method can protect the operator to the greatest extent and avoid radiation exposure.

[0005] The technical solution adopted by this invention to solve its technical problem is:

[0006] According to a first aspect of the present invention, an automated synthesis system for a radioactive tracer targeting SV2A is provided, characterized in that it comprises:

[0007] A gas supply circuit is used to supply gas to the system.

[0008] A cyclotron is used to bombard the heavy oxygen water in the first reaction vessel to generate a liquid target.

[0009] The first reaction bottle is used to generate a liquid target, and the inlet end of the first reaction bottle is also connected to the gas delivery circuit pipeline; the outlet end of the first reaction bottle is connected to the inlet end pipeline of the anion exchange column.

[0010] The anion exchange column is used to collect the liquid target. 18 F - The inlet end of the anion exchange column is also connected to the first elution bottle, and the outlet end of the anion exchange column is connected to the first recovery bottle and the second reaction bottle respectively.

[0011] The second reaction flask is used to make the... 18 F - Fluorination reaction with precursor produces a product containing [ 18 The first mixture of F]BIBD-181 product, the first port of the second reaction bottle is connected to the gas delivery circuit, the first raw material bottle, the second raw material bottle and the transfer bottle pipeline respectively; the second port of the second reaction bottle is connected to the gas delivery circuit pipeline;

[0012] The transfer bottle is used to terminate the fluorination reaction and transfer the first mixture. The outlet end of the transfer bottle is connected to the inlet end of the reversed polymer solid-phase extraction column.

[0013] The reversed-phase polymer solid-phase extraction column is used to wash the first mixture to obtain a product containing the […]. 18 The second mixture of F]BIBD-181 product, the inlet end of the reversed-phase polymer solid-phase extraction column is also connected to the pipelines of the first washing bottle, the second washing bottle and the third washing bottle respectively; the outlet end of the reversed-phase polymer solid-phase extraction column is connected to the pipelines of the second recovery bottle and the high-performance liquid chromatograph respectively, and the second recovery bottle is connected to the gas delivery circuit pipeline.

[0014] The high-performance liquid chromatograph is used to separate and purify the second mixture to obtain [ 18 F]BIBD-181 crude product, the outlet end of the high performance liquid chromatograph is connected to the rotary evaporator pipe;

[0015] The rotary evaporator flask is used to remove the [[] by rotary evaporation. 18 The solvent in the crude product F]BIBD-181 was used to obtain the [ 18 The F]BIBD-181 product, wherein the rotary evaporator is connected to the solvent bottle and the product bottle via pipes respectively;

[0016] The rotary evaporator is connected to the high-performance liquid chromatograph and the gas delivery circuit pipeline.

[0017] According to an embodiment of the present invention, the gas delivery circuit includes:

[0018] The gas source is nitrogen.

[0019] An air pump is connected to the air source through a gas circuit consisting of a first air supply pipe and a second air supply pipe;

[0020] The first reaction bottle is connected to the first gas delivery pipe.

[0021] According to an embodiment of the present invention, a buffer bottle is provided between the air pump and the system.

[0022] According to an embodiment of the present invention, a solution bottle is installed on the side of the second gas pipeline near the gas pump for recovering solvents such as acetonitrile, alcohol and water vaporized during the reaction.

[0023] According to an embodiment of the present invention, the second gas pipeline includes a first gas transmission branch, a second gas transmission branch, and a third gas transmission branch;

[0024] The outlet end of the first recycling bottle is connected to the first gas transmission branch line;

[0025] The outlet end of the second recovery bottle is connected to the second gas supply branch line;

[0026] The second port of the second reaction bottle is connected to the third gas supply branch.

[0027] According to an embodiment of the present invention, the gas transmission circuit further includes a third gas transmission pipeline;

[0028] The first port of the second reaction vessel is connected to the first gas supply pipe through the third gas supply pipe.

[0029] According to an embodiment of the present invention, the gas transmission circuit further includes a fourth gas transmission pipe, a fifth gas transmission pipe, and a sixth gas transmission pipe;

[0030] The fourth gas delivery pipeline is connected in parallel with the second gas delivery pipeline, and the high-performance liquid chromatograph and the rotary evaporator are connected in parallel to the fourth gas delivery pipeline;

[0031] The fifth gas pipeline connects the second cleaning bottle and the gas source;

[0032] The sixth gas pipeline is used to connect the third cleaning bottle and the gas source.

[0033] According to an embodiment of the present invention, the first reaction flask contains deoxygenated water;

[0034] Add 0.2 mL of acetonitrile and 0.9 mL of an aqueous solution of amino polyether (10 mg) and potassium carbonate (1.8 mg) to the first eluent;

[0035] The first raw material bottle contains 0.5 mL of anhydrous acetonitrile;

[0036] 1 mg of precursor solution was added to the second raw material bottle; the precursor solution was a solution of (R)-1-[3-(3-fluoropropyl)-4-pyridinemethyl]-4-(3,4,5-trifluorophenyl)-2-pyrrolidone) dissolved in anhydrous acetonitrile;

[0037] The transfer bottle contains 9 mL of water for injection;

[0038] The first cleaning bottle contains 10 mL of water for injection;

[0039] The second cleaning bottle contains 1 mL of anhydrous ethanol;

[0040] The third cleaning bottle contains 1.0 mL of water for injection;

[0041] The solvent bottle contains 1.0 mL of anhydrous ethanol;

[0042] According to an embodiment of the present invention, the product bottle contains the [ 18 F] BIBD-181 product weight 10% antioxidant solution, wherein the antioxidant solution is an ethanol solution of sodium ascorbate, and the concentration of sodium ascorbate is 0.5% of the antioxidant solution.

[0043] According to an embodiment of the present invention, several valves are designed in the pipeline of this system to switch the type and direction of the fluid flowing in the pipeline. The pipeline design involved in the present invention has some overlap. In order to clearly describe each step, all overlapping parts in the pipeline are not explicitly pointed out. The specific pipeline design is based on the content shown in the accompanying drawings. The flow of all gas and liquid in the synthesis equipment during the synthesis process is achieved by automatically controlling the opening and closing of valves after inputting the code editing program.

[0044] According to an embodiment of the present invention, the anion exchange column is a tetramethylammonium strong anion exchange column;

[0045] The reversed-phase polymer solid-phase extraction column is a hydrophilic-lipophilic balanced column.

[0046] According to a second aspect of the present invention, an automated synthesis method for a radioactive tracer targeting SV2A using the above-described system includes the following specific steps:

[0047] A liquid target is generated by bombarding the oxygenated water in the first reaction bottle with a cyclotron.

[0048] The liquid target was collected using an anion exchange column. 18 F- and the 18 F - Transferred to the second reaction flask;

[0049] The anhydrous acetonitrile in the first raw material bottle is transferred to the second reaction bottle for an azeotropic reaction to remove the... 18 F - The solvent in the solution is used to obtain the purified product. 18 F - ;

[0050] The precursor solution in the second feed bottle is transferred to the second reaction bottle for fluorination to obtain a product containing [ 18 The first mixture of F]BIBD-181 products;

[0051] The reaction was terminated by injecting the water for injection from the transfer bottle into the second reaction bottle, and the first mixture was transferred to the transfer bottle;

[0052] The first mixture was washed using a reversed-phase polymer solid-phase extraction column to obtain a sample containing the […]. 18 The second mixture of F]BIBD-181 products;

[0053] The second mixture was transferred to a high-performance liquid chromatograph for separation and purification to obtain [ 18 F]BIBD-181 crude product;

[0054] The [ 18 The crude product of F]BIBD-181 was transferred to a rotary evaporator flask, where the [[] was removed by rotary evaporation. 18 The solvent in the crude product F]BIBD-181 was used to obtain the [ 18 F]BIBD-181 product;

[0055] The [ 18 F]BIBD-181 product is transferred to a product bottle for storage.

[0056] According to an embodiment of the present invention, the step of generating a liquid target by bombarding the deoxygenated water in the first reaction vessel with a cyclotron includes:

[0057] By continuously bombarding heavily oxygenated water with a proton beam of 10 MeV and 45-50 μA generated by a cyclotron for 50-60 minutes, a process occurs... 18 O(p, n) 18 F nuclear reaction, producing [a substance] containing 18 F - Liquid target.

[0058] According to an embodiment of the present invention, the anhydrous acetonitrile in the first raw material bottle is transferred to the second reaction flask for an azeotropic reaction to remove the... 18 F - The solvent in the solution is used to obtain the purified product. 18 F - include:

[0059] The anhydrous acetonitrile in the first raw material bottle is transferred to the second reaction bottle;

[0060] Under a nitrogen atmosphere, the second reaction flask was heated to 95°C and held for 90-100 seconds, then the temperature was increased by 5°C and held for 90-100 seconds to carry out an azeotropic reaction, removing the [unspecified substance]. 18 F - The solvent in the solution is used to obtain the purified product. 18 F - ;

[0061] During this process, nitrogen gas is continuously bubbled into the second reaction flask.

[0062] According to an embodiment of the present invention, the precursor solution in the second raw material bottle is transported to the second reaction bottle for fluorination reaction to obtain a product containing [ 18 The first mixture of F]BIBD-181 products includes:

[0063] The precursor solution in the second raw material bottle is transferred to the second reaction bottle;

[0064] High-pressure air is bubbled into the second reaction flask, and the flask is heated to 95-105°C under high pressure (80-100 kPa) for fluorination reaction for 12-15 min to obtain a product containing […]. 18 The first mixture of F]BIBD-181 products.

[0065] Beneficial effects

[0066] The present invention provides an automated synthesis method and system for a radioactive tracer targeting SV2A, which has the following advantages compared with the prior art:

[0067] This invention will provide a method for preparing [ 18 An automated synthesis method for BIBD-181 (F). This method enables automated, high-dose, and high-purity synthesis of […]. 18[F]BIBD-181. This method completely overcomes the previous reliance on purely manual labeling in synthesis. It increases the yield of synthesized radiopharmaceuticals, can meet the needs of 6-8 patients at a time, and the integrated operation process improves the quality of the radiopharmaceuticals. Furthermore, all equipment is housed in a lead-shielded modular enclosure, maximizing operator protection and minimizing radiation exposure compared to manual labeling methods. In summary, this invention can promote the development of standardized production processes for multi-scenario applications, fill the gap in clinical translation technology for SV2A-PET probes, provide molecular imaging tools for the diagnosis and monitoring of neurodegenerative diseases, epilepsy, and other synapse-related diseases, and simultaneously establish a translational medical research paradigm for the development of novel small-molecule tracers.

[0068] This invention, based on an automated synthesis module, has for the first time successfully established an automated synthesis method for a radioactive tracer targeting SV2A. 18 The preparation method of F]BIBD-181. This method integrates functions such as fluoride ion loading, online fluorination reaction, and product separation and purification into one automated module controlled by program code, realizing […]. 18 F]BIBD-181 online automated synthesis. The process utilizes electrically operated valves to control the opening and closing of pipelines, thereby enabling the addition of precursors and solvents, as well as the transfer of mixed liquids during separation and purification, avoiding radiation exposure to the human body during manual labeling;

[0069] The device of this invention has an automatic heating and cooling device. During the synthesis process, the precursor is dissolved in acetonitrile three times in the reaction flask, and the water solvent in the reaction system can be removed by the automatic heating device, which improves the efficiency of the whole reaction.

[0070] In this invention, the addition and transfer of solution are achieved by opening and closing electric valves to compress rubber tubing, thus avoiding the use of a large number of three-way valves and resulting in a 5%-10% increase in yield after reaction compared to other synthesis modules.

[0071] This invention addresses the problem of mass production for clinical diagnosis of AD patients. 18 F]BIBD-181 is of great significance. Attached Figure Description

[0072] Figure 1 This is a diagram of an automated synthesis system for a radioactive tracer targeting SV2A in an embodiment of the present invention.

[0073] Figure 2 This is a flowchart illustrating the automated synthesis process of a radioactive tracer targeting SV2A in an embodiment of the present invention.

[0074] Figure 3 In the automated synthesis process of the radioactive tracer targeting SV2A in this embodiment of the invention, [18 F] Enlarged view of section A of the BIBD-181 product synthesis module;

[0075] Figure 4 This is an enlarged view of the high-performance liquid chromatography module B during the automated synthesis process of the radioactive tracer targeting SV2A in this embodiment of the invention.

[0076] Figure 5 This is an enlarged view of the rotary evaporation module C during the automated synthesis process of the radioactive tracer targeting SV2A in an embodiment of the present invention.

[0077] In the diagram: First reaction flask-1, First elution flask-2, First raw material flask-3, Second raw material flask-4, Transfer flask-5, First washing flask-6, Second washing flask-7, Third washing flask-8, Reverse polymer solid phase extraction column-9, Second recovery flask-10, Second reaction flask-11, Anion exchange column-12, First recovery flask-13, Gas source-14, Gas pump-15, Buffer flask-16, Collection tube-17, Syringe-18, Rotary evaporation flask-19, Solvent flask-20, Product flask-21. Detailed Implementation

[0078] The present invention will be further described in detail below with reference to specific embodiments, but the implementation of the present invention should not be limited to the scope of the embodiments described.

[0079] An automated synthesis system for a radioactive tracer targeting SV2A, comprising:

[0080] Gas supply circuit, used to supply gas to the system;

[0081] A cyclotron is used to bombard the heavy oxygen water in the first reaction vessel to generate a liquid target.

[0082] The first reaction bottle 1 is used to generate the liquid target. The inlet end of the first reaction bottle 1 is also connected to the gas supply circuit pipeline. The outlet end of the first reaction bottle 1 is connected to the inlet end pipeline of the anion exchange column 12.

[0083] Anion exchange column 12 is used to collect liquid target. 18 F - The inlet end of the anion exchange column 12 is also connected to the pipe of the first elution bottle 2, and the outlet end of the anion exchange column 12 is connected to the pipes of the first recovery bottle 13 and the second reaction bottle 11 respectively.

[0084] The second reaction flask 11 is used to... 18 F - Fluorination reaction with precursor produces a product containing [ 18The first mixture of F]BIBD-181 product, the first port of the second reaction bottle 11 is connected to the gas supply circuit, the first raw material bottle 3, the second raw material bottle 4 and the transfer bottle 5 respectively; the second port of the second reaction bottle 11 is connected to the gas supply circuit pipeline;

[0085] Transfer bottle 5 is used to terminate the fluorination reaction and transfer the first mixture. The outlet end of transfer bottle 5 is connected to the inlet end of the reversed polymer solid phase extraction column 9.

[0086] Reverse polymer solid-phase extraction column 9 is used to wash the first mixture to obtain a product containing [ 18 The second mixture of F]BIBD-181 product, the inlet end of the reversed-phase polymer solid-phase extraction column 9 is also connected to the pipelines of the first cleaning bottle 6, the second cleaning bottle 7 and the third cleaning bottle 8 respectively; the outlet end of the reversed-phase polymer solid-phase extraction column 9 is connected to the pipelines of the second recovery bottle 10 and the high-performance liquid chromatograph respectively, and the second recovery bottle 9 is connected to the gas transmission circuit pipeline.

[0087] High-performance liquid chromatography (HPLC) was used to separate and purify the second mixture to obtain [ 18 F]BIBD-181 crude product, the outlet end of the high performance liquid chromatograph is connected to the rotary evaporator 19 pipe;

[0088] Rotary flask 19, used for removing [[] by rotary evaporation 18 The solvent in the crude product F]BIBD-181 was used to obtain [ 18 For product F]BIBD-181, rotary evaporator 19 is connected to solvent bottle 20 and product bottle 21 via pipes respectively;

[0089] Rotary flask 19 is connected to the high performance liquid chromatograph and the gas delivery circuit pipeline.

[0090] Specifically, the gas supply circuit includes: gas source 14 and gas pump 15.

[0091] The air pump 15 is connected to the air source 14 through a gas circuit consisting of the first and second air supply pipes;

[0092] The first reaction bottle 1 is connected to the first gas delivery pipe.

[0093] Specifically, a buffer bottle 16 is installed between the air pump and the system.

[0094] Specifically, the second gas pipeline includes a first gas branch line, a second gas branch line, and a third gas branch line;

[0095] The outlet end of the first recycling bottle 13 is connected to the first gas transmission branch line;

[0096] The outlet end of the second recycling bottle 10 is connected to the second gas transmission branch line;

[0097] The second port of the second reaction bottle 11 is connected to the third gas supply branch.

[0098] Specifically, the gas transmission circuit also includes a third gas transmission pipeline;

[0099] The first port of the second reaction vessel 11 is connected to the first gas supply pipe through the third gas supply pipe.

[0100] Specifically, the gas transmission circuit also includes a fourth gas transmission pipeline, a fifth gas transmission pipeline, and a sixth gas transmission pipeline;

[0101] The fourth gas delivery pipeline is connected in parallel with the second gas delivery pipeline, and the high performance liquid chromatograph and rotary evaporator 19 are connected in parallel to the fourth gas delivery pipeline;

[0102] The fifth gas pipeline connects the second cleaning bottle 7 and the gas source 14;

[0103] The sixth gas pipeline is used to connect the third cleaning bottle 8 and the gas source 14.

[0104] Specifically, the first reaction bottle 1 contains deoxygenated water;

[0105] Add a mixed solution of amino polyether, potassium carbonate, acetonitrile, and water to the first eluent flask 2;

[0106] The first raw material bottle 3 contains anhydrous acetonitrile;

[0107] The second raw material bottle 4 contains the precursor solution; the precursor solution is a solution of (R)-1-[3-(3-fluoropropyl)-4-pyridinemethyl]-4-(3,4,5-trifluorophenyl)-2-pyrrolidone dissolved in anhydrous acetonitrile;

[0108] Transfer bottle 5 contains water for injection;

[0109] The first cleaning bottle 6 contains water for injection;

[0110] The second cleaning bottle 7 contains anhydrous ethanol;

[0111] The third cleaning bottle 8 contains water for injection;

[0112] Solvent bottle 20 contains anhydrous ethanol.

[0113] Specifically, anion exchange column 12 is a tetramethylammonium strong anion exchange column;

[0114] The reversed-phase polymer solid-phase extraction column 9 is a hydrophilic-lipophilic balanced column.

[0115] Secondly, such as Figure 1-5 As shown, this invention provides an automated synthesis method for a radioactive tracer targeting SV2A in an application system, comprising the following specific steps:

[0116] A liquid target is generated by bombarding the heavy oxygen water in the first reaction bottle 1 with a cyclotron.

[0117] Liquid target is collected via anion exchange column 12. 18 F - and will 18 F - Transferred to the second reaction flask 11;

[0118] The anhydrous acetonitrile in the first raw material bottle 3 is transferred to the second reaction bottle 11 for an azeotropic reaction to remove [acetonitrile]. 18 F - The solvent in the solution is used to obtain a pure product. 18 F - ;

[0119] The precursor solution in the second raw material bottle 4 is transferred to the second reaction bottle 11 for fluorination reaction to obtain a product containing [ 18 The first mixture of F]BIBD-181 products;

[0120] The reaction was terminated by injecting the water for injection in transfer bottle 5 into the second reaction bottle 11, and the first mixture was transferred to transfer bottle 5.

[0121] The first mixture was washed using a reversed-phase polymer solid-phase extraction column 9 to obtain a sample containing […]. 18 The second mixture of F]BIBD-181 products;

[0122] The second mixture was transferred to a high-performance liquid chromatograph for separation and purification to obtain [ 18 F]BIBD-181 crude product;

[0123] Will[ 18 The crude product of F]BIBD-181 was transferred to rotary evaporator flask 19 and removed by rotary evaporation. 18 The solvent in the crude product F]BIBD-181 was used to obtain [ 18 F]BIBD-181 product;

[0124] Will[ 18 F]BIBD-181 product is transferred to a product bottle for storage.

[0125] Specifically, the process of generating a liquid target by bombarding the deoxygenated water in the first reaction vessel with a cyclotron includes:

[0126] By continuously bombarding heavily oxygenated water with a proton beam of 10 MeV and 45-50 μA generated by a cyclotron for 50-60 minutes, a process occurs... 18 O(p, n) 18 F nuclear reaction, producing [a substance] containing 18 F - Liquid target.

[0127] Specifically, the anhydrous acetonitrile in the first raw material bottle 3 is transferred to the second reaction bottle 11 for an azeotropic reaction to remove [acetonitrile]. 18 F - The solvent in the solution is used to obtain a pure product. 18 F - include:

[0128] The anhydrous acetonitrile in the first raw material bottle 3 is transferred to the second reaction bottle 11;

[0129] Under a nitrogen atmosphere, the second reaction flask 11 was heated to 95°C and held for 90-100 seconds, then the temperature was increased by 5°C and held for 90-100 seconds to carry out an azeotropic reaction, removing [the impurities]. 18 F - The solvent in the solution is used to obtain a pure product. 18 F - ;

[0130] During this process, nitrogen gas is continuously bubbled into the second reaction flask 11;

[0131] The precursor solution in the second raw material bottle 4 is transferred to the second reaction bottle 11 for fluorination reaction to obtain a product containing [ 18 The first mixture of F]BIBD-181 products includes:

[0132] The precursor solution in the second raw material bottle 4 is transferred to the second reaction bottle 11;

[0133] High-pressure air is blown into the second reaction flask 11, and the second reaction flask 11 is heated to 95-105℃ under high pressure to carry out a fluorination reaction for 12-15 min, obtaining a product containing […]. 18 The first mixture of F]BIBD-181 products.

[0134] Example 1 [ 18 F]BIBD-181 Cold Experiment

[0135] To verify the correctness of the written program, a preliminary experiment was conducted to observe whether the tubing of the ferrule was properly connected. For example... Figure 1 As shown, first install the ferrule correctly, connect the N2 system and the waste gas and waste liquid devices, fix the reaction bottle in place, and do not add reactants to the reaction tubes. Add appropriate amounts of water and acetonitrile solution to the other reagent bottles as substitutes. Turn on the program switch to test whether the gas can flow normally in the tube of the ferrule and whether the liquid in the reagent bottle can be added normally.

[0136] Example 2 [ 18 F - In the synthesis of BIBD-181 18 F -Load and transfer

[0137] like Figure 1-3 As shown, heavy oxygen water was continuously bombarded for 50-60 minutes by a proton beam of 10 MeV and 45-50 μA generated by a cyclotron, resulting in... 18 O(p, n) 18 The F-nuclear reaction, first passed through the accelerator... 18 O(p, n) 18 F reaction generates radioactive HF (containing) 18 F - The valves V18 and V14 in the first gas delivery pipe of the automated synthesis module, which are connected to the vacuum pump, are opened, creating negative pressure in the entire system. 18 F - It is transferred through the pipeline to the first reaction flask 1 on the CFN-MPS200 ferrule;

[0138] Open valves V19 and V15 of the second gas delivery pipeline and valve V7 of the first recovery bottle 13 in sequence; then open valves VP35 and VP36 of the pipeline between the anion exchange column 12 and the first recovery bottle 13, and valves VP34, VP33, VP1, and VP3 of the pipeline between the anion exchange column 12 and the first reaction bottle 1 in sequence; then open valve V5 between the first reaction bottle 1 and the first gas delivery pipeline and valve V1 in the first gas delivery pipeline in sequence; finally, open valve VU1 of the nitrogen source 14 to... 18 F - Excess H2 is loaded onto anion exchange column 12 (QMA column) via tubing, and then... 18 O is washed into the first recovery bottle 13, and the above valves are closed after completion.

[0139] Next, sequentially open valves V19 and V15 of the second gas delivery pipeline and valve V16 of the third gas delivery branch; then sequentially open valves VP39 and VP38 between the second port of the second reaction bottle 11 and the second gas delivery branch; then sequentially open valves VP37 and VP36 between the second reaction bottle 11 and the anion exchange column 12; then sequentially open valves VP34, VP33, VP1 and valve VP4 at the outlet of the first eluent bottle 2, add 0.2 mL of acetonitrile and 0.9 mL of aqueous solution containing amino polyether (10 mg) and potassium carbonate (1.8 mg) (K2.2.2 / K2CO3) to the first eluent bottle 2, and eluent the anion exchange column 12. 18 F - Displace the contents and add them to the second reaction flask 11 (RV). Turn on the heating switch VA3 of the second reaction flask 11 and heat it to 40°C for 30 seconds. After completion, close the valves.

[0140] Example 3 [ 18Dehydration and drying before fluorination reaction in BIBD-181 automated synthesis.

[0141] Next, open valves V19 and V15 of the second gas pipeline and valve V16 of the third gas branch line in sequence; then open valves VP39 and VP38 between the second port of the second reaction bottle 11 and the second gas branch line in sequence; turn on the heating switch VA3 of the second reaction bottle 11, heat to 95°C and maintain for 30 seconds, then open valve V1, valve VP37 of the first port of the second reaction bottle 11, valves VP22, VP20, VP17, VP18, VP19, VP8 of the third gas pipeline and valve VU1 of the gas source 14 in sequence, continue heating at 95°C for 60 seconds, raise to 100°C, heat for 250 seconds, then close VA3 and stop heating;

[0142] During this stage, VP8, VP19, and VP18 are kept open. While keeping valves VU1 and V1 open to purge nitrogen, open valves VP2 and VP5 at the outlet of the first raw material bottle 3. After adding 0.5 mL of anhydrous acetonitrile through the pipeline, close VP and VP2.

[0143] Ensure valves VP8, VP19, and VP18 are open; after confirming that all anhydrous acetonitrile in the first raw material bottle 3 has been added, continue to purge nitrogen gas to ensure that all anhydrous acetonitrile inside the pipeline enters the second reaction bottle 11 for 5 seconds, then close valves VP8, VP19, and VP18.

[0144] Open valves VU1 and V1 to introduce nitrogen gas; then open valves V19, V15, V16, VP39, VP38, VP37, VP22, VP20, VP17, VP18, VP19, and VP8 in sequence; (in this embodiment, there are multiple processes of closing and opening valves. Each opening and closing is equivalent to a valve self-check. Valves that are energized for a long time and in an open state are prone to problems such as squeezing the reaction pipeline, so they are opened and closed frequently, which also serves as a self-check). Then open VA3 to introduce compressed air, turn on the heater to raise it to 95°C and maintain it for 150 seconds, adjust the temperature to 90°C, heat for 50 seconds and then stop, during which nitrogen gas is slowly introduced. Finally, close all the above valves in sequence (V16, V15, V19, VP39, VP38, VP8, VP19, VP18, VP17, VP20, VP22, VP37, VU1, and V1).

[0145] Example 4 [ 18 A key step in the automated synthesis of F]BIBD-181 – fluorination reaction

[0146] Open valves VA3, VU1, V1, V19, V15, and V16 in sequence; then open valves VP39, VP38, VP37, VP22, VP20, VP17, and valves VP2 and VP6 at the outlet of the second raw material bottle 4; add the precursor solution into the reaction bottle. Continue for 15 seconds, observing that all the precursor solution has been added, then close valves VP6 and VP2; open valves VP8, VP19, and VP18, and purge nitrogen gas to blow the remaining precursor solution in the pipeline into the second reaction bottle 11, continue for 5-10 seconds, then close valve VP19;

[0147] High-pressure air is blown into the second reaction flask 11 through VA3. The heater of the second reaction flask 11 is turned on, and VP37, VP22, VP20, VP17, VP38, and VP39 are turned off. Valves V16 and V15 are turned off. The temperature is heated to 95-105℃. The reaction is allowed to proceed for 12-15 minutes. The heater is then turned off, and the reaction system begins to cool down. VA3 is then turned off.

[0148] Example 5: Reaction Termination and Transfer of the Reaction System

[0149] like Figure 1-4 As shown, sequentially open valves VU1, V1, V18, V15, V16, VP39, VP38, VP37, VP22, VP20, VP17, VP18, and valves VP25 and VP10 at the outlet of transfer bottle 5, holding for 10 seconds. Add 2-4 mL of sterile water for injection from transfer bottle 5 to terminate the reaction. Close VP10 and VP25, and close VP8, VP19, VP18, VP38, VP39, and VP37; close V18.

[0150] Open valve VU1; open valves V1 and V3; purge nitrogen gas, open valves VP39, VP38, VP37, VP22, VP20, VP17, VP18, VP25, and VP10; wait 3 seconds, then open the liquid switch VA7 of the second reaction bottle 11 and continue for 10 seconds; a pop-up message will appear saying "!Transfer OK?"; at this time, observe whether the first mixture in the second reaction bottle 11 has been completely transferred to the transfer bottle 5. If the transfer is successful, then close valves VP10 and VP25; close VP8, VP19, VP38, VP39, and VP37; close VP22, VP20, VP17, VP18, VP25, and VP10; close valves VU1, V1, and V3.

[0151] Open valve VU1; open valve V1; open valves V19, V15, and valve V17 of the second gas delivery branch; hold for 5 seconds; open valves VP45 and VP44 between the reversed-phase polymer solid-phase extraction column 9 and the second recovery bottle 10, valves VP43, VP31, and VP26 between the reversed-phase polymer solid-phase extraction column 9 and the transfer bottle 5, and valve VP25 at the outlet of the transfer bottle 5; wait 2 seconds, then open valve VP10 for 15 seconds; allow the first mixture to flow to the reversed-phase polymer solid-phase extraction column 9 (HLB column), loading the organic matter onto the reversed-phase polymer solid-phase extraction column 9, while the remaining liquid enters the second recovery bottle 10. After the message "!TransferOK?" pops up, close valves VP10 and VP25; wait 1 second; close valves VP26, VP31, VP43, VP44, and VP45; close valves V19, V15, and V17.

[0152] Open valves VU1, V1, V19, V15, and V17 sequentially for 2 seconds; then open valves VP45, VP44, VP43, VP31, and VP15, wait 2 seconds, and then open valve VP11 at the outlet of the first cleaning bottle 6 for 15 seconds to flush water-soluble impurities on the reversed polymer solid-phase extraction column 9 to the second recovery bottle 10. Observe whether the water for injection in the first cleaning bottle 6 has completely flowed to the reversed polymer solid-phase extraction column 9. After completion, close VP11, VP43, VP31, and VP15; close VP45 and VP44, wait 5 seconds, and then close V19, V15, and V17.

[0153] Open valve H2 connected to the collection tube 17 of the high-performance liquid chromatograph (HPLC), creating a negative pressure within the collection tube 17. Open valve VU1 and hold for 2 seconds to purge nitrogen gas. Open valve V2 in the fifth gas delivery pipe, as well as valves VP14, VP16, VP32, VP44 and VP43, VP31, VP15 between the HPLC and the reversed-phase polymer solid-phase extraction column 9. Wait 1 second, then open valve VP12 at the outlet of the second washing bottle 7 and hold for 1 second; close VP12; wait 2 seconds, then open VP12 and hold for 2 seconds; close VP12 and hold for 2 seconds; open VP12 and hold for 2 seconds; close VP12 and hold for 2 seconds. This allows a 1 mL ethanol gradient from the second washing bottle 7 to pass through the reversed-phase polymer solid-phase extraction column 9, allowing the ethanol containing […] to pass through the column. 18 The second mixture of F]BIBD-181 product was eluted from the reversed-phase polymer solid-phase extraction column 9 and flowed into the collection tube 17 above the HPLC. Then V2 was turned off; VP12 was turned off; after 5 seconds, VP15 and VP31 were turned off.

[0154] Next, open V1 in sequence; then open valves VP8, VP19, VP24, VP30, and VP41 of the sixth gas delivery pipeline and valve VP42 at the outlet of the third cleaning bottle 8; after 5 seconds, use 1.0 mL of water for injection from the third cleaning bottle 8 to clean the reversed-phase polymer solid-phase extraction column 9 and pipeline along the pipeline. After fully collecting the second mixture, inject it into the collection tube 17 above the HPLC, and close VU1; close V1 and H2; close VP14, VP16, VP32, VP44, VP43, and VP42; close VP41, VP30, VP24, VP19, and VP8.

[0155] Example 6: The reaction system was introduced into HPLC and [ 18 Isolation and purification of F]BIBD-181

[0156] like Figure 1-5 As shown, open valve P_ON, the HPLC pump starts running, open VP14, VP16, VP32, VP44, VP43, VP31; open valves VP26, VP19, VP8, open valves V1, VU1, H2; hold for 1 second; open valve H8 between collection tube 17 and syringe 18; syringe 18 at H8 starts drawing liquid from collection tube 17, hold for 2 seconds, open H4; hold for 1 second; open H9; syringe 18 squeezes liquid into the HPLC pump, when all liquid in all syringes 18 has entered the HPLC, close H8; hold for 2 seconds; close H4; hold for 1 second; close H9.

[0157] Ensure the HPLC is on; a pop-up message will appear saying "!Collect Start?". At 12-13 minutes, start collecting the components by clicking to turn on valve H6. Turn on valves VE8 and VE3 to begin collecting the components. The collection time should not exceed 2 minutes. When a pop-up message appears saying "!Collect Finish?", click to close valve H6. Close valves VE8 and VE3 for 2 seconds. Turn off the HPLC pump for 2 seconds. All collected components will flow into rotary evaporator flask 19.

[0158] Transfer the collected components to rotary evaporator flask 19, open valve H5; open VU1 and VU6; after purging nitrogen, open H7, VE3, and VE8; continue for 5 seconds, then add 1.0 mL of pharmaceutical ethanol from bottle 9 to form an azeotrope with water, reducing evaporation time and accelerating drug production; a pop-up message "!Transfer OK?" appears; after clicking, the device shuts down H7, VE3, and VE8.

[0159] At this point, the collected components are completely transferred to the evaporation flask; rotary evaporate for 3-5 minutes, turn on VE9 (to evaporate the gas) and Motor (rotary valve); turn on VE2; continue heating for 20 seconds; raise the temperature to 80°C; hold for 60 seconds; raise the temperature to 100°C; hold for 60 seconds; reheat to 130°C; hold for 40 seconds; a pop-up message "!Dry up OK?" appears; stop heating; hold for 20 seconds; turn off VE9 and Motor.

[0160] Open VE8, VE6, and VE4; open VU6 and VU1; turn on the motor rotation button and add 10 mL of physiological saline containing 10% EtOH and 0.5% VcNa from bottle 10 to final product bottle 21. Mix thoroughly until a pop-up message "!Saline load OK?" appears; continue for 30 seconds; turn off the motor; close valves VE8, VE6, and VE4; open VE4, VE5, and VE7; continue for 1 second; open VE1; continue for 2 seconds. Finally, transfer the product filter membrane to final product bottle 21 (Product).

[0161] Although preferred embodiments of the invention have been described, those skilled in the art, upon learning the basic inventive concept, can make other changes and modifications to these embodiments. Therefore, the appended claims are intended to be interpreted as including both the preferred embodiments and all changes and modifications falling within the scope of the invention.

[0162] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims of this invention and their equivalents, this invention also intends to include these modifications and variations.

Claims

1. An automated synthesis system for a radioactive tracer targeting SV2A, characterized in that, include: A gas supply circuit is used to supply gas to the system. A cyclotron is used to bombard the heavy oxygen water in the first reaction vessel to generate a liquid target. The first reaction bottle (1) is used to generate a liquid target. The inlet end of the first reaction bottle (1) is also connected to the gas delivery circuit pipeline. The outlet end of the first reaction bottle (1) is connected to the inlet end pipeline of the anion exchange column (12). The anion exchange column (12) is used to collect the liquid target. 18 F - The inlet end of the anion exchange column (12) is also connected to the pipe of the first elution bottle (2), and the outlet end of the anion exchange column (12) is connected to the pipes of the first recovery bottle (13) and the second reaction bottle (11). The second reaction flask (11) is used to make the... 18 F - Fluorination reaction with precursor produces a product containing [ 18 The first mixture of F]BIBD-181 product, the first port of the second reaction bottle (11) is connected to the gas supply circuit, the first raw material bottle (3), the second raw material bottle (4) and the transfer bottle (5) respectively; the second port of the second reaction bottle (11) is connected to the gas supply circuit pipeline; The transfer bottle (5) is used to terminate the fluorination reaction and transfer the first mixture. The outlet end of the transfer bottle (5) is connected to the inlet end of the reverse polymer solid phase extraction column (9). The reversed-phase polymer solid-phase extraction column (9) is used to wash the first mixture to obtain a product containing the […]. 18 The second mixture of F]BIBD-181 product, the inlet end of the reversed-phase polymer solid-phase extraction column (9) is also connected to the pipelines of the first cleaning bottle (6), the second cleaning bottle (7) and the third cleaning bottle (8); the outlet end of the reversed-phase polymer solid-phase extraction column (9) is connected to the pipelines of the second recovery bottle (10) and the high-performance liquid chromatograph, and the second recovery bottle (9) is connected to the gas delivery circuit pipeline; The high-performance liquid chromatograph is used to separate and purify the second mixture to obtain [ 18 F]BIBD-181 crude product, the outlet end of the high performance liquid chromatograph is connected to the pipeline of the rotary evaporator (19); The rotary evaporator flask (19) is used to remove the [[] by rotary evaporation. 18 The solvent in the crude product F]BIBD-181 was used to obtain the [ 18 The F]BIBD-181 product, wherein the rotary evaporator (19) is connected to the solvent bottle (20) and the product bottle (21) via pipes respectively; The rotary evaporator (19) is connected to the high performance liquid chromatograph and the gas delivery circuit pipeline.

2. The automated synthesis system for a radioactive tracer targeting SV2A according to claim 1, characterized in that, The gas delivery circuit includes: Gas source (14); An air pump (15) is connected to the air source (14) through a gas circuit consisting of a first air supply pipe and a second air supply pipe; The first reaction bottle (1) is connected to the first gas delivery pipe.

3. The automated synthesis system for a radioactive tracer targeting SV2A according to claim 2, characterized in that, The second gas pipeline includes a first gas branch line, a second gas branch line, and a third gas branch line; The outlet end of the first recycling bottle (13) is connected to the first gas transmission branch line; The outlet end of the second recycling bottle (10) is connected to the second gas transmission branch line; The second port of the second reaction bottle (11) is connected to the third gas supply branch.

4. The automated synthesis system for a radioactive tracer targeting SV2A according to claim 2, characterized in that, The gas transmission circuit also includes a third gas transmission pipeline; The first port of the second reaction vessel (11) is connected to the first gas supply pipe through the third gas supply pipe.

5. The automated synthesis system for a radioactive tracer targeting SV2A according to claim 1, characterized in that, The gas transmission circuit also includes a fourth gas transmission pipeline, a fifth gas transmission pipeline, and a sixth gas transmission pipeline; The fourth gas delivery pipeline is connected in parallel with the second gas delivery pipeline, and the high performance liquid chromatograph and the rotary evaporator (19) are connected in parallel to the fourth gas delivery pipeline; The fifth gas pipeline connects the second cleaning bottle (7) and the gas source (14). The sixth gas pipeline is used to connect the third cleaning bottle (8) and the gas source (14).

6. The automated synthesis system for a radioactive tracer targeting SV2A according to claim 1, characterized in that, The first reaction bottle (1) contains heavy oxygen water; A mixed solution of amino polyether and potassium carbonate in acetonitrile and water is added to the first eluent (2); The first raw material bottle (3) contains anhydrous acetonitrile; The second raw material bottle (4) contains a precursor solution; the precursor solution is a solution of (R)-1-[3-(3-fluoropropyl)-4-pyridinemethyl]-4-(3,4,5-trifluorophenyl)-2-pyrrolidone) dissolved in anhydrous acetonitrile; The transfer bottle (5) contains water for injection; The first cleaning bottle (6) contains water for injection; The second cleaning bottle (7) contains anhydrous ethanol; The third cleaning bottle (8) contains water for injection; The solvent bottle (20) contains anhydrous ethanol.

7. The automated synthesis system for a radioactive tracer targeting SV2A according to claim 1, characterized in that, The anion exchange column (12) is a tetramethylammonium strong anion exchange column; The reverse polymer solid-phase extraction column (9) is a hydrophilic-lipophilic balanced column.

8. An automated method for synthesizing a radioactive tracer targeting SV2A using the system described in any one of claims 1-7, characterized in that, The specific steps include the following: A liquid target is generated by bombarding the heavy oxygen water in the first reaction bottle (1) with a cyclotron. The liquid target was collected via an anion exchange column (12). 18 F - and the 18 F - It is transferred to the second reaction flask (11); The anhydrous acetonitrile in the first raw material bottle (3) is transferred to the second reaction bottle (11) for an azeotropic reaction to remove the... 18 F - The solvent in the solution is used to obtain the purified product. 18 F - ; The precursor solution in the second raw material bottle (4) is transferred to the second reaction bottle (11) for fluorination to obtain a product containing [ 18 The first mixture of F]BIBD-181 products; The reaction was terminated by injecting the water for injection in the transfer bottle (5) into the second reaction bottle (11), and the first mixture was transferred into the transfer bottle (5); The first mixture was washed with a reversed-phase polymer solid-phase extraction column (9) to obtain a mixture containing the […]. 18 The second mixture of F]BIBD-181 products; The second mixture was transferred to a high-performance liquid chromatograph for separation and purification to obtain [ 18 F]BIBD-181 crude product; The [ 18 F]BIBD-181 crude product was transferred to a rotary evaporator flask (19) for removal by rotary evaporation. 18 The solvent in the crude product F]BIBD-181 was used to obtain the [ 18 F]BIBD-181 product; The [ 18 F]BIBD-181 product is transferred to a product bottle for storage.

9. An automated synthesis method for a radioactive tracer targeting SV2A according to claim 8, characterized in that, The process of generating a liquid target by bombarding the heavy oxygen water in the first reaction bottle with a cyclotron includes: By continuously bombarding heavily oxygenated water with a proton beam of 10 MeV and 45-50 μA generated by a cyclotron for 50-60 minutes, a process occurs... 18 O(p, n) 18 F nuclear reaction, producing [a substance] containing 18 F - Liquid target.

10. An automated synthesis method for a radioactive tracer targeting SV2A according to claim 8, characterized in that, The anhydrous acetonitrile in the first raw material bottle (3) is transferred to the second reaction bottle (11) for an azeotropic reaction to remove the... 18 F - The solvent in the solution is used to obtain the purified product. 18 F - include: The anhydrous acetonitrile in the first raw material bottle (3) is transferred to the second reaction bottle (11); Under a nitrogen atmosphere, the second reaction flask (11) was heated to 95°C and held for 90-100 seconds, then heated by 5°C and held for 90-100 seconds to carry out an azeotropic reaction, removing the aforementioned substances. 18 F - The solvent in the solution is used to obtain the purified product. 18 F - ; During this process, nitrogen gas is continuously bubbled into the second reaction flask (11); The precursor solution in the second raw material bottle (4) is transferred to the second reaction bottle (11) for fluorination reaction to obtain a product containing [ 18 The first mixture of F]BIBD-181 products includes: The precursor solution in the second raw material bottle (4) is transferred to the second reaction bottle (11); High-pressure air is blown into the second reaction flask (11), and the second reaction flask (11) is heated to 95-105℃ under high pressure to carry out a fluorination reaction for 12-15 min, to obtain a product containing [ 18 The first mixture of F]BIBD-181 products.

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