1-(3-bromo-4-(2-fluoro[ 18 Process for the preparation of 1-(3-bromo-4-(2-fluoro[ ethyl)oxy]ethoxy)benzylguanidine and its use

Abstract

This invention provides a 1-(3-bromo-4-(2-fluoro) 18 F]Ethoxy)Ethoxy)Benzylguanidine (referred to as 18 This invention discloses a method for preparing F-TTRC01 and its application in the diagnosis of neuroendocrine tumors. It is synthesized via the following route. This invention employs novel starting materials and a novel preparation route, utilizing high-dose... 18 F ions were labeled, and the product was successfully prepared using an automated synthesis method. 18 F-TTRC01 significantly shortens the reaction time and reduces the radiation dose to operators. The resulting... 18 F-TTRC01 injection can be used for the diagnosis and efficacy evaluation of neuroendocrine tumors, with outstanding clinical results.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmacy, and particularly relates to a preparation method of 1-(3-bromo-4-(2-fluoro[ 18 F]ethoxy)ethoxy)benzyl guanidine and application thereof in the field of neuroendocrine tumor diagnosis. BACKGROUND

[0002] Neuroendocrine neoplasm (NEN) originates from peptidergic neurons and neuroendocrine cells, is a series of heterogeneous tumors from low-grade malignancy showing inertia and slow growth to high-grade malignancy with extensive metastatic ability, and can occur anywhere in the body. Research data at home and abroad suggest that the incidence of NEN is rising. The epidemiological survey results in the United States show that the incidence of NEN is rising more significantly compared with other types of tumors. Nuclear medicine imaging technology, including single photon emission computed tomography (SPECT) and positron emission computed tomography (PET), has the main advantages of non-invasive, real-time, visual and specific diagnosis and treatment at the cellular and molecular levels compared with CT, MRI and ultrasound imaging technologies, can provide effective clinical data for early diagnosis, treatment and efficacy evaluation of tumors, and has become an important method for diagnosing neuroendocrine tumors. The nuclear medicine molecular probes currently reported for neuroendocrine tumor imaging can be divided into somatostatin receptor-targeting type and other types. 18 F-FDG, 123 / 131 I-metastinyl benzyl guanidine, 18 F-DOPA).

[0003] The somatostatin receptor type diagnostic drugs mainly include: 99m Tc-Octreoscan, 111 In-DTPAOC, 68 Ga-DOTATOC, 68 Ga-DOTA-NOC, 64 Cu-DOTA-TATE, etc.

[0004] The above imaging drugs, whether somatostatin receptor type drugs or 18 F-FDG, 123 / 131 I-metastinyl benzyl guanidine, 18 F-DOPA, 11 C-5-serotonin, etc., all have obvious shortcomings, resulting in that they cannot be widely used in clinical practice. For example 111 In-DTPAOC has a too long half-life (67h) as a diagnostic drug, too high radiation dose to the human body, and relatively high energy of two kinds of gamma rays, resulting in low spatial resolution of the image. 99mTc-Octreoscan is affected by imaging technology, and has very poor sensitivity in diagnosing lesions with diameter <1cm in lymph nodes or liver. As for 68 Ga-labeled somatostatin receptor drugs are affected by 68 Ga radionuclide sources are not convenient, and can only rely on generators, and the half-life (68min) is too short to be delivered, which limits its clinical use. 18 F-FDG is the most widely used probe in tumor PET imaging, but for neuroendocrine tumors, it has insufficient targeting, low activity for most G1 and G2 NETs with good differentiation, and high background interference. 123 / 131 I-metaiodobenzylguanidine can specifically concentrate in adrenal medulla and tumor cells rich in adrenergic receptors, but 123 / 131 I radionuclide cannot be mass-produced commercially at this stage, and as a diagnostic drug, the half-life is too long, the abdominal background is too high, and it cannot be popularized in clinical practice. 18 F-DOPA is an imaging agent targeting catecholamine metabolism, which is complex, time-consuming, low-yield, and has a narrow application. SUMMARY

[0005] 18 F-TTRC01, chemical name 1-(3-bromo-4-(2-fluoro 18 ethoxy) ethoxy) benzyl guanidine, has the following structure:

[0006]

[0007] wherein F is 18 F, molecular formula: C 12 H 17 Br 18 FN3O2, molecular weight: 333.19.

[0008] 18 F-TTRC01 is a drug containing radionuclide 18 F, and the F-TTRC01 injection obtained by single preparation according to the current preparation route and technical means can only be used for animal experiments and basic research. 18 Due to the following disadvantages, it cannot be applied in clinical practice:

[0009] 1. In the original preparation route, there are active [H] atoms in the structure of the reaction precursors, the reaction route is long, and there are many uncertain factors such as the type and content of impurities in the preparation process.

[0010]

[0011] 2. The original preparation route adopted a manual "two-step" preparation scheme. After the labeling reaction was completed, it reacted with the key intermediate to obtain the labeled intermediate, which was then separated by HPLC. After separation, it was hydrolyzed and finally the pH value was adjusted, resulting in a total reaction time of about 2.5 hours, and the labeling personnel were exposed to radiation for a long time.

[0012] 3. The original preparation method was complex and cumbersome, with low yield (10-14% after attenuation correction), low specific activity, and low single-batch yield. 18 F-TTRC01 injection has low activity and poor batch-to-batch stability, and is subject to significant errors due to human operation. The injection prepared according to the current protocol does not meet the requirements for clinical use.

[0013] 4. The original preparation scheme has complex and cumbersome steps, which is not conducive to the development of automated synthesis processes, and is costly and difficult to implement.

[0014] 5. To meet 18 F-TTRC01 injection meets clinical use requirements and needs to be further investigated. 18 The preparation scheme of F-TTRC01 injection has been redesigned, with a modified labeling precursor, simplified labeling process, and shortened preparation time. Theoretically, this reduces the possibility of impurity generation, increases yield, and facilitates the development of automated synthesis processes, thereby improving… 18 The single-dose yield and batch-to-batch stability of F-TTRC01 injection are designed to meet future large-scale clinical needs.

[0015] To address the shortcomings of the aforementioned imaging agents and the various drawbacks of the original preparation methods, the inventors of this application conducted in-depth research. As a result, they discovered that by designing new labeling precursors and preparation routes, a method easily applicable to multiple large-scale preparations could be developed. 18 The automated synthesis process of F-TTRC01 injection solution meets the requirements for large-scale clinical use.

[0016] This invention addresses the shortcomings of existing technologies and aims to provide a 1-(3-bromo-4-(2-fluoro) 18 The preparation method of F]ethoxy)ethoxy)benzylguanidine, thereby improving 18 F: Initial reaction dose, preparation yield, and specific activity; reduce reaction time, impurity content, radiation dose, and usage cost.

[0017] Another object of the present invention is to provide an automated synthesis process for the radiopharmaceutical.

[0018] Another object of the present invention is to provide the application of the radiopharmaceutical in the field of neuroendocrine tumor diagnosis.

[0019] To achieve the above objectives, the present invention mainly adopts the following technical solutions:

[0020] 1. A method for preparing 1-(3-bromo-4-(2-fluoro[ 18 F]ethoxy)ethoxy)benzyl guanidine, characterized in that the method is performed in a one-pot manner, and the preparation route is as follows:

[0021]

[0022] In the present application, a brand-new starting material (marker precursor) and preparation route are adopted, and a large dose of 18 F ion is used for labeling, and 18 F-TTRC01 is successfully prepared in an automatic synthesis manner, so that the reaction time is greatly shortened, the radiation dose to the operator is reduced, the chemical impurities are reduced, the radiochemical yield and specific activity are improved, the batch production quantity and the yield stability between batches are increased, the clinical use requirements are met, the in vitro stability within 6 hours is good, the transportation is convenient, and the cost is saved. 18 F-TTRC01 injection obtained by the method described in the present application can be used for the diagnosis and efficacy evaluation of neuroendocrine tumors, and clinical research shows that, compared with a commonly used drug 18 F-FDG, there are obvious advantages in key organ radiation damage, target-to-background ratio, lesion absolute uptake value, and diagnosis of small and metastatic lesions, and the clinical effect is outstanding.

[0023] According to specific embodiments, the specific conditions are as shown below:

[0024]

[0025] K2CO3, 18 F - and a marker precursor TTRC01-OTs-BOC4 and 0.5 mL of anhydrous acetonitrile are added to a reaction bottle, and the reaction is performed at 90°C for 10 min under a closed condition to obtain 18 F-TTRC01-BOC4. After the reaction is completed, a trifluoroacetic acid solution is added, and the reaction is continuously performed at 90°C for 10 min under a closed condition. After the reaction is completed, the reaction mixture is cooled to room temperature, filtered by using a 0.22 μm filter membrane, and then separated by using an HPLC semi-preparative column, and the HPLC conditions are as follows: the mobile phase is a mixture of water (1% TFA) and acetonitrile, and the volume ratio of the two is 3:1; the gradient is isocratic; and the flow rate is 5 mL / min. Physiological saline is added to the obtained crude product, and then NaHCO3 is added until no bubbles are generated, so that the pH is adjusted to neutral, thereby obtaining 18 F-FP2BG, and the radiochemical purity is greater than 99%.

[0026] An automatic synthesis process of 1-(3-bromo-4-(2-fluoro[ 18 F]ethoxy)ethoxy)benzyl guanidine is as follows:

[0027] 1) by accelerator production 18 F ions;

[0028] 2) by anion column capture of the 18 F ions from step 1)

[0029] 3) elution of the 18 F ions from step 2) through an anion column with 1-2 mL of a tetrabutylammonium salt phase transfer catalyst eluent or an organic-aqueous phase mixed eluent composed of cryptand and sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate and other strong base weak acid salts to obtain a first reaction solution into a reaction bottle

[0030] 4) water removal and activation of the 18 F reaction solution from step 3) by program-controlled heating temperature, time, inert gas flow rate, addition of anhydrous organic solvent (repeated 2-3 times) and vacuum degree of the automatic synthesizer

[0031] 5) addition of 0.5-3 mL of an anhydrous aprotic organic solvent solution of the labeling precursor TTRC01-OTs-BOC4 into the reaction bottle, wherein the reaction precursor is 5-15 mg and the reaction temperature is 80-120°C, and the reaction is carried out under closed conditions for 5-50 min

[0032] 6) cooling of the reaction bottle after completion of step 5) to room temperature, addition of 0.2-1.5 mL of a 10%-100% trifluoroacetic acid solution, and reaction under closed conditions at 25-120°C for 5-30 min

[0033] 7) cooling of the reaction bottle after completion of step 6) to room temperature, addition of 3-6 mL of water for dilution and mixing, and purification of the mixed solution by semi-preparative HPLC (conditions: chromatographic column: C18 reverse phase preparative column; mobile phase: acetonitrile, water (0.1-1% TFA), volume ratio 1 / 4-4 / 1; isocratic elution, flow rate 2-10 mL / min)

[0034] 8) collection of the mobile phase containing 18 F-TTRC01, enrichment by a solid phase extraction column; washing of the solid phase extraction column with 5-20 mL of water, then eluting the solid phase extraction column with 0.5-3 mL of a phosphoric acid ethanol solution or a hydrochloric acid ethanol solution, and collecting the eluent into a product bottle containing 10-20 mL of physiological saline and ascorbic acid to prepare 18 F-TTRC01 injection.

[0035] The beneficial effects of the present application are at least:

[0036] Compared with the existing preparation scheme, the 1-(3-bromo-4-(2-fluoro 18The preparation method of the (2-ethoxy)ethoxy)benzyl guanidine has the following excellent effects: the preparation method of the F-TTRC01 of the present application has the following excellent effects: 18 In the preparation method of the F-TTRC01, the chemical reagents used for synthesis of the labeled precursor and the control product are all commercially available products, which are widely available; the preparation technical route of the F-TTRC01 is simple, and the side reaction is less; the F-TTRC01 is prepared by using the automatic synthesis module, and the F-TTRC01 has the advantages of high-dose starting radionuclide activity, simple process, short reaction time, less impurities, easy separation and purification, small radiation dose, small human error, high radiochemical yield, high specific activity, and the like; the F-TTRC01 prepared by a single preparation has the advantages of high dose, and can be used for clinical use of multiple people, and is convenient for clinical promotion. 18 18 18 The F-TTRC01 has a high dose, and can be used for clinical use of multiple people, and is convenient for clinical promotion.

[0037] In addition, the F-TTRC01 has the advantages of the following advantages: 18 The F-TTRC01 has good initial uptake and retention of neuroendocrine tumors, and good target-to-non-target ratios. Compared with the commonly used imaging drugs in the clinic, the F-TTRC01 has the advantages of the following advantages: 18 Compared with the F-FDG, the F-TTRC01 can image the primary lesions and metastatic lesions, has high accuracy and sensitivity, excellent biological performance, and is convenient for clinical qualitative and quantitative analysis, and therefore has high clinical application value in the diagnosis of neuroendocrine tumors. BRIEF DESCRIPTION OF DRAWINGS

[0038] [ Figure 1 ] indicates that the F-TTRC01 is prepared by the automatic synthesis process. 18 The F-TTRC01 is prepared by the automatic synthesis process.

[0039] [ Figure 2 ] indicates that the F-TTRC01 is prepared by the automatic synthesis process. 18 The F-TTRC01 is prepared by the automatic synthesis process.

[0040] [ Figure 3 ] indicates that the F-TTRC01 is prepared by the automatic synthesis process. 18 The F-TTRC01 is prepared by the automatic synthesis process. 19 The F-TTRC01 is prepared by the automatic synthesis process.

[0041] [ Figure 4 ] indicates that the F-TTRC01 is prepared by the automatic synthesis process. 18 The F-TTRC01 is prepared by the automatic synthesis process.

[0042] [ Figure 5 ] indicates that the F-TTRC01 is prepared by the automatic synthesis process. 18 The F-TTRC01 is prepared by the automatic synthesis process. 18 The F-TTRC01 is prepared by the automatic synthesis process.

[0043] [ Figure 6 ] indicates that the F-TTRC01 is prepared by the automatic synthesis process. 18 ​​F-TTRC01 uptake distribution in major organs of patients. DETAILED DESCRIPTION

[0044] The present application is described in detail below by way of examples, but the present application is not limited to these examples.

[0045] I. 18 Preparation of F-TTRC01

[0046] Materials: TTRC01-OTs-BOC4 in the following synthetic route was prepared by ourselves. Potassium carbonate, trifluoroacetic acid, anhydrous acetonitrile, K 222 , anhydrous ethanol, phosphoric acid were purchased from Sigma Aldrich. 18 F - Prepared by ourselves from GE cyclotron.

[0047] HPLC instrument and method:

[0048] (1) Instrument:

[0049] Waters ARC type quaternary high pressure liquid chromatography system, 2998 type full wavelength UV detector, Raytest GabiNova radioactivity detector, chromatographic column: Waters XBridge OBD C18 5μm 10*250mm, automatic synthesis instrument Trasis All in one-36, the equipment includes pneumatic unit, injector electronic rotation system, automatic sample addition system, negative pressure system, HPLC purification system.

[0050] (2) 18 Automated synthesis of F-TTRC01:

[0051]

[0052] 1) The existing preparation scheme generally uses 10-50mCi of 18 F ion as the starting dose. In order to meet the clinical use, a new preparation scheme is used in the automatic synthesis instrument in this embodiment, 18 F ion starting dose is 100-1000mCi, which is much larger than the existing preparation method; the rest of the auxiliary materials are used as little as possible under the condition of meeting the labeling yield.

[0053] 2) 18 The F ion solution anion enrichment small column is preferably a Waters SEP-PAK Light QMA small column, and the QMA small column activation solution is preferably 0.5mol / L sodium bicarbonate solution.

[0054] 3) The preferred 18 F ion elution solution is Kryptofix K 222Mixed solution with potassium carbonate; Hole ether K 222 The amount of 10 mg, the amount of potassium carbonate is 3 mg, and the eluent is 1 mL of a mixed solution of acetonitrile and water in a volume ratio of 9:1.

[0055] 4) 18 The water removal and drying process of F ions is particularly important for nucleophilic substitution reactions. If the drying is not complete, it will seriously affect the efficiency of the nucleophilic substitution reaction. In addition, compared with the existing preparation scheme, the water removal and drying scheme adopted by the present application does not need to add anhydrous acetonitrile for azeotropic water removal multiple times. The preferred water removal and drying scheme is shown in the following table:

[0056] Table 1 Water removal and drying conditions

[0057] Temperature (°C) Airflow properties and pressure (mbar) Vacuum state and pressure (mbar) Time (s) 115 Low airflow 500 Negative pressure - 500 100 110 Low airflow 1000 Negative pressure - 1000 100 100 Low airflow 1000 Negative pressure - 1000 100 90 Low airflow 1000 Negative pressure - 1000 120 90 High airflow 300 Negative pressure - 1000 30

[0058] 5) Preferably, the amount of the labeled precursor TTRC01-OTs-BOC4 is 10 mg, the aprotic solvent is 1 mL of anhydrous acetonitrile, the labeling temperature is 90°C, and the closed reaction is 10 min.

[0059] 6) Preferably, 0.5 mL of 15% trifluoroacetic acid solution is used as the hydrolysis reaction medium, the reaction temperature is 90°C, and the reaction is carried out under closed conditions for 5 min.

[0060] 7) Preferably, the HPLC system of the automatic synthesis instrument Trasis Allinone-36 is used to separate the hydrolysis product, and the HPLC conditions are: column: Xbridge BEH C18 OBD Prep column, 130A, 5μm, 10*250mm; mobile phase: acetonitrile / water (0.1% TFA) = 3:1; flow rate: flow rate 5 mL / min.

[0061] 8) The preferred solid phase extraction column is a Waters SEP-PAK CM column.

[0062] 9) The preferred product eluent is 5% phosphoric acid ethanol solution 1 mL.

[0063] 10) The automatic synthesis method of 1-(3-bromo-4-(2-fluoro[ 18 F]ethoxy)ethoxy)benzyl guanidine provided by the embodiment of the present application is shown in the process flow chart as Figure 1 .

[0064] Specific conditions can be: producing F ions by a cyclotron 18 , capturing through a QMA anion column (No. 5 shown) Figure 1 , and then using a mixed eluent containing K 222 and potassium carbonate (No. 6 shown) Figure 1The first reaction solution was obtained by passing through a QMA column and entering a reaction bottle, dried and water removed, then TTRC01-OTs-BOC4 solution was added Figure 1 The reaction was carried out at 90°C for 10 min. After the reaction was completed, the mixture was cooled to room temperature, 0.5 mL of 15% trifluoroacetic acid solution was added Figure 1 The reaction was carried out at 90°C for 5 min. After the reaction was completed, the mixture was cooled to room temperature, 5 mL of water was added for dilution, and the diluted solution was transferred to an HPLC unit for purification. The product solution was collected in a transfer bottle Figure 1 The reaction was carried out at 90°C for 10 min. After the reaction was completed, the mixture was cooled to room temperature, 0.5 mL of 15% trifluoroacetic acid solution was added Figure 1 The reaction was carried out at 90°C for 5 min. After the reaction was completed, the mixture was cooled to room temperature, 5 mL of water was added for dilution, and the diluted solution was transferred to an HPLC unit for purification. The product solution was collected in a transfer bottle Figure 1 The reaction was carried out at 90°C for 10 min. After the reaction was completed, the mixture was cooled to room temperature, 0.5 mL of 15% trifluoroacetic acid solution was added 18 F-TTRC01 injection. According to the above scheme, the starting 18 The amount of F was 200-1000 mCi, and the preparation was carried out 6 times 18 F-TTRC01 injection. According to the above scheme, the starting Figure 4 A portion of the product was analyzed by analytical HPLC, and the radiochemical yield was >99% (see Figure 2 ), and the peak time in the analytical HPLC was consistent with that of the control sample, as shown in Figure 3 .

[0065] Table 2. 18 F-TTRC01 radiochemical conversion rate under different starting doses of 18 F-TTRC01 radiochemical conversion rate under different starting doses of

[0066] Starting activity (mCi) 943 760 488 248 953 817 HPLC purified activity (mCi) 422 354 205 100 375 375 Radiochemical conversion (%) 44.8 46.6 42.0 40.3 39.3 45.9

[0067] Two, 18 Application of F-TTRC01 in the diagnosis of neuroendocrine tumors

[0068] F-TTRC01 injection meeting the clinical requirements was obtained by the preparation scheme, which was used for the diagnosis and prognosis evaluation of patients with neuroendocrine tumors. 18 F-TTRC01 injection in neuroendocrine tumors, but the present application is not limited thereto. 18 F-TTRC01 injection in neuroendocrine tumors, but the present application is not limited thereto.

[0069] This case involved a 45-year-old female patient weighing 60 kg. A CT scan revealed a retroperitoneal mass, suspected to be a neuroendocrine tumor. The patient was subsequently treated... 18 F-TTRC01 and 18 An F-FDG PET-CT scan was performed to further confirm the cause of the illness. The patient received an injection via the antecubital vein. 18 F-TTRC01 5.65mCi was injected 10 minutes after the injection and then PET / CT was performed in list mode. The scanning range was from the top of the skull to the mid-femur, and a total of 6 beds were scanned. 18 The distribution of F-TTRC01 in the patient's body is as follows: Figure 5 As shown, the drug is primarily cleared through the urinary system, with a rapid clearance rate, short residence time in the kidneys, and rapid excretion into the bladder. Whole-body background uptake is low; it can be found in normal organs such as the heart, liver, gallbladder, pancreas, stomach wall, parts of the intestines, kidneys, bladder, parotid gland, submandibular gland, and thyroid gland. 18 Physiological uptake of F-TTRC01. Major tissues and organs such as TACs... Figure 6 As shown. 18 The radioactive uptake of F-TTRC01 in normal tissues and organs gradually decreases or remains at a low level over time after injection, but it remains in tumors for a long period, maintaining a high level of radioactive uptake. No adverse symptoms or signs related to this radiopharmaceutical were reported by the patient after injection. The patient was subsequently... 18 F-FDG PET-CT examination, performing a "head-to-head" comparison, with the patient receiving an injection via the antecubital vein. 18 F-FDG 10.15mCi was injected 10 minutes later and then PET / CT was performed in list mode, with the scanning range from the top of the skull to the mid-femur, and a total of 6 beds were scanned.

[0070] 18 F-FDG and 18 The comparison of F-TTRC01 uptake and distribution in patients is as follows: Figure 5 As shown, a cystic-solid mass with increased radioactive uptake is seen next to the right aorta (at the level of the right renal hilum). The mass has relatively smooth margins and measures approximately 4.9*5.5cm. 18 F-TTRC01 (SUVmax: 11.7), 18 F-FDG (SUVmax: 4.2). Baseline (gluteal muscles): 18 F-FDG (SUVmax: 0.94); 18 F-TTRC01 (SUVmax: 1.28), Target-to-Body Ratio (TBR): 18 F-FDG is 4.47. 18F-TTRC01 reached 9.14. 18 F-FDG 18 F-TTRC01 has a lower injection dose (5.65mCi vs 10.15mCi) in the same patient, and due to 18 F-TTRC01 has a higher target-to-background ratio (9.14 vs 4.47), resulting in higher image quality and lower radiation damage to critical organs such as the brain and heart. 18 F-TTRC01 is similar to 18 F-FDG in terms of lesion detection rate, but the lesion SUVmax (11.7 vs 4.2) and TBR value are significantly higher than 18 F-FDG, which helps to detect small lesions and metastatic lesions, and is superior to 18 F-FDG in terms of lesion detection rate in a larger sample size.

[0071] Industrial applicability

[0072] From the above results, compared with the existing preparation method, the preparation method of the present application has a simple route, less side reaction, can be prepared by automatic synthesis module, allows high dose starting radionuclide activity, simple process, short reaction time, less impurities, easy separation and purification, small radiation dose, small human error, and high radiochemical yield, high specific activity, etc., the dose of 18 F-TTRC01 obtained by single preparation is high, which can be used for clinical use by many people, and is convenient for clinical promotion. In addition, compared with the 18 F-TTRC01 prepared by the method of the present application has obvious advantages in the diagnosis of neuroendocrine tumors, and has excellent clinical application prospect. 18 F-FDG commonly used in the present clinical.

Claims

1. A 1-(3-bromo-4-(2-fluoro) 18 The preparation method of F]ethoxy)ethoxy)benzylguanidine, characterized in that, The preparation process is carried out using a "one-pot" method, and the preparation route is as follows: ； It includes the following steps: 1) Prepared by accelerator 18 F ion solution, in which 18 The initial activity of F is 100~1000 mCi; 2) Pass the product obtained in 1) through an anion exchange column. 18 F ion capture by solution; 3) Pass the eluent of the tetrabutylammonium salt phase transfer catalyst through the anion exchange column to... 18 F ions are eluted into the reaction flask; the tetrabutylammonium salt phase transfer catalyst is one or more of tetrabutylammonium bicarbonate, tetrabutylammonium carbonate, tetrabutylammonium fluoride, and tetrabutylammonium bromide; the concentration of the tetrabutylammonium salt phase transfer catalyst solution is 0.02~0.2 M; 4) By setting different heating temperatures, inert gas flow rates, pressures, and times in the program, the reaction flask in step 3) is affected. 18 F ions are dehydrated and dried, then an anhydrous organic solvent is added for dehydration and drying again, and this process is repeated 2 to 3 times. The dehydration and drying conditions are as follows: heating temperature 90-120℃, air flow rate 200-1000mbar, negative pressure -300--1000mbar, and time 30-600s; 5) Cool the reaction flask from step 4) to room temperature, add the labeled precursor TTRC01-OTs-BOC4, and mix it with... 18 The F ion undergoes a nucleophilic substitution reaction to give a labeled intermediate. 18 F-TTRC01-BOC4; the reaction solvent is an aprotic organic solvent, the reaction temperature is 80~120℃, and the reaction is carried out under closed conditions for 5~50 min. 6) Cool the reaction flask from step 5) to room temperature, add a 10%–100% trifluoroacetic acid (TFA) solution, and react under sealed conditions at 25–120°C for 5–30 minutes to obtain the desired product. 18 F-TTRC01 crude product; 7) Cool the reaction flask from step 6) to room temperature, add water to dilute and mix, and purify the crude product using semi-preparative HPLC; 8) Collecting items containing 18 The mobile phase of F-TTRC01 was enriched by solid-phase extraction (SPE) using a solid-phase extraction (SPE) column. The SPE column was then rinsed with water and eluted with either phosphoric acid ethanol solution or hydrochloric acid ethanol solution. The eluent was collected in a product vial containing physiological saline and ascorbic acid to prepare the injectable product. 18 F-TTRC01; The preparation method is carried out in a synthesis room equipped with radiation shielding conditions using an automated radiopharmaceutical synthesizer; The synthesizer is a synthesizer whose synthesis program can be edited according to the radiopharmaceutical preparation scheme; The synthesizer includes a radionuclide transfer unit, a positive and negative pressure device, an inert gas inlet device, a heating unit, a sample addition unit for each component, and a purification unit.

2. The preparation method according to claim 1, characterized in that, The anion exchange column in step 2) is a SEP-PAK Light QMA column, which is pre-activated using one or more solutions of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, and physiological saline.

3. The preparation method according to claim 1, characterized in that, The aprotic organic solvent in step 5) is one or more of anhydrous acetonitrile, anhydrous dimethyl sulfoxide, and anhydrous N,N-dimethylformamide.

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