Preparation method and application of 1-(3-bromo-4-(2-fluoro [18F] ethyoxyl) ethyoxyl) benzyl guanidine

Abstract

The invention provides a preparation method of 1-(3-bromo-4-(2-fluoro [18F] ethyoxyl) ethyoxyl) benzyl guanidine (called 18F-TTRC01) and application of the 1-(3-bromo-4-(2-fluoro [18F] ethyoxyl) ethyoxyl) benzyl guanidine in the field of neuroendocrine tumor diagnosis. The compound is synthesized through the following route. According to the invention, a brand new initial raw material and a preparation route are adopted, a large dose of 18F ions are used for labeling, and an automatic synthesis mode is adopted to successfully prepare the 18F-TTRC01, so that the reaction time is greatly shortened, and the radiation dose to operators is reduced. The obtained 18F-TTRC01 injection can be used for diagnosis and curative effect evaluation of neuroendocrine tumors, and has an outstanding clinical effect. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology and particularly relates to a 1-(3-bromo-4-(2-fluoro- 18 F] Preparation method of ethoxy)ethoxy)benzylguanidine and its application in the field of neuroendocrine tumor diagnosis. Background Art

[0002] Neuroendocrine neoplasms (NENs) originate from peptidergic neurons and neuroendocrine cells. They are a series of heterogeneous tumors ranging from indolent, slow-growing low-grade malignancies to highly malignant tumors with extensive metastatic capacity, and can occur throughout the body. Domestic and foreign research data indicate that the incidence of NENs is increasing. The results of an epidemiological survey in the United States show that the incidence of NENs is rising more significantly than other types of tumors. Nuclear medicine imaging techniques include single-photon emission computed tomography (SPECT) and positron emission tomography (PET). Compared with imaging techniques such as CT, MRI, and ultrasound, their main advantage is that they can perform non-invasive, real-time, visual, and specific diagnosis and treatment of diseases at the cellular and molecular levels, and can provide effective clinical data for early diagnosis, treatment, and efficacy evaluation of tumors. They have become an important method for diagnosing neuroendocrine tumors. Currently, the nuclear medicine molecular probes reported for neuroendocrine tumor imaging can be divided into somatostatin receptor-targeted and other ( 18 F-FDG, 123 / 131 I-meta-iodobenzylguanidine, 18 F-DOPA).

[0003] Somatostatin receptor 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 drugs or 18 F-FDG, 123 / 131 I-meta-iodobenzylguanidine, 18 F-DOPA, 11 Drugs such as C-5-hydroxytryptamine have obvious disadvantages, which prevent them from being widely used in clinical practice. 111 As a diagnostic drug, In-DTPAOC has a half-life (67h) that is too long, and the radiation dose to the human body is too high. The energy of its two gamma rays is high and their abundance is similar, resulting in low spatial resolution of the image. 99mDue to the influence of imaging technology, Tc-Octreoscan has very poor diagnostic sensitivity for lesions in lymph or liver with a diameter of less than 1 cm. 68 Ga-labeled somatostatin receptor drugs 68 Ga nuclides are difficult to source and can only be used from generators. Also, due to reasons such as its short half-life (68 minutes), it cannot be delivered, limiting its large-scale clinical use. 18 F-FDG is currently the most widely used probe in tumor PET imaging. However, for neuroendocrine tumors, it is not targeted enough and has low diagnostic value for most G1 and G2 NET tumors with low proliferation activity and good differentiation, and has large background interference. 123 / 131 I-metaiodobenzylguanidine can be specifically concentrated in the adrenal medulla and adrenergic receptor-rich tumor cells, but 123 / 131 At present, radionuclide I cannot be supplied on a large scale commercially, and as a diagnostic drug, its half-life is too long and its abdominal background is too high, making it difficult to popularize in clinical practice. 18 F-DOPA is an imaging agent that targets catecholamine metabolism. Its radioactive preparation is complex, time-consuming, low-yield, and has a narrow range of applications. Summary of the invention

[0005] 18 F-TTRC01, chemical name 1-(3-bromo-4-(2-fluoro[ 18 F] Ethoxy)ethoxy)benzylguanidine, the structural formula is as follows:

[0006]

[0007] Among them, F is 18 F, molecular formula: C 12 H 17 Br 18 FN 3 O 2 , molecular weight: 333.19.

[0008] 18 F-TTRC01 contains radioactive nuclides 18 The drug F is prepared in a single step according to the current preparation route and technical means. 18 F-TTRC01 injection can only be used for basic research such as animal experiments and cannot be used in clinical practice due to the following disadvantages:

[0009] 1. The original preparation route contained active [H] atoms in the reaction precursor structure and the reaction route was long, which led to 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 the pH value was adjusted. As a result, the total reaction time was too long, about 2.5 hours, and the labeling personnel were exposed to the radiation environment for a long time.

[0012] 3. The original preparation method was complicated and cumbersome, with low yield (10-14% after attenuation correction), low specific activity, and a single 18 The F-TTRC01 injection has low activity and poor stability between batches. The errors caused by human operation are large. The injection prepared by the current scheme does not meet the requirements for clinical use.

[0013] 4. The complicated and tedious steps of the original preparation scheme are not conducive to the development of automated synthesis processes, and are costly and difficult to implement.

[0014] 5. To meet 18 F-TTRC01 injection meets the requirements for clinical use and needs to be 18 The preparation scheme of F-TTRC01 injection was redesigned, new labeling precursors were modified, the labeling process was simplified, the preparation time was shortened, the possibility of impurities was theoretically reduced, the yield was increased, and the development of automated synthesis process was facilitated, thereby improving 18 The single-dose production and batch-to-batch stability of F-TTRC01 injection can meet the large-scale clinical needs in the future.

[0015] In view of the shortcomings of the above-mentioned developer and the various drawbacks of the original preparation scheme, the inventors of the present application conducted in-depth research. As a result, it was found that by designing a new labeling precursor and preparation route, a method that is easy to prepare in large quantities multiple times was developed. 18 The automated synthesis process of F-TTRC01 injection meets the requirements of large-scale clinical use.

[0016] The present invention is made in view of the defects of the prior art, and its purpose is to provide a 1-(3-bromo-4-(2-fluoro- 18 F] ethoxy) ethoxy) benzylguanidine preparation method, thereby improving 18 F initial reaction dose, preparation yield and specific activity; reduce reaction time, impurity content, radiation dose and use 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 application of the radiopharmaceutical in the field of neuroendocrine tumor diagnosis.

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

[0020] 1. A 1-(3-bromo-4-(2-fluoro[ 18 F] The preparation method of ethoxy)ethoxy)benzylguanidine is characterized in that it is carried out in a "one-pot method" and the preparation route is as follows:

[0021]

[0022] In the present invention, a completely new starting material (labeled precursor) and preparation route are used, and a large dose of 18 The F ion was labeled and the automated synthesis method was used to successfully prepare 18 F-TTRC01 greatly shortens the reaction time, reduces the radiation dose to operators, reduces chemical impurities, improves the radiochemical yield and specific activity, increases batch production and batch-to-batch production stability, meets clinical use requirements, and has good in vitro stability within 6 hours, which is convenient for transportation and saves costs. 18 F-TTRC01 injection can be used for the diagnosis and efficacy evaluation of neuroendocrine tumors. Clinical studies have shown that it is comparable to commonly used drugs. 18 Compared with F-FDG, it has obvious advantages in radiation damage to key organs, target-to-target ratio, absolute uptake value of lesions and diagnosis of tiny and metastatic lesions, and has outstanding clinical effects.

[0023] According to a specific embodiment, the specific conditions are as follows:

[0024]

[0025] Add K to the reaction flask 2 CO 3 , 18 F - and labeled precursor TTRC01-OTs-BOC 4 and 0.5 mL of anhydrous acetonitrile, reacted at 90 ° C for 10 min under sealed conditions to obtain 18 F-TTRC01-BOC 4 After the reaction was completed, trifluoroacetic acid solution was added and the reaction was continued at 90°C for 10 min under closed conditions. After the reaction was completed, the mixture was cooled to room temperature, filtered with a 0.22 μm filter membrane, and then separated with an HPLC semi-preparative column. The HPLC conditions were as follows: the mobile phase was a mixture of water (1% TFA) and acetonitrile, with a volume ratio of 3:1; isocratic; the flow rate was 5 mL / min. Physiological saline was added to the crude product, followed by NaHCO 3 , until no more bubbles appear, adjust the pH to neutral, and obtain 18 F-FP2BG, radiochemical purity >99%.

[0026] A 1-(3-bromo-4-(2-fluoro[ 18 The automated synthesis process of [F] ethoxy) ethoxy) benzylguanidine is as follows:

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

[0028] 2) The anion column captures the obtained 18 F ions;

[0029] 3) 1-2 mL of tetrabutylammonium salt phase transfer catalyst eluent or organic-aqueous mixed eluent composed of cryptand and strong base and weak acid salts such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, etc. is passed through an anion column and eluted 18 The F ions obtain the first reaction solution and enter the reaction bottle;

[0030] 4) The heating temperature, time, inert gas flow rate, addition of anhydrous organic solvent (repeat 2-3 times) and vacuum degree of step 3) are controlled by the program of the automated synthesizer. 18 F ion reaction solution is used for water removal and activation;

[0031] 5) Label the precursor TTRC01-OTs-BOC 4 0.5-3 mL of anhydrous aprotic organic solvent solution is added to the reaction bottle, wherein the reaction precursor is 5-15 mg, the reaction temperature is 80-120°C, and the reaction is carried out under closed conditions for 5-50 minutes;

[0032] 6) Cool the reaction flask after step 5) to room temperature, add 0.2-1.5 mL of 10%-100% trifluoroacetic acid solution, and react at 25-120° C. in a sealed condition for 5-30 min;

[0033] 7) After step 6), the reaction flask was cooled to room temperature, 3-6 mL of water was added to dilute and mix, and the mixture was purified by semi-preparative HPLC (conditions: chromatographic column: C18 reverse preparative column; mobile phase: acetonitrile, water (0.1-1% TFA), volume ratio of 1 / 4-4 / 1; isocratic elution, flow rate 2-10 mL / min);

[0034] 8) Collect 18 The mobile phase of F-TTRC01 is enriched by a solid phase extraction column; the solid phase extraction column is eluted with 5-20 mL of water, and then the solid phase extraction column is eluted with 0.5-3 mL of phosphoric acid ethanol solution or hydrochloric acid ethanol solution, and the eluate is collected in 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 invention are at least:

[0036] Compared with the existing preparation scheme, the 1-(3-bromo-4-(2-fluoro[ 18 The preparation method of F] ethoxy) ethoxy) benzylguanidine has the following excellent effects: 18 In the preparation method of F-TTRC01, the chemical reagents used in the synthesis of the labeling precursor and the reference substance involved are all commercially available commodities with a wide range of sources and are easily available; 18 The preparation technology of F-TTRC01 is simple and has few side reactions; 18 F-TTRC01 is prepared by an automated synthesis module, which allows high-dose starting radionuclide activity, simple process, short reaction time, few impurities, easy separation and purification, small radiation dose, small human error, high radiochemical yield, high specific activity, etc., and can be obtained by single preparation. 18 F-TTRC01 has a high dosage and can be used by multiple people in clinical practice, facilitating clinical promotion.

[0037] In addition, the present invention 18 F-TTRC01 has good initial uptake and retention in neuroendocrine tumors and a good target to non-target ratio. 18 Compared with F-FDG, both primary lesions and metastatic lesions can be visualized, with high accuracy and sensitivity, excellent biological properties, and convenient for clinical qualitative and quantitative analysis. Therefore, it has great clinical application value in the diagnosis of neuroendocrine tumors. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] [ Figure 1 ]express 18 Schematic diagram of the automated synthesis process of F-TTRC01.

[0039] [ Figure 2 ]express 18 Radio-HPLC spectrum of F-TTRC01 (RCP>98%).

[0040] [ Figure 3 ]express 18 F-TTRC01 was placed at room temperature for 4 hours. 19 HPLC spectrum of co-injection of F-TTRC01.

[0041] [ Figure 4 ]express 18 HPLC spectrum of separation and purification of F-TTRC01.

[0042] [ Figure 5 ]express 18 F-TTRC01 and 18Head-to-head comparative PET-CT images of F-FDG in patients with neuroendocrine tumors.

[0043] [ Figure 6 ]express 18 Uptake and distribution of F-TTRC01 in major organs of patients. DETAILED DESCRIPTION

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

[0045] one, 18 Preparation of F-TTRC01

[0046] Materials: Prepare TTRC01-OTs-BOC in the following synthetic route by yourself 4 . Potassium carbonate, trifluoroacetic acid, anhydrous acetonitrile, K 222 , anhydrous ethanol, and phosphoric acid were purchased from Sigma Aldrich. 18 F - Prepared by GE's cyclotron.

[0047] HPLC Instruments and Methods:

[0048] (1) Instruments:

[0049] Waters ARC quaternary high pressure liquid chromatography system, 2998 full wavelength UV detector, Raytest GabiNova radioactivity detector, chromatographic column: Waters XBridge OBD C18 5μm 10*250mm, automated synthesizer Trasis All in one-36, the equipment includes pneumatic unit, syringe 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 to 50 mCi 18 F ions were used as the starting dose. To meet clinical use, this example used a new preparation scheme in an automated synthesizer. 18 The initial dose of F ions is 100-1000 mCi, which is much larger than the existing preparation method; the remaining auxiliary materials are used in as small a amount as possible while meeting the labeling yield.

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

[0054] 3) Preferred 18 The F ion elution solution is cryptand K 222 Mixed solution with potassium carbonate; cryptand K 222 The dosage is 10 mg, the dosage 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 dehydration and drying process of F ions is particularly critical for the nucleophilic substitution reaction. If the drying is incomplete, the efficiency of the nucleophilic substitution reaction will be seriously affected. In addition, compared with the existing preparation scheme, the dehydration and drying scheme adopted in the present invention does not require multiple additions of anhydrous acetonitrile for azeotropic dehydration. The preferred dehydration and drying scheme is shown in the following table:

[0056] Table 1 Dehydration and drying conditions

[0057] Temperature(℃) 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) Preferred marker precursor TTRC01-OTs-BOC 4 The dosage was 10 mg, the aprotic solvent was 1 mL of anhydrous acetonitrile, the marking temperature was 90°C, and the reaction was carried out in a closed state for 10 min.

[0059] 6) 0.5 mL of 15% trifluoroacetic acid solution is preferably used as the hydrolysis reaction medium, the reaction temperature is 90° C., and the reaction is carried out in a closed condition for 5 minutes.

[0060] 7) The HPLC system of the automated synthesizer Trasis Allinone-36 was preferably used to separate the hydrolyzate. HPLC conditions were as follows: chromatographic column: Xbridge BEH C18 OBD Prep column, 130A, 5 μm, 10*250 mm; mobile phase: acetonitrile / water (0.1% TFA) = 3:1; flow rate: 5 mL / min.

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

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

[0063] 10) A 1-(3-bromo-4-(2-fluoro[ 18 The process flow chart of the automated synthesis method of [F] ethoxy)ethoxy)benzylguanidine is as follows Figure 1 shown.

[0064] The specific conditions can be: produced by cyclotron 18 F ions, through the QMA anion column ( Figure 1 then capture with K 222 and potassium carbonate mixed eluent ( Figure 1 2) passed through the QMA column and then entered the reaction bottle to obtain the first reaction solution, which was dried to remove water, and then TTRC01-OTs-BOC was added 4 Solution( Figure 1 8), 90°C, sealed and reacted for 10 min. After the reaction was completed, cooled to room temperature, 0.5 mL of 15% trifluoroacetic acid solution ( Figure 1 9), sealed at 90°C for 5 min, cooled to room temperature after the reaction, added 5 mL of water for dilution, and the mixture was transferred to HPLC unit for purification, and the product solution was collected in a transfer bottle ( Figure 1 16), add 10 mL of water to dilute, and pass the dilution through a Waters SEP-PAK CM column ( Figure 1 13), wash the CM column with 10 mL of water, and then wash with 1 mL of 5% phosphoric acid ethanol solution ( Figure 1 The CM column is washed with the eluent through a sterile filter membrane to the product bottle to obtain 18 F-TTRC01 injection. According to this scheme, start 18 The measurement range of F was 200-1000mCi, and a total of 6 times 18 The F-TTRC01 injection preparation experiment was conducted. The results of six experiments were statistically analyzed. The uncorrected radiochemical yield was 20-30%, and the radiochemical conversion rate was 43.15% ± 3.05. For details, see Table 1. Figure 4 A portion of the product was taken and analyzed by analytical HPLC. The radiochemical yield was >99% (see Figure 2 ), and the peak time of the sample was consistent with that of the reference substance in analytical HPLC. Figure 3 .

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

[0066] Initial activity (mCi) 943 760 488 248 953 817 HPLC purification activity (mCi) 422 354 205 100 375 375 Radiochemical conversion rate (%) 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] Through this preparation scheme, we can obtain 18F-TTRC01 injection is used for the diagnosis and prognosis assessment of patients with neuroendocrine tumors. 18 The application of F-TTRC01 injection in neuroendocrine tumors, but the present invention is not limited thereto.

[0069] This example is a 45-year-old female patient weighing 60 kg. CT scan showed a retroperitoneal mass, suspected of a neuroendocrine tumor. 18 F-TTRC01 and 18 F-FDG PET-CT examination further confirmed the cause. 18 List mode PET / CT imaging was performed 10 minutes after the injection of F-TTRC01 5.65mCi. The scanning range was from the top of the skull to the middle of the femur, and a total of 6 beds were scanned. 18 The distribution of F-TTRC01 in patients Figure 5 As shown, the drug is mainly cleared through the urinary system, with a fast clearance rate, short retention time in the kidneys and rapid excretion into the bladder. The drug has low whole-body background uptake; in normal organs, it can be seen in the heart, liver, gallbladder, pancreas, stomach wall and part of the intestine, kidney, bladder, parotid gland, submandibular gland, and thyroid gland. 18 Physiological uptake of F-TTRC01. TACs in major tissues and organs such as Figure 6 shown. 18 The radioactive uptake value of F-TTRC01 in normal tissues and organs gradually decreases or remains at a low level as time passes after injection, but it remains in tumors for a long time, and tumors always maintain a high level of radioactive uptake. After drug injection, the patient did not report any adverse symptoms and signs related to this radioactive drug. 18 F-FDG PET-CT examination, for head-to-head comparison, patients were injected via cubital vein 18 List mode PET / CT imaging was performed 10 minutes after the injection of F-FDG 10.15 mCi. The scanning range was from the top of the skull to the middle of the femur, and a total of 6 beds were scanned.

[0070] 18 F-FDG and 18 Comparison of the uptake and distribution of F-TTRC01 in patients Figure 5 As shown in the figure, a cystic solid mass with increased radioactive uptake was seen on the right side of the abdominal aorta (right renal hilum level), with smooth edges and a size of about 4.9*5.5 cm. 18 F-TTRC01 (SUV max: 11.7), 18 F-FDG (SUVmax: 4.2). Background (gluteal muscle): 18F-FDG (SUVmax: 0.94); 18 F-TTRC01 (SUVmax: 1.28), target-to-body ratio (TBR): 18 F-FDG is 4.47, 18 F-TTRC01 reached 9.14. 18 F-FDG compared 18 The injection dose of F-TTRC01 was lower in the same patient (5.65 mCi vs 10.15 mCi), due to 18 F-TTRC01 has a higher target-to-species ratio (9.14 vs 4.47), resulting in higher image quality and less radiation damage to key organs such as the brain and heart. 18 F-TTRC01 is comparable to 18 F-FDG was similar, but the SUVmax (11.7 vs 4.2) and TBR values ​​of the lesions were significantly higher 18 F-FDG is helpful for detecting small lesions and metastatic lesions, and is superior to F-FDG in terms of lesion detection rate with a larger sample size. 18 F-FDG.

[0071] Industrial Applicability

[0072] It can be seen from the above results that compared with the existing preparation method, the preparation method of the present invention has a simple route, few side reactions, can be prepared using an automated synthesis module, allows high-dose starting radionuclide activity, simple process, short reaction time, few impurities, easy separation and purification, small radiation dose, small human error, and high radiochemical yield, high specific activity, etc., and a single preparation can obtain 18 F-TTRC01 has a high dosage and can be used by many people in clinical practice, which is convenient for clinical promotion. 18 F-TTRC01 and currently commonly used 18 Compared with F-FDG, it has obvious advantages in the diagnosis of neuroendocrine tumors and has extremely excellent clinical application prospects.

Claims

1. A 1-(3-bromo-4-(2-fluoro[ 18 F] ethoxy)ethoxy)benzylguanidine preparation method, characterized in that, The "one-pot method" is adopted, and the preparation route is as follows:

2. The preparation method according to claim 1, comprising the steps of: (1) Provide 18 F ion solution, wherein 18 The initial activity of F is 20 to 1000 mCi; (2) 18 The F ion solution and TTRC01-OTs-BOC4 were mixed and a nucleophilic substitution reaction occurred in the presence of a non-protonic organic solvent to obtain a labeled intermediate. 18 F-TTRC01-BOC4; the reaction temperature is 80-120°C, and the reaction is carried out in a closed condition for 5-50 minutes; (3) adding 10% to 100% trifluoroacetic acid (TFA) solution to the reaction product of step (2), and reacting at 25 to 120° C. in a sealed condition for 5 to 30 minutes to obtain 18 F-TTRC01.

3. The preparation method according to claim 1, comprising the steps of: 1) Prepared by accelerator 18 F ion solution, wherein 18 The initial activity of F is 20 to 1000 mCi; 2) Pass the anion column to obtain 18 F ion solution capture; 3) Pass a tetrabutylammonium salt phase transfer catalyst eluent or an organic-aqueous phase mixed eluent through the anion column to 18 The F ions are eluted into a reaction bottle, and the organic-aqueous phase mixed eluent comprises a cryptand a strong base weak acid salt, wherein the strong base weak acid salt is at least one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and cesium carbonate; 4) The heating temperature, inert gas flow rate and pressure and time in step 3) are set by the program to 18 The F ions are dried and dehydrated, and then an anhydrous organic solvent is added to dehydrate and dry again, and this is repeated 2 to 3 times; 5) Cool the reaction flask after step 4) to room temperature, add the labeled precursor TTRC01-OTs-BOC4, and make it 18 F ions undergo nucleophilic substitution reaction to obtain labeled intermediates 18 F-TTRC01-BOC4; the reaction solvent is an aprotic organic solvent, the reaction temperature is 80-120°C, and the reaction is carried out under closed conditions for 5-50 minutes; 6) Cool the reaction flask after step 5) to room temperature, add 10% to 100% trifluoroacetic acid (TFA) solution, and react for 5 to 30 minutes under sealed conditions at 25 to 120°C to obtain 18 F-TTRC01 crude product; 7) Cooling the reaction flask after completing step 6) to room temperature, adding water to dilute and mix, and purifying the crude product by semi-preparative HPLC; 8) Collect 18 The mobile phase of F-TTRC01 is enriched by a solid phase extraction column, and then the solid phase extraction column is eluted with water, and the solid phase extraction column is eluted with a phosphoric acid ethanol solution or a hydrochloric acid ethanol solution, and the eluate is collected into a product bottle containing physiological saline and ascorbic acid to prepare an injection. 18 F-TTRC01.

4. The preparation method according to claim 1, characterized in that: The preparation method is carried out in a synthesis room with radioactive ray shielding conditions using a radioactive drug automated synthesizer; The synthesizer is a synthesizer that can edit the synthesis program according to the radiopharmaceutical preparation plan; The synthesizer comprises a radionuclide transfer unit, a positive and negative pressure condition device, an inert gas access device, a heating unit, a component sample addition unit and a purification unit.

5. The preparation method according to claim 3, characterized in that: The anion column in step 2) is a SEP-PAK Light QMA column, which is activated in advance using one or more solutions selected from potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, and physiological saline solution.

6. The preparation method according to any one of claims 3 to 5, characterized in that: The tetrabutylammonium salt phase transfer catalyst in step 3) is one or more of tetrabutylammonium bicarbonate, tetrabutylammonium carbonate, tetrabutylammonium fluoride, and tetrabutylammonium bromide; the cryptand is K 222； The concentration of the tetrabutylammonium salt phase transfer catalyst solution is 0.02-0.2M, and the amount of the cryptand is 3-20mg. The dosage of the strong base and weak acid salt is 0.5-10 mg; the volume of the mixed solution of the cryptand and the strong base and weak acid salt is 0.5-2 mL.

7. The preparation method according to claim 3, characterized in that: The dehydration and drying conditions in step 4) are: heating temperature 90-120° C., air flow rate 200-1000 mbar, negative pressure -300--1000 mbar, and time 30-600 s.

8. The preparation method according to claim 3, 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.

9. A 1-(3-bromo-4-(2-fluoro[ 18 F] ethoxy)ethoxy)benzylguanidine, characterized in that Obtained according to the preparation method according to any one of claims 1 to 8.

10. 1-(3-bromo-4-(2-fluoro-[ 18 F] Application of ethoxy)ethoxy)benzylguanidine in the diagnosis of neuroendocrine tumors.

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