A fapi derivative containing a 4-cyanothiazolidine modification and uses thereof

Abstract

The application discloses a FAPI derivative containing 4-cyano thiazolidine modification and application thereof, relates to the field of drug compounds for diagnosing tumors, and provides a FAPI derivative containing 4-cyano thiazolidine modification, a chemical structural formula of which is shown as formula I. The FAPI derivative has good stability, is simple to prepare, has high radiochemical purity and good biological performance, and can be further used for clinical PET / CT tumor imaging, effectively solving the problems of low tumor uptake rate, short retention time and inability to further delay imaging of F-labeled FAPI probes. 18 The FAPI derivative containing 4-cyano thiazolidine modification can solve the problems of low tumor uptake rate, short retention time and inability to further delay imaging of F-labeled FAPI probes, and make up for the defects of the prior art.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical compounds for diagnosing tumors, in particular to a FAPI derivative containing 4-cyano thiazolidine modification and its application. BACKGROUND

[0002] Studies have shown that the occurrence, development and metastasis of tumors are closely related to the surrounding microenvironment, and among them, cancer-associated fibroblasts (CAFs) have become a hot spot for tumor detection and treatment in recent years due to the high expression of fibroblast activation protein (FAP). Based on this, FAP small molecule inhibitors containing the parent structure 4-quinoline acyl-glycyl-2-cyanopyrrolidine (FAPI) have been developed.

[0003] At present, the most commonly used 18 F - labeled FAPI imaging agents are 18 F-AIF-NOTA-FAPI-04 and 18 F-AIF-NOTA-FAPI-42, FAPI-42 is a structural modification based on the structure of FAPI-04 by adding a piperazine ring, however, the above-mentioned 18 F - labeled FAPI probes for clinical imaging have the problems of low tumor uptake rate, short retention time, and inability to further delay imaging, which cannot significantly improve the tumor diagnosis effect. SUMMARY

[0004] To solve the above problems, the present application provides a FAPI derivative containing 4-cyano thiazolidine modification and its application.

[0005] In a first aspect, the present application provides a FAPI derivative containing 4-cyano thiazolidine modification, the chemical structural formula of the FAPI derivative containing 4-cyano thiazolidine modification is shown as formula I;

[0006] The formula I:

[0007] .

[0008] Further, the preparation method of the FAPI derivative containing 4-cyano thiazolidine modification comprises the following steps: ;

[0009] Compound 1 is added to a DMF solution containing HBTU and DIPEA, then compound 2 is added to the reaction system, and the reaction is stirred at room temperature under nitrogen protection for 3h; after the reaction is completed, purification post-treatment is carried out, and light yellow solid compound 3 is obtained;

[0010] The compound 3 is dissolved in dichloromethane under nitrogen protection, and the reaction system is cooled to 0°C in an ice-salt bath. Trifluoroacetic acid is added dropwise, and after the dropwise addition is completed, the ice-salt bath is removed, and the reaction is stirred at room temperature under nitrogen protection for 12 h. After the reaction is completed, purification post-treatment is performed to obtain the compound 4 as a light yellow solid.

[0011] The compound 4 is dissolved in a DMF solution containing HBTU and DIPEA, and then the compound 5 is added to the reaction system. The reaction is stirred at room temperature under nitrogen protection for 2 h. After the reaction is completed, purification post-treatment is performed to obtain the compound 6 as a light yellow oil.

[0012] The compound 6 is dissolved in dichloromethane under nitrogen protection, and the reaction system is cooled to 0°C in an ice-salt bath. Trifluoroacetic acid is added dropwise, and after the dropwise addition is completed, the ice-salt bath is removed, and the reaction is stirred at room temperature under nitrogen protection for 12 h. After the reaction is completed, purification post-treatment is performed to obtain the FAPI derivative containing a 4-cyano thiazolidine modification, i.e., the compound 7.

[0013] In a second aspect, based on the same inventive concept, the present application provides an application of the FAPI derivative containing a 4-cyano thiazolidine modification in the first aspect in the preparation of a tracer precursor compound targeting FAP, the preparation of a diagnostic drug targeting fibroblast activation protein, the preparation of a nuclide imaging drug for tumors with high expression of FAP protein, and the preparation of a FAP-targeted probe.

[0014] In a third aspect, based on the same inventive concept, the present application provides a radioactive preparation, which comprises the FAPI derivative containing a 4-cyano thiazolidine modification in the first aspect labeled with a radionuclide.

[0015] Further, the chemical structural formula of the FAPI derivative containing a 4-cyano thiazolidine modification labeled with a radionuclide is shown in Formula II.

[0016] The Formula II is as follows:

[0017] .

[0018] Further, the preparation method of the FAPI derivative containing a 4-cyano thiazolidine modification labeled with a radionuclide comprises the following steps:

[0019] A precursor solution containing a radionuclide 18 F - and the FAPI derivative containing a 4-cyano thiazolidine modification is subjected to heating and stirring treatment; after the reaction is completed, purification post-treatment is performed to obtain the radioactive preparation.

[0020] Alternatively, a precursor solution containing a radionuclide 18 F- The precursor solution containing the 4-cyanothiazolidine-modified FAPI derivative was subjected to ultrasonic-microwave synergistic treatment; after the reaction, purification was performed to obtain the radioactive preparation.

[0021] Wherein, the microwave power W1 and the ultrasonic power W2 in the ultrasonic-microwave co-processing satisfy: 820W≤W1≤1050W, 550W≤W2≤680W, 1.4≤W1 / W2≤1.9; preferably, W1=1000W, W2=625W, W1 / W2=1.6.

[0022] Fourthly, based on the same inventive concept, the present invention provides the application of the radioactive agent described in the third aspect in the preparation of FAP-targeted probes.

[0023] Furthermore, it can be applied to the preparation of products for detecting diseases or conditions related to fibroblast activation proteins; said conditions include tumors or inflammation; said tumors include breast cancer, ovarian cancer, lung cancer, colorectal cancer, prostate cancer, lung cancer, fibrosarcoma, bone and connective tissue sarcoma, renal cell carcinoma, gastric cancer, pancreatic cancer, or skin melanoma; said inflammation includes osteoarthritis, rheumatoid arthritis, granulation tissue, liver fibrosis, pulmonary fibrosis, or cirrhosis.

[0024] Furthermore, the imaging method includes at least one of single-photon emission computed tomography (SPECT) and positron emission tomography (PET).

[0025] Furthermore, the FAP-targeted probe is prepared as an injectable and administered via intravenous injection.

[0026] The technical solutions provided in the embodiments of the present invention have at least the following advantages compared with the prior art:

[0027] This invention provides a 4-cyanothiazolidine-modified FAPI derivative and its applications. The chemical structure of this FAPI derivative is shown in Formula I. This FAPI derivative exhibits good stability, simple preparation, high radiochemical purity, and good biological properties, and can be further used in clinical PET / CT tumor imaging, effectively solving the problems of existing clinical imaging methods. 18 F-labeled FAPI probes address the shortcomings of existing technologies by overcoming issues such as low tumor uptake, short retention time, and inability to further delay imaging. Attached Figure Description

[0028] The accompanying drawings, which are incorporated in and form part of this specification, illustrate embodiments consistent with the invention and, together with the description, serve to explain the principles of the invention.

[0029] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the following will briefly introduce the drawings needed to be used in the embodiments or prior art description. Obviously, for those of ordinary skill in the art, other drawings can also be obtained based on these drawings without any creative effort.

[0030] Figure 1 Preparation flow chart of NOTA-FAPI-4C provided for Example 1.

[0031] Figure 2 NMR spectrum of NOTA-FAPI-4C provided for Example 1.

[0032] Figure 3 Radiographic spectrum of F-AIF-NOTA-FAPI-4C provided for Example 2. 18 Radiographic spectrum of F-AIF-NOTA-FAPI-4C provided for Example 2.

[0033] Figure 4 TLC spectrum of F-AIF-NOTA-FAPI-4C provided for Example 2. 18 TLC spectrum of F-AIF-NOTA-FAPI-4C provided for Example 2.

[0034] Figure 5 UV spectrum of F-AIF-NOTA-FAPI provided for Example 5. 19 UV spectrum of F-AIF-NOTA-FAPI provided for Example 5.

[0035] Figure 6 Stability test results of F-AIF-NOTA-FAPI-4C provided for Example 2. 18 Stability test results of F-AIF-NOTA-FAPI-4C provided for Example 2.

[0036] Figure 7 Micro-PET / CT imaging spectrum of F-AIF-NOTA-FAPI-4C provided for Example 2. 18 Micro-PET / CT imaging spectrum of F-AIF-NOTA-FAPI-4C provided for Example 2. DETAILED DESCRIPTION

[0037] In order to make the objects, technical solutions and advantages of the embodiments of the present application clearer, the following will combine the drawings in the embodiments of the present application to clearly and completely describe the technical solutions in the embodiments of the present application. Obviously, the described embodiments are a part of the embodiments of the present application, rather than all the embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without any creative effort belong to the protection scope of the present application.

[0038] Unless otherwise specifically indicated, all raw materials, reagents, instruments and equipment used in the present application can be purchased on the market or prepared by existing methods. For example, compound 1 can be self-prepared according to the preparation method disclosed in the prior art 1 (DOI: 10.1155 / 2022 / 6596702), and compound 2 can be self-prepared according to the preparation method disclosed in WO2022130270A1, WO2023247487A1, etc. At the same time, if there is no special limitation or specific description, the steps and parameters involved can be carried out according to the existing technology disclosed FAPI derivative preparation process steps and parameters, or directly using existing equipment according to the instruction manual. The present application file will not be described one by one.

[0039] The present application will be further described in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present application and not to limit the scope of the present application. The experimental methods in the following examples are not specified, which are generally determined according to the national standard. If there is no corresponding national standard, it is carried out according to the general international standard, the conventional condition, or according to the condition suggested by the manufacturer.

[0040] Example 1

[0041] This example provides a FAPI derivative containing 4-cyanothiazolidine modification, denoted as NOTA-FAPI-4C, whose chemical structural formula is shown as formula I;

[0042] The formula I:

[0043] .

[0044] The preparation method of the above-mentioned FAPI derivative containing 4-cyanothiazolidine modification is shown as formula II, which comprises the following steps: Figure 1

[0045] Compound 1 (6.1 g, 14.68 mmol) was added to a solution of HBTU (6.5 g, 17.2 mmol), DIPEA (4.74 g, 36.7 mmol) in DMF (40 mL), and the reaction solution was reacted at room temperature for 15 min. Then compound 2 (6.3 g, 18.4 mmol) was added to the reaction system, and stirred at room temperature under nitrogen protection for 3 h. The reaction solution was added to saturated sodium bicarbonate aqueous solution (300 mL), extracted with ethyl acetate (200 mL × 3), and the organic phase was combined, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 30 / 1-20 / 1) to obtain yellow solid compound 3 (5.01 g, yield 60%). LC-MS m / z (ESI): 569.2 [M+H] + .​

[0046] Compound 3 (1.9 g, 3.3 mmol) was dissolved in dichloromethane (30 mL) under nitrogen protection, and the reaction system was cooled to 0 °C in an ice-salt bath. Trifluoroacetic acid (25 mL) was added dropwise, and after the addition was completed, the ice-salt bath was removed, and the reaction was stirred at room temperature for 12 h under nitrogen protection. The reaction solution was rotary evaporated under reduced pressure, and the residue was washed with diethyl ether. The supernatant was poured out, and the precipitate was dried under reduced pressure with an oil pump to obtain a crude product. The crude product was purified by C18 reverse phase preparative column (C18 19 x 250 mm, flow rate: 12 mL / min, wavelength: 220 nm, H2O (0.1% TFA) / MeCN = 0% ~ 2.5%, 50 min) to obtain compound 4 (1.536 g, yield 80%) as a light yellow solid. LC-MS m / z (ESI): 469.2 [M+H] + .

[0047] Compound 4 (582 mg, 1 mmol) was dissolved in a solution of HBTU (526 mg, 1.4 mmol) and DIPEA (903 mg, 7.0 mmol) in DMF (20 mL), and the reaction was allowed to react at room temperature for 15 min. Then compound 5 (482 mg, 1.2 mmol) was added to the reaction system, and the reaction was stirred at room temperature for 3 h under nitrogen protection. TLC (DCM:MeOH = 5:1, Rf = 0.5) showed that the reaction was complete. The reaction solution was added to saturated aqueous sodium bicarbonate solution (100 mL), and extracted with ethyl acetate (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 6 (1.075 g, yield 100%) as a light yellow oil. LC-MS m / z (ESI): 866.4 [M+H] + .

[0048] Compound 6 (400 mg, 0.46 mmol) was dissolved in dichloromethane (25 mL) under nitrogen protection, and the reaction system was cooled to 0 °C in an ice-salt bath. Trifluoroacetic acid (20 mL) was added dropwise. After the addition was completed, the ice-salt bath was removed, and the reaction was stirred at room temperature for 12 h under nitrogen protection. LCMS showed that the reaction was completed. The reaction solution was rotary evaporated under reduced pressure, and the residue was washed with diethyl ether. The supernatant was poured out, and the precipitate was dried under reduced pressure with an oil pump. The crude product was dissolved in pure water (20 mL) and purified by C18 reverse phase preparative column (C18 19x250 mm, flow rate: 12 mL / min, wavelength: 220 nm, H2O (0.1% TFA) / MeCN = 0% ~20%, 100 min) to obtain a white precursor compound 7, i.e. NOTA-FAPI-4C (153 mg, yield 38%). LC-MS m / z (ESI): 754.2 [M+H] + , and the NMR results are shown in Figure 2 .

[0049] Example 2

[0050] This example provides a 4-cyanothiazolidine modified FAPI derivative labeled with a radionuclide, denoted as 18 F-AIF-NOTA-FAPI-4C, and its chemical structural formula is shown in formula II.

[0051] The formula II is:

[0052] .

[0053] The preparation method of the above 18 F-AIF-NOTA-FAPI-4C includes the following steps:

[0054]

[0055] 18 F - was produced by reaction from a cyclotron and was captured by a Sep-QMA small column (10 mL of pure water activation). 18 F - After that, a mixture of 0.6 mL of normal saline and 0.4 mL of acetonitrile was used to elute 18 F -To the reaction bottle, 1 mL acetonitrile was added in two times and evaporated dry at 80 ℃. After the end, the precursor solution (1 mg of NOTA-FAPI-4C prepared in Example 1 + 0.5 mL acetonitrile + 10 μL aluminum chloride solution + 225 μL AcOH / NaOAc buffer solution) was added to the reaction bottle, heated to 110 ℃ and reacted for 15 min. After cooling to room temperature, 8 mL of normal saline was added to the reaction bottle and mixed evenly with the reaction solution, and then all the liquid was passed through a Sep-C18 column (10 mL of ethanol activation), at this time the product was captured, 10 mL of normal saline was used to flush the Sep-C18 column and blow dry. Finally, 2 mL of 50% ethanol was used to elute the Sep-C18 column and passed through a 0.22 μm microporous filter into the product bottle to obtain 18 F-AlF-NOTA-FAPI-4C injection. After the reaction was completed, the retention time of 18 F-AlF-NOTA-FAPI-4C was determined by HPLC method Figure 3 , and the specific method was as follows: C18 chromatographic column (5 μm, 250 mm × 4.6 mm), flow rate 1 ml / min, ultraviolet detection wavelength 254 nm, mobile phase was a mixture of water (A) and acetonitrile (B), the gradient condition of acetonitrile in the mobile phase: 0~ 15 min, 5 %~ 95 %. The radiochemical purity of 18 F-AlF-NOTA-FAPI-4C was determined by thin layer chromatography (TLC), and the results are shown in Figure 4 .

[0056] Example 3

[0057] This example provides a radionuclide-labeled FAPI derivative containing 4-cyanothiazolidine modification (denoted as 18 F-AIF-NOTA-FAPI-4C-1), which is only different from Example 2 in that:

[0058] (1) The preparation method of "heating to 110 ℃ and reacting for 15 min" is adjusted to "synchronous ultrasonic-microwave synergistic treatment under the conditions of microwave power W1 of 1000 W and ultrasonic power W2 of 625 W for 15 min".

[0059] Example 4

[0060] This example provides a radionuclide-labeled FAPI derivative containing 4-cyanothiazolidine modification (denoted as 18 F-AIF-NOTA-FAPI-4C-2), which is only different from Example 2 in that:

[0061] (1) The preparation method of "heating to 110 °C for 15 min" is adjusted to "synchronous ultrasonic-microwave synergistic treatment for 15 min under the conditions of microwave power W1 of 625 W and ultrasonic power W2 of 1000 W".

[0062] Example 5

[0063] Standard 19 Preparation method of F-AIF-NOTA-FAPI:

[0064]

[0065] NOTA-FAPI-4C prepared in Example 1 (20.34 mg, 0.027 mmol), AcOH / NaOAc buffer solution (10 ml), aluminum chloride (4.68 mg, 0.0351 mmol), potassium fluoride (3.132 mg, 0.054 mmol) were added to a pressure-resistant bottle (48 ml), and heated and stirred at 90 °C for 60 min. After the reaction was completed, the reaction solution was extracted with a blue water film, and purified by C18 reverse phase preparation column (C18 19x250mm, flow rate: 12 mL / min, wavelength: 220 nm, (AcOH / NaOAc buffer solution / MeCN=0%-20%, 100 min) to obtain white solid ALF-FAPI-4C (16.5 mg, yield 76.7%). LC-MS m / z (ESI): 798.4 [M+H] + . 1HNMR (400 MHz, D20) δ 8.68 (d, J = 4.9 Hz, 1H), 7.91 (dd, J = 17.4, 11.3 Hz, 2H), 7.53 (dd, J = 4.7, 4.1 Hz, 1H), 7.43 (dd, J = 8.8, 3.1 Hz, 1H), 5.24-5.19 (m, 1H), 4.87-4.82 (m, 2H), 4.61 (d, J = 3.3 Hz, 1H), 4.44-4.15 (m, 6H), 3.63 (ddd, J = 24.6, 16.9, 9.6 Hz, 5H), 3.45 (ddd, J = 21.2, 17.3, 8.5 Hz, 4H), 3.34 (d, J = 4.2 Hz, 1H), 3.22 (s, 1H), 3.20-2.97 (m, 6H), 2.89-2.80 (m, 2H), 2.78-2.62 (m, 3H), 2.17 (m, 4H), 1.94 (s, 1H), 1.62 (s, 1H).

[0066] As shown in Figure 5 F-AlF-NOTA-FAPI-4C, the present application adopts 18 F instead of 19 F 18 F - F-AlF-NOTA-FAPI-4C and uses mass spectrometry and nuclear magnetic resonance to identify the structure, by comparing the HPLC retention time of the standard 19 F-AlF-NOTA-FAPI-4C and 19 F-AlF-NOTA-FAPI-4C, 18 F-AlF-NOTA-FAPI-4C, 18 F-AlF-NOTA-FAPI-4C-1 and 18 F-AlF-NOTA-FAPI-4C-2, it is proved that the structure of the prepared 18 F-AlF-NOTA-FAPI-4C is the structure described in the present application.

[0067] Comparative Example 1

[0068] This example provides a prior radioisotope-labeled FAPI derivative, i.e. 18 F-AIF-NOTA-FAPI-42, the chemical structural formula of the FAPI derivative -NOTA-FAPI-42 is as follows:

[0069] .

[0070] Test Example 1

[0071] This example relates to the results obtained in Example 2 above. 18 F-AIF-NOTA-FAPI-4C, obtained in Example 3 18 F-AIF-NOTA-FAPI-4C-1 and the results obtained in Example 4 18 F-AIF-NOTA-FAPI-4C-2 underwent abnormal toxicity testing and stability studies.

[0072] Abnormal toxicity test results showed that the preparation prepared by tail vein injection in mice... 18 F-AlF-NOTA-FAPI-4C, 18 F-AIF-NOTA-FAPI-4C-1 or 18 No adverse reactions or deaths were observed 48 hours and one week after F-AIF-NOTA-FAPI-4C-2 administration. Autopsy revealed no organ damage. This indicates that it is non-toxic to the body and can be further studied in vivo.

[0073] Stability test: Take 18 F-AlF-NOTA-FAPI-4C, 18 F-AIF-NOTA-FAPI-4C-1 or 18 F-AIF-NOTA-FAPI-4C-2 (1 mL, 74 MBq) was added to mouse plasma and incubated at 37°C for 60 min. Separately, 1 mL of 37 MBq... 18 F-AlF-NOTA-FAPI-4C, 18 F-AIF-NOTA-FAPI-4C-1 or 18 F-AIF-NOTA-FAPI-4C-2 was injected intravenously into healthy ICR rats, and urine was collected 5 minutes later. The radiochemical purity of both groups of liquids was determined by passing them through a 0.22 μm liquid filter membrane under the same HPLC analysis conditions as in Example 1. The retention time in both plasma and urine was determined to be 4.5 min, with no impurity peaks observed, indicating that in vitro and in vivo defluorination did not occur. 18 The test results of F-AlF-NOTA-FAPI-4C are as follows: Figure 6 As shown.

[0074] Test Example 2

[0075] This example relates to the results obtained in Example 2 above. 18 F-AIF-NOTA-FAPI-4C and Comparative Example 1 provide the existing18 F-AlF-NOTA-FAPI-42 was used for Micro-PET / CT imaging test.

[0076] The test method is as follows: 6 tumor-bearing mice of HT-1080 (human fibrosarcoma cells) are evenly divided into 2 groups. After induction of anesthesia, they are fixed in a 37°C constant temperature animal chamber (Minerve Vétérinaire, Esternay, France) to keep the animal temperature constant, and at the same time, 2.5 L / min of air mixed with 2% isoflurane gas is given to maintain anesthesia. Then, 0.5 mL of F-AlF-NOTA-FAPI-4C (7.4 MBq) prepared in Example 2 and the clinical conventional imaging agent F-AlF-NOTA-FAPI-42 (7.4 MBq) are injected into the tail vein of the mice, respectively. 18 F-AlF-NOTA-FAPI-4C (0.5 mL, 7.4 MBq) and the clinical conventional imaging agent F-AlF-NOTA-FAPI-42 (0.5 mL, 7.4 MBq) are injected into the tail vein of the mice, respectively. 18 F-AlF-NOTA-FAPI-42 (0.5 mL, 7.4 MBq), and static collection is performed at 10 min, 30 min, 60 min, 90 min, and 120 min after injection. Image reconstruction is performed using a 3D Ordered Subsets Expectation Maximization (OSEM) algorithm based on a Monte Carlo system model. Image analysis is performed using PMOD software (PMOD Technologies LLC, Zurich, Switzerland) to delineate the volume of interest (ROI). CT image scanning: tube voltage 80 kV, tube current 1 mA, exposure time 40 s, pre-processing selection 160 um layer thickness, reconstruction using Feldkamp filtered back projection algorithm, and performing beam hardening correction and ring artifact correction.

[0077] The test results show that the F-AlF-NOTA-FAPI-4C prepared in Example 2 of the present application and the existing clinical conventional imaging agent F-AlF-NOTA-FAPI-42 have the same imaging effect. 18 F-AlF-NOTA-FAPI-4C and the existing clinical conventional imaging agent F-AlF-NOTA-FAPI-42 18 F-AlF-NOTA-FAPI-42 is mainly metabolized through the urinary system, except for the kidneys, bladder, and tumors, and the radioactivity uptake of the remaining tissue organs is relatively low at each time point. The two injected imaging agents F-AlF-NOTA-FAPI-4C and F-AlF-NOTA-FAPI-42 have the same imaging effect. 18 F-AlF-NOTA-FAPI-4C and F-AlF-NOTA-FAPI-42 18 The maximum standard uptake value body weight (SUVbw) of the tumor at 10 min, 30 min, 60 min, 90 min, and 120 min for F-AlF-NOTA-FAPI-42 is shown in Table 1.

[0078] Table 1 Maximum standard uptake value body weight of the tumor at different times

[0079] Test sample 10 min 30 min 60 min 90 min 120 min Example 2 12.85±2.39 15.71±3.26 16.96±3.17 13.85±2.15 12.70±0.65 Comparative Example 1 7.31±0.53 8.05±1.12 9.09±1.02 9.17±0.87 8.53±1.00

[0080] As shown in Table 1, the present invention provided in Embodiment 2 18 F-AlF-NOTA-FAPI-4C compared with existing clinically routine imaging agents provided in Comparison 1 at various time points. 18 F-AlF-NOTA-FAPI-42 exhibits higher tumor uptake and relatively slower metabolism, which is more beneficial for tumor diagnosis; simultaneously, the method provided in Embodiment 2 of this invention... 18 micro-PET / CT image of F-AIF-NOTA-FAPI-4C as shown below Figure 7 As shown. Furthermore, compared to 18 F-AlF-NOTA-FAPI-4C was prepared by ultrasonic-microwave synergistic processing under different parameters. 18 F-AIF-NOTA-FAPI-4C-1 and 18 Tumor uptake of F-AIF-NOTA-FAPI-4C-2 showed significant differences, such as 18 The maximum standard uptake value of F-AIF-NOTA-FAPI-4C-1 at 60 min was 18.03 ± 2.49 kg body weight, which was higher than that obtained by heat treatment. 18 F-AlF-NOTA-FAPI-4C has been improved; while 18 The maximum standard uptake value of F-AIF-NOTA-FAPI-4C-2 at 60 min decreased to 13.26±3.01 kg body weight. The inventors speculate that this may be due to the difference in the spatial stereoconformation of the compound caused by the synergistic treatment of ultrasound and microwave, which needs further verification.

[0081] At the same time, injection 18 F-AlF-NOTA-FAPI-4C and 18 After 120 minutes of F-AlF-NOTA-FAPI-42 administration, the tumor / brain, tumor / liver, tumor / lung, and tumor / kidney ratios were 204.86 ± 24.58 vs 178 ± 36.57, 17.48 ± 4.23 vs 7.30 ± 2.15, 10.02 ± 2.15 vs 6.09 ± 1.63, and 1.26 ± 0.57 vs 0.32 ± 0.02, respectively, suggesting... 18 F-AlF-NOTA-FAPI-4C is more advantageous for delayed imaging of tumors in various sites due to its higher target-to-nucleus ratio (T / NT). Bone showed relatively low radioactive uptake at all time points, consistent with biodistribution results, confirming its in vivo stability.

[0082] In summary, the present application discloses a kind of 4-cyano thiazolidine modified FAPI derivative and its application, the FAPI derivative is good in stability, simple in preparation, high in radiochemical purity and good in biological performance, can be further used for clinical PET / CT tumor imaging, effectively solve the problems such as 18 F-AlF-NOTA-FAPI-42 and other existing clinical imaging 18 F-labeled FAPI class probe has the problems of low tumor uptake rate, short retention time and unable to further delay imaging, which makes up for the deficiencies of the prior art.

[0083] Various embodiments of the present application can exist in the form of a range; it should be understood that the description in the form of a range is only for the convenience and brevity, and should not be understood as a hard limit on the scope of the present application; therefore, it should be considered that the described range has specifically disclosed all possible sub-ranges and single values within the range. For example, it should be considered that the range from 1 to 6 has specifically disclosed sub-ranges, such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., and single numbers within the range, such as 1, 2, 3, 4, 5 and 6, which applies to any range. In addition, whenever a numerical range is indicated in this document, it refers to any cited number (fraction or integer) within the indicated range.

[0084] The above is only a specific embodiment of the present application, so that those skilled in the art can understand or implement the present application. Various modifications of these embodiments will be apparent to those skilled in the art, and the general principles defined herein can be implemented in other embodiments without departing from the spirit or scope of the present application. Therefore, the present application will not be limited to these embodiments shown herein, but will conform to the widest range consistent with the principles and novel features applied herein.

Claims

1. A FAPI derivative containing a 4-cyanothiazolidine modification, characterized in that, A chemical structural formula of the FAPI derivative containing 4-cyano thiazolidine modification is shown as Formula I; The Formula I: 。 2. FAPI derivative containing a 4-cyanothiazolidine modification according to claim 1, characterized in that, A preparation method of the FAPI derivative containing 4-cyano thiazolidine modification comprises the following steps: ； Compound 1 is added to a DMF solution containing HBTU and DIPEA for dissolution, and then compound 2 is added to the reaction system, and the reaction is stirred at room temperature under nitrogen protection for 3 hours; after the reaction is completed, purification post-treatment is performed, and light yellow solid compound 3 is obtained; Under nitrogen protection, compound 3 is added to dichloromethane for dissolution, and the reaction system is cooled to 0 DEG C in an ice salt bath, and trifluoroacetic acid is added dropwise, after the dropwise addition is completed, the ice salt bath is removed, and the reaction is stirred at room temperature under nitrogen protection for 2 hours; after the reaction is completed, purification post-treatment is performed, and light yellow solid compound 4 is obtained; Compound 4 is added to a DMF solution containing HBTU and DIPEA for dissolution, and then compound 5 is added to the reaction system, and the reaction is stirred at room temperature under nitrogen protection for 2 hours; after the reaction is completed, purification post-treatment is performed, and light yellow oil compound 6 is obtained; Under nitrogen protection, compound 6 is added to dichloromethane for dissolution, and the reaction system is cooled to 0 DEG C in an ice salt bath, and trifluoroacetic acid is added dropwise, after the dropwise addition is completed, the ice salt bath is removed, and the reaction is stirred at room temperature under nitrogen protection for 12 hours; after the reaction is completed, purification post-treatment is performed, and the FAPI derivative containing 4-cyano thiazolidine modification, compound 7, is obtained.

3. Use of the FAPI derivative containing 4-cyano thiazolidine modification according to claim 1 or 2 in the preparation of a tracer precursor compound targeting FAP, in the preparation of a diagnostic drug targeting fibroblast activation protein, in the preparation of a nuclide imaging drug for tumors with high expression of FAP protein, and in the preparation of a probe targeting FAP.

4. A radiopharmaceutical formulation, characterized in that, The radioactive preparation comprises the FAPI derivative containing 4-cyano thiazolidine modification according to claim 1 or 2 labeled with a radionuclide.

5. The radiopharmaceutical of claim 4, wherein, A chemical structural formula of the FAPI derivative containing 4-cyano thiazolidine modification labeled with a radionuclide is shown as Formula II; The Formula II: 。 6. The radiopharmaceutical of claim 5, wherein, A preparation method of the FAPI derivative containing 4-cyano thiazolidine modification labeled with a radionuclide comprises the following steps: The radionuclide-containing 18 F - and the precursor solution of the FAPI derivative containing 4-cyanothiazolidine modification are subjected to heating stirring treatment; after the reaction is completed, purification post-treatment is carried out, and the radioactive preparation is obtained. or, a radionuclide 18 F - and the precursor solution of the FAPI derivative containing 4-cyanothiazolidine modification is subjected to ultrasonic-microwave synergistic treatment; after the reaction is completed, purification post-treatment is carried out, and the radioactive preparation is obtained. In the ultrasonic-microwave synergistic treatment, the microwave power W1 and the ultrasonic power W2 satisfy: 820 W≤W1≤1050 W, 550 W≤W2≤680 W, and 1.4≤W1 / W2≤1.

9.

7. Use of the radioactive preparation according to any one of claims 4-6 in the preparation of a probe targeting FAP.

8. Use according to claim 7, characterized in that, It is applied to the preparation of a product for detecting diseases or conditions related to fibroblast activation protein; the conditions include tumors or inflammation; the tumors include breast cancer, ovarian cancer, colorectal cancer, prostate cancer, lung cancer, fibrosarcoma, bone and connective tissue sarcoma, renal cell carcinoma, gastric cancer, pancreatic cancer or skin melanoma; the inflammation includes osteoarthritis, rheumatoid arthritis, granulation tissue, liver fibrosis, pulmonary fibrosis or cirrhosis.

9. Use according to claim 7, characterized in that, The imaging mode comprises at least one of single photon emission computed tomography and positron emission tomography.

10. Use according to claim 7, characterized in that, The FAP-targeted probe is prepared into an injection and administered by intravenous injection.

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