Synthesis method and application of C11 labeled molecular imaging probe

Abstract

The invention provides a synthesis method and application of a carbon 11 labeled molecular imaging probe, and belongs to the technical field of nuclear imaging, the synthesis method of the carbon 11 labeled molecular imaging probe provided by the invention comprises the following steps: taking cesium carbonate as a catalyst, mixing a molecular imaging probe precursor and excessive 11C-CH3I, and reacting to generate the carbon 11 labeled molecular imaging probe. According to the invention, cesium carbonate is used as a catalyst for the first time to synthesize the C11 labeled molecular imaging probe, and the synthesized molecular imaging probe can complete imaging in various tissues and has the advantages of high radiochemical purity and high biological safety.

Description

Technical Field

[0001] The present invention relates to the field of nuclear imaging technology, and in particular, to a synthesis method and application of a carbon-11 labeled molecular imaging probe. Background Art

[0002] Positron emission tomography (PET) is currently the only imaging technology that can display molecular metabolism, receptors, and neurotransmitter activities in vivo. PET-CT can simultaneously obtain PET functional images and CT anatomical images, overcoming the problem of lack of anatomical information in PET images. PET-CT has played an important role in the fields of tumor diagnosis, metabolic physiology, and molecular targets.

[0003] PET-CT uses positron radionuclide-labeled drugs to achieve imaging and tracing. Currently, the imaging agents used in PET-CT mainly include 18 F imaging agents, 11 C imaging agents, 68 Ga imaging agents. Among them, 11 C imaging agents are widely used for their advantage of not changing the structure of the drug itself. Currently, common 11 C imaging agents include 11 C-acetate, 11 C-carbon monoxide, 11 C-methionine, 11 C-choline, 11 C-flumazenil, 11 C-raclopride.

[0004] Different types of PET-CT imaging agents have different clinical applications. Among them, 11 C-acetate is commonly used for the imaging of prostate cancer and liver cancer, 11 C-flumazenil is mainly used for the localization of epilepsy, 11 C-raclopride is mainly used for the imaging of schizophrenia and Parkinson's disease, 11 C-choline is mainly used for the imaging of the urinary system, 11 C-methionine is used for the imaging of gliomas. Developing PET-CT imaging agents that can be applied to multi-organ imaging is of great significance for PET-CT.

[0005] 11 C-rosuvastatin compound is a tracer for PET. The Chinese invention patent with the publication number CN112457257A discloses 11 the preparation method of C-rosuvastatin compound and 11 C-rosuvastatin compound as a PET tracer. However, in this patent 11The synthesis of the C-rosuvastatin compound uses aqueous tetrabutylphosphonium hydroxide as a catalyst. Tetrabutylphosphonium hydroxide is a corrosive reagent with the characteristics of being flammable and explosive, posing a relatively large safety hazard to operators during the preparation process. At the same time, the aqueous tetrabutylphosphonium hydroxide is a liquid catalyst, and its preparation and transfer are relatively cumbersome, which also increases 11 the preparation difficulty of the C-rosuvastatin compound. Summary of the Invention

[0006] The purpose of the present invention is to provide a simple-to-prepare imaging agent that can be used for multi-organ PET-CT imaging.

[0007] To achieve the above purpose, a synthesis method of a carbon-11 labeled molecular imaging probe, the synthesis method is using cesium carbonate as a catalyst, mixing a molecular imaging probe precursor and an excessive amount of 11 C-CH3I, and reacting to generate a carbon-11 labeled molecular imaging probe.

[0008] Preferably, the molecular imaging probe precursor is desmethyl rosuvastatin.

[0009] Preferably, the reaction conditions are: reaction temperature 100~120°C, reaction duration 5~10 min.

[0010] Preferably, the mass ratio of cesium carbonate to the molecular imaging probe precursor is 1:(1.5~3).

[0011] Preferably, the carbon-11 labeled molecular imaging probe generated by the reaction is obtained by liquid chromatography separation.

[0012] Preferably, the liquid chromatography conditions are: mobile phase A: 0.1% acetic acid solution; mobile phase B: methanol; the chromatographic column is a C18 column; the mobile phase program is: 0 min: 50% A, 10 min: 40% A, 20 min: 30% A, 22 min: 50% A, 25 min: 50% A; the flow rate is 3 mL / min, the column temperature is 32°C, and the detection wavelength is 254 nm.

[0013] Preferably, the carbon-11 labeled molecular imaging probe generated by the reaction is quality controlled by Radio-HPLC.

[0014] Preferably, the conditions of the Radio-HPLC are: using a TFA-water-acetonitrile solution with a volume ratio of 1:67.5:31.5 as the mobile phase, the chromatographic column is a C18 column, setting the flow rate at 1.15 mL / min, the column temperature at 32°C, and the detection wavelength at 242 nm.

[0015] Preferably, the molecular imaging probe precursor is dissolved in an organic solvent.

[0016] Preferably, the organic solvent is selected from any one or more of DMSO, DMAC, and sulfolane.

[0017] The finally synthesized imaging agent carbon-11 labeled molecular imaging probe for multi-organ PET-CT imaging in the present invention is 11 C-rosuvastatin compounds. In the traditional synthesis process, 11 C-rosuvastatin compounds are prepared by catalyzing desmethyl rosuvastatin and 11 C-CH3I with tetrabutylphosphonium hydroxide. However, tetrabutylphosphonium hydroxide is a liquid catalyst, which has the disadvantages of cumbersome preparation and complex operation in the use process. At the same time, tetrabutylphosphonium hydroxide is corrosive, has a pungent smell and is toxic. If it contacts the human tissue of the operator, it will pose a threat to the personal safety of the operator; in addition, the tetrabutylphosphonium hydroxide solution is a flammable liquid, which is prone to cause fires and explosions and has low safety.

[0018] In the synthesis method of the carbon-11 labeled molecular imaging probe provided by the present invention, cesium carbonate, a solid material with low toxicity and higher safety, is used as a catalyst to replace tetrabutylphosphonium hydroxide to catalyze the reaction of the molecular imaging probe precursor and 11 C-CH3I to generate a carbon-11 labeled molecular imaging probe. In the synthesis method provided by the present invention, the solid catalyst can be directly used without preparing a solution, and the use is simple; at the same time, cesium carbonate, as a solid catalyst, is also convenient to separate from the synthesis product in the later stage; in addition, cesium carbonate, as an inorganic base, can react with an acidic solution to generate carbon dioxide while acting as a catalyst and a pH regulator for the reaction system. The generated carbon dioxide can effectively isolate oxygen and avoid interference of the reaction by oxygen.

[0019] In addition, the synthesis method provided by the present invention has developed a purification and quality control method specifically applicable to the carbon-11 labeled molecular imaging probe. The purification method directly purifies the crude product of the carbon-11 labeled molecular imaging probe by HPLC. The finally prepared probe has extremely high purity and convenient operation. On this basis, the quality control method provided by the present invention can ensure that the radiochemical purity of the prepared carbon-11 labeled molecular imaging probe is 100%, so that the prepared 11 C-rosuvastatin compounds can be directly applied to PET-CT imaging.

[0020] The second aspect of the present invention provides an application of the carbon-11 labeled molecular imaging probe prepared by the synthesis method described in the first aspect.

[0021] Preferably, the application includes using the carbon-11 labeled molecular imaging probe for tracer imaging of PET-CT in any one or more of the blood system, liver, bile duct, pancreas, intestine, and kidney.

[0022] In the prior art, the11 C-rosuvastatin compounds are mainly used for PET hepatobiliary transport imaging. For the first time, the present invention 11 extends the application of C-rosuvastatin compounds to the tracer imaging of whole-body multi-tissue PET-CT and verifies 11 the imaging performance of C-rosuvastatin compounds.

[0023] Compared with the prior art, the present invention has the following beneficial effects: 1. The synthesis method of the carbon-11 labeled molecular imaging probe provided by the present invention uses cesium carbonate as a catalyst, making the whole synthesis method safe and the product easy to separate; 2. Through the synthesis method provided by the present invention, the radiochemical purity of the finally synthesized carbon-11 labeled molecular imaging probe can reach 100%, and the product purity is extremely high, laying a foundation for the subsequent use of the probe for PET-CT imaging; 3. For the first time, the present invention 11 uses C-rosuvastatin compounds for multi-tissue PET-CT imaging, which has an inspiring effect on the research of whole-body PET-CT. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 It is the HPLC chromatogram of the crude product of the carbon-11 labeled molecular imaging probe in Example 1 of the present invention; Figure 2 It is the HPLC chromatogram of the rosuvastatin calcium reference substance in Example 1 of the present invention; Figure 3 It is in Example 1 of the present invention 11 the Radio-HPLC chromatogram of C-rosuvastatin compounds; Figure 4 It is in Example 2 of the present invention 11 the Radio-HPLC chromatogram of C-rosuvastatin compounds after standing for 1 h; Figure 5 It is the maximum density projection image of the abdominal coronal plane of rats after single administration at different time periods in Example 3 of the present invention; Figure 6 It is in Example 3 of the present invention after long-term combined use of a transporter inhibitor and 11 C-rosuvastatin compounds, the maximum density projection image of the abdominal coronal plane of rats after administration at different time periods; Figure 7 It is in Example 3 of the present invention 11 the time curve of the radioactivity concentration of C-rosuvastatin compounds in the intestinal tissue of rats; Figure 8 It is in Example 3 of the present invention 11Time curve of radioactivity concentration of C-rosuvastatin compounds in rat bile tissue; Figure 9 In Example 3 of the present invention 11 Time curve of radioactivity concentration of C-rosuvastatin compounds in rat liver tissue; Figure 10 In Example 3 of the present invention 11 Time curve of radioactivity concentration of C-rosuvastatin compounds in rat renal cortex tissue; Figure 11 In Example 3 of the present invention 11 Time curve of radioactivity concentration of C-rosuvastatin compounds in rat renal medulla tissue; Figure 12 In Example 3 of the present invention 11 Time curve of radioactivity concentration of C-rosuvastatin compounds in rat pancreatic tissue; Figure 13 In Example 3 of the present invention 11 Time curve of radioactivity concentration of C-rosuvastatin compounds in rat plasma tissue; Figure 14 In Example 3 of the present invention 11 Time curve of radioactivity concentration of C-rosuvastatin compounds in rat blood cells; Figure 15 After long-term administration in Example 4 of the present invention 11 HE staining results of rat liver and kidney after administration of C-rosuvastatin compounds. Detailed implementation manners

[0025] To make the above objects, features and advantages of the present invention more obvious and understandable, the specific embodiments of the present invention will be described in detail below. It should be noted that the following embodiments are only used to illustrate the implementation methods and typical parameters of the present invention, and are not used to limit the parameter range described in the present invention. Reasonable changes derived therefrom are still within the protection scope of the claims of the present invention.

[0026] It should be noted that the endpoints and any values within the ranges disclosed in this document are not limited to the exact ranges or values. These ranges or values should be understood to include values close to these ranges or values. For numerical ranges, between the endpoint values of each range, between the endpoint values of each range and individual point values, and between individual point values, they can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be regarded as specifically disclosed in this document.

[0027] As described in the background art, in the prior art, a PET-CT imaging agent can often only be used for PET-CT imaging of one tissue or a few tissues. In view of this, a specific embodiment of the present invention provides a carbon-11 labeled molecular imaging probe applicable to multi-tissue imaging. The carbon-11 labeled molecular imaging probe is synthesized by the following method: using cesium carbonate as a catalyst, mixing a molecular imaging probe precursor and an excess of 11 11C-CH3I, and reacting to generate a carbon-11 labeled molecular imaging probe. Among them, the mass ratio of cesium carbonate to the molecular imaging probe precursor is 1:(1.5 - 3), and the molecular imaging probe precursor is desmethyl rosuvastatin. The reaction temperature is 100 - 120 °C, and the reaction duration is 5 - 10 min.

[0028] In the above synthesis method, cesium carbonate as a catalyst mainly has the following advantages: 1. Compared with the existing liquid catalysts, the solid catalyst cesium carbonate is more convenient to use; 2. Compared with the existing liquid catalyst tetrabutylphosphonium hydroxide, cesium carbonate has higher safety; 3. Compared with the existing liquid catalyst tetrabutylphosphonium hydroxide, cesium carbonate is easier to separate from the product in the subsequent process; 4. In the whole reaction system, cesium carbonate, in addition to acting as a catalyst, also acts as a pH regulator to control the overall pH of the reaction system; 5. As an alkaline salt, cesium carbonate can react with an acidic solution to generate carbon dioxide, and the generated carbon dioxide can be used as a protective gas to isolate oxygen in the environment, avoiding oxygen from participating in the reaction system and ensuring the purity of the final product.

[0029] The carbon-11 labeled molecular imaging probe prepared by the above synthesis method has a radiochemical purity of up to 100%, with extremely high purity, laying a foundation for its subsequent application.

[0030] The technical solution of the present invention will be further described below through specific examples. Unless otherwise defined, all terms, symbols, and other scientific terms used in the following examples are intended to have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. In some cases, terms with conventional understood meanings are defined herein for the purpose of clarification or easy reference, and such definitions herein should not be construed as indicating a significant difference from the conventional understanding in the art. The technical methods described or cited herein are generally well understood by those skilled in the art and are adopted by conventional methods. Unless otherwise stated, the use of commercially available kits, reagents, and instruments follows the protocols and parameters given by the manufacturers.

[0031] Example 1

[0032] Synthesis of carbon-11 labeled molecular imaging probe

[0033] Weigh 1 mg of demethyl rosuvastatin, 0.2 mL, and 0.5 mg of cesium carbonate into a reaction flask for accelerator production. 11 C-CO2 is reduced by lithium aluminum hydride and undergoes an addition reaction with methyl iodide to form 11 C-CH3I. Transfer 11 C-CH3I to the reaction flask. After reacting at 110 °C for 8 minutes, a crude product of the carbon-11 labeled molecular imaging probe is obtained.

[0034] Purify the above-mentioned crude product of the carbon-11 labeled molecular imaging probe by HPLC. The HPLC conditions are as follows: Mobile phase A: 0.1% acetic acid solution; Mobile phase B: methanol; The chromatographic column is YMC-Pack Pro-C18 RS (10 mm × 254 nm); The mobile phase program is: 0 min: 50% A, 10 min: 40% A, 20 min: 30% A, 22 min: 50% A, 25 min: 50% A; The flow rate is 3 mL / min, the column temperature is 32 °C, and the detection wavelength is 254 nm. The HPLC chromatogram of the crude product of the carbon-11 labeled molecular imaging probe is as Figure 1 shown.

[0035] Use the rosuvastatin calcium reference standard for detection under the aforementioned HPLC conditions. The HPLC chromatogram of the rosuvastatin calcium reference standard is Figure 2 shown. From Figure 1 and Figure 2 it can be confirmed that Figure 1 the sample at 24.598 min in 11 C-rosuvastatin compounds is the target product. Collect the effluent during this time period to obtain 11 pure C-rosuvastatin compounds.

[0036] Collect the purified 11 C-rosuvastatin compounds and perform quality control on 11 C-rosuvastatin compounds by Radio-HPLC. Use rosuvastatin calcium as the reference standard to detect 11 the radiochemical purity of C-rosuvastatin compounds. The specific method is as follows: Use TFA-water-acetonitrile (1% - 67.5% - 31.5%) as the mobile phase, select an Agilent Eclipse XDB-C18 (4.6 mm × 150 mm, 3.5 μm) chromatographic column, set the flow rate at 1.15 mL / min, the column temperature at 32 °C, and the detection wavelength at 242 nm. 11 The Radio-HPLC chromatogram of 11 C-rosuvastatin compounds is as Figure 3 shown.

[0037] It can be seen that the carbon-11 labeled molecular imaging probe prepared by the synthesis method of the present invention11 The radiochemical purity of C-rosuvastatin compounds can reach 100%.

[0038] Meanwhile, Radio-HPLC was used for verification 11 The concentration and specific activity of the pure C-rosuvastatin compounds were determined using calcium rosuvastatin as the reference standard 11 The amount of substance of the C-rosuvastatin compound solution was combined 11 The specific activity was calculated by combining the radioactive activity of the C-rosuvastatin compound solution. The formula for calculating the specific activity is as follows:

[0039] The data of three parallel samples of the calcium rosuvastatin reference standard and 11 The calculation process of the specific activity of the C-rosuvastatin compounds is shown in Table 1

[0040] Table 1

[0041] Finally, the relevant test results of the 11 C-rosuvastatin compounds prepared in this example are shown in Table 2

[0042] Table 2 Parameter Character Clear and transparent Quality control RCP(%) 100 Concentration (mg / mL) 0.196 Specific activity (GBq / μmol) 0.48

[0043] Example 2

[0044] 11 Stability test of C-rosuvastatin compounds

[0045] The pure C-rosuvastatin compounds prepared in Example 1 were dissolved in ethanol and allowed to stand for 1 h, then 11 Radio-HPLC detection was performed on the C-rosuvastatin compounds. The specific method was the same as that in Example 1. The specific Radio-HPLC chromatogram is as 11 shown Figure 4 as follows

[0046] Comparison Figure 3 and Figure 4 showed that the C-rosuvastatin compounds prepared in the present invention 11 had strong stability and could still maintain 100% radiochemical purity in vitro for 1 h

[0047] Example 3

[0048] 11 PET-CT imaging performance test of C-rosuvastatin compounds

[0049] Rats were taken and anesthetized with isoflurane. After anesthesia, abdominal PET scans were performed on the rats. Then, 11 C-rosuvastatin compounds were injected at a constant rate. After 30 s, abdominal PET dynamic scans were continued for 60 min while keeping the rats immobile. After the PET scans were completed, CT scans were performed. The scanning energy window was 350 - 650 Kev, and the scanning time was recorded (the start and end times of PET scans were recorded to the second for decay correction). During the scans, arterial blood samples of approximately 0.1 - 0.2 mL were collected from the femoral artery catheter at 15 s, 30 s, 45 s, 60 s, 2 min, 5 min, 15 min, 30 min, 45 min, and 60 min after the administration of 11 C-rosuvastatin compounds. The blood sampling times were accurate to the second and recorded (for decay correction). After blood sampling was completed between 5 - 45 min, the blood volume lost by the rats was replenished with the same volume of saline while ensuring patency of the femoral artery catheter. After the blood was anticoagulated with sodium heparin, plasma and blood cells were separated by centrifugation at 4℃ and 3000 rpm for gamma counting. The start and end times of gamma counting were recorded (recorded to the second for decay correction).

[0050] After the PET / CT scans were completed, the animals were euthanized, and various tissues were collected, including the liver, kidneys, duodenum, jejunum, ileum, colon, and their corresponding intestinal contents, skeletal muscle, heart, and brain. After collection, the weights of each tissue were recorded and used for gamma counting. The start and end times of gamma counting were recorded (recorded to the second for decay correction). After the gamma counting test was completed, the samples were directly frozen at -80℃.

[0051] After the PET / CT scans were completed, image reconstruction was performed. The PMOD software was used to process the images and data. Regions were outlined: liver, renal cortex, renal medulla, bladder, thigh skeletal muscle, heart, intestine, bile duct, and the radioactivity concentration (i.e., the radioactivity value per unit volume) was obtained. Then, the activities at each time point were decay-corrected. The percentage injected dose per gram of tissue (%ID / g) of each organ was calculated based on the administered dose, or the standardized uptake value (SUV) of each organ was calculated based on the animal's body weight. Data such as the mean and standard deviation were calculated using Microsoft Office Excel. The formulas are as follows:

[0052]

[0053]

[0054] Use Microsoft Office Excel to calculate data such as the percentage injected dose rate per gram of tissue (%ID / g), mean value, and standard deviation.

[0055]

[0056]

[0057] After administration alone at different time intervals, the maximum density projection images of the rat abdomen in the coronal plane are as Figure 5 shown.

[0058] After co - administration of the transporter inhibitor and 11 C - rosuvastatin compounds for a long time, after administration at different time intervals, the maximum density projection images of the rat abdomen in the coronal plane are as Figure 6 shown.

[0059] From Figure 5 and Figure 6 it can be seen that the 11 C - rosuvastatin compounds prepared in Example 1 have excellent in - vivo imaging effects.

[0060] 11 The time - activity concentration curve of C - rosuvastatin compounds in rat intestinal tissue is as Figure 7 shown, where RSV: 11 C - rosuvastatin compounds, LPV - RTV: inhibitor.

[0061] 11 The time - activity concentration curve of C - rosuvastatin compounds in rat bile tissue is as Figure 8 shown, where RSV: 11 C - rosuvastatin compounds, LPV - RTV: inhibitor.

[0062] 11 The time - activity concentration curve of C - rosuvastatin compounds in rat liver tissue is as Figure 9 shown, where RSV: 11 C - rosuvastatin compounds, LPV - RTV: inhibitor.

[0063] 11 The time - activity concentration curve of C - rosuvastatin compounds in rat renal cortex tissue is as Figure 10 shown, where RSV: 11 C - rosuvastatin compounds, LPV - RTV: inhibitor.

[0064] 11The time curve of the radioactivity concentration of C-rosuvastatin compounds in the renal medulla tissue of rats is as Figure 11 shown, where RSV: 11 C-rosuvastatin compounds, LPV-RTV: inhibitor.

[0065] 11 The time curve of the radioactivity concentration of C-rosuvastatin compounds in the pancreatic tissue of rats is as Figure 12 shown, where RSV: 11 C-rosuvastatin compounds, LPV-RTV: inhibitor.

[0066] 11 The time curve of the radioactivity concentration of C-rosuvastatin compounds in the plasma tissue of rats is as Figure 13 shown, where RSV: 11 C-rosuvastatin compounds, LPV-RTV: inhibitor.

[0067] 11 The time curve of the radioactivity concentration of C-rosuvastatin compounds in the blood cells of rats is as Figure 14 shown, where RSV: 11 C-rosuvastatin compounds, LPV-RTV: inhibitor.

[0068] From Figures 7 to 14 it can be seen that 11 C-rosuvastatin compounds can be applied to the imaging of various tissues such as the kidney, liver, blood, and pancreas, and the scope of application is extremely wide.

[0069] Example 4

[0070] 11 Detection of the transport activity and biosafety of C-rosuvastatin compounds

[0071] Using SAAM II software, the radioactivity concentration-time data of C-rosuvastatin compounds in the whole blood, liver, bile, intestine, renal cortex, renal cortex, and pancreas of each rat were simultaneously fitted by an eight-compartment model. The differential equation is as follows: 11 = CL = CL BL * C B - (CL LD + CL LM + CL LB ) * C L Eq.1; = CL BI * C D - CLI0 * C I Eq. 2; = CL CK * C C - CL K0 * C K Eq. 3; = CL BP * C B - CL P0 * C P Eq. 4; = CL BD * C L - CL DI * C D Eq. 5; = CL BC * C B - CL CK * C C Eq. 6, wherein, B, L, K, I, P, C, D respectively represent blood, liver, renal medulla, intestine, pancreas, renal cortex, bile. A: amount; C: concentration; M: metabolism; 0: irreversible loss. Therefore, CL BL : sinusoidal uptake clearance rate of liver; CL LB : sinusoidal efflux clearance of liver; CL LM : hepatic metabolic efflux clearance; CL LD : bile uptake clearance rate; CL DI : bile efflux clearance rate; CL I0 : intestinal clearance rate (including intestinal reabsorption); CL BC : renal cortex uptake clearance rate; CL CK : renal cortex efflux clearance rate; CL K0 : renal medulla efflux clearance rate; CL BP : pancreatic uptake clearance rate; CL P0 : pancreatic efflux clearance rate. CL CB cannot be analyzed by modeling, and this parameter is not included in the eight-compartment model. Therefore, CL BC is 11 the net uptake clearance rate of C-rosuvastatin compounds transported into the kidney.

[0072] Finally 11 The pharmacokinetic model fitting key tissue site clearance rates of C-rosuvastatin compounds and after co-administering inhibitors for a long time are shown in Table 3.

[0073] Table 3 <![CDATA 11 C-rosuvastatin compounds]]> <![CDATA 11 C - Rosuvastatin compounds + inhibitors]]> <![CDATA[CL BL (mL / min / kg)]]> 56.09±12.79 66.59±15.08 <![CDATA[CL LB (mL / min / kg)]]> 6.59±3.95 6.00±2.09 <![CDATA[CL LD (mL / min / kg)]]> 0.38±0.11 0.15±0.08 <![CDATA[CL DI (mL / min / kg)]]> 0.18±0.05 0.12±0.10 <![CDATA[CL BP (mL / min / kg)]]> 1.79±1.11 2.70±0.29 <![CDATA[CL BC (mL / min / kg)]]> 9.57±2.19 16.13±8.68 <![CDATA[CL CK (mL / min / kg)]]> 12.44±7.16 13.56±6.20 Using UPLC-QQQ-MS / MS, the relative quantification of the metabolic degree of 11 C-rosuvastatin compounds in rats was carried out with the peak area ratio of metabolites to the original drug. The results were as follows: at 15 min, the peak area ratios of pentenoic acid derivative metabolites to the original drug were 0.00442±0.00377 and 0.00859±0.00774 respectively, indicating that the metabolism was <1%. At 60 min, the peak area ratios of pentenoic acid derivative metabolites to the original drug were 0.06246±0.04228 and 0.04437±0.06017<7%, indicating that the metabolism was <10%. It shows that during the whole process of PET-CT scanning, 11 C-rosuvastatin compounds have metabolic stability, and the metabolites basically do not affect PET-CT imaging.

[0074] Long-term administration 11 After C-rosuvastatin compounds, HE staining was performed on the livers and kidneys of rats, and the relevant results were as Figure 15 shown. Among them, Figure 15 A in 11 was the HE staining result of the liver of rats after long-term administration of Figure 15 C-rosuvastatin compounds, and Figure 15 B in 11 was the control result of HE staining of rat liver; Figure 15 C in 11 was the HE staining result of the kidney of rats after long-term administration of 11 C-rosuvastatin compounds, and

[0075] Although the present disclosure is disclosed as above, the protection scope of the present disclosure is not limited thereto. Those skilled in the art can make various changes and modifications without departing from the spirit and scope of the present disclosure, and these changes and modifications will all fall within the protection scope of the present invention.

Claims

1. A method for synthesizing a carbon-11 labeled molecular imaging probe, characterized in that, The synthesis method uses cesium carbonate as a catalyst to mix the molecular imaging probe precursor and an excess of 11 C-CH3I, and reacts to generate a carbon-11 labeled molecular imaging probe.

2. The synthesis method according to claim 1, wherein The molecular imaging probe precursor is desmethyl rosuvastatin.

3. The synthesis method according to claim 1, characterized in that, The reaction conditions are: reaction temperature 100 - 120 °C, reaction duration 5 - 10 min.

4. The synthesis method according to claim 1, wherein The mass ratio of cesium carbonate to the molecular imaging probe precursor is 1:(1.5 - 3).

5. The synthesis method according to claim 1, characterized in that, The carbon-11 labeled molecular imaging probe generated by the reaction is obtained by liquid chromatography separation.

6. The synthesis method according to claim 5, wherein The liquid chromatography conditions are: mobile phase A: 0.1% acetic acid solution; mobile phase B: methanol; the chromatographic column is a C18 column; the mobile phase program is: 0 min: 50% A, 10 min: 40% A, 20 min: 30% A, 22 min: 50% A, 25 min: 50% A; the flow rate is 3 mL / min, the column temperature is 32 °C, and the detection wavelength is 254 nm.

7. The synthesis method according to claim 1, characterized in that, The carbon-11 labeled molecular imaging probe generated by the reaction is quality controlled by Radio-HPLC.

8. The synthesis method according to claim 7, characterized in that, The conditions of the Radio-HPLC are: using a TFA-water-acetonitrile solution with a volume ratio of 1:67.5:31.5 as the mobile phase, the chromatographic column is a C18 column, the flow rate is set at 1.15 mL / min, the column temperature is 32 °C, and the detection wavelength is 242 nm.

9. The synthesis method according to claim 1, characterized in that, The molecular imaging probe precursor is dissolved in an organic solvent, and the organic solvent is selected from any one or more of DMSO, DMAC, and sulfolane.

10. Use of a carbon-11 labeled molecular imaging probe prepared by the synthesis method according to any one of claims 1 to 9, characterized in that, The application includes using the carbon-11 labeled molecular imaging probe for tracer imaging of PET-CT in any one or more of the blood system, liver, bile duct, pancreas, intestine, and kidney.

Images