阅读说明：本技术 一种正电子探针及其制备方法与应用 (Positron probe and preparation method and application thereof ) 是由 黄顺 于 2019-10-11 设计创作，主要内容包括：本发明公开了一种正电子探针及其制备方法和应用。本发明所述的正电子探针为<Sup>18</Sup>F标记的正电子探针,其结构如式为：<Image he="133" wi="700" file="DDA0002229423730000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>本发明的正电子探针,制备简单、快速,产率高、比活度大；可用作肿瘤的广谱PET显像,具有诊断和监测治疗疗效的临床价值。其制备方法简单、快速,可实现全自动化生产,可满足科学研究与临床需求。(The invention discloses a positron probe and a preparation method and application thereof. The positron probe of the invention is 18 The structure of the F-labeled positron probe is as follows: The positron probe is simple and rapid to prepare, high in yield and large in specific activity; can be used for broad-spectrum PET imaging of tumors and has clinical values of diagnosis and monitoring of treatment efficacy. The preparation method is simple and rapid, can realize full-automatic production, and can meet the requirements of scientific researchAnd clinical requirements.)

1. A positron probe characterized by: the positron probe is¹⁸The chemical structural formula of the F-labeled positron probe is

2. The method for preparing a positron probe according to claim 1, comprising the steps of: eluting with 1.5mL of eluent¹⁸Collecting eluate in QMA column, heating to 110 deg.C, continuously blowing high-purity nitrogen gas, and removing H by azeotropic distillation₂o; adding 1mL of mixed solution dissolved with 5mg of precursor into a reaction bottle, and reacting for 10-15min at 90-110 ℃; after cooling, the target product is obtained by semi-preparative High Performance Liquid Chromatography (HPLC) separation.

3. The method for preparing a positron probe according to claim 2, wherein the chemical structure of the precursor is:

4. The method for preparing a positron probe according to claim 2, wherein the washing the QMA column with a solution comprises: 12.0mg of 4,7,13,16,21, 24-hexaoxy-1, 10-diazabicyclo [8.8.8 ]]Hexacosane was dissolved in 0.9mL acetonitrile, 3.0mgK₂CO₃Or 4.3mg KHCO₃Dissolve in 0.1mL of water.

5. the method for preparing a positron probe according to claim 2, wherein the solvent used for dissolving the precursor is selected from the group consisting of: one or more of anhydrous acetonitrile, anhydrous dimethyl sulfoxide (DMSO) or anhydrous N, N-Dimethylformamide (DMF).

6. The method for preparing a positron probe according to claim 2, wherein the reaction temperature is 90 ℃ and the reaction time is 15 min.

7. The method for preparing a positron probe according to claim 2, wherein the semi-preparative HPLC separation conditions are: and C-18 column, wherein the mobile phase comprises an A phase and a B phase, the A phase is aqueous solution, the B phase is acetonitrile, and the volume ratio of the A phase solution to the B phase solution is 3: 2, the total flow rate is 4 mL/min.

8. Use of a positron probe according to claim 1 for the preparation of a reagent for PET imaging of tumors.

Technical Field

The invention belongs to the field of radiochemistry and nuclear medicine research, and relates to a compound enzyme preparation¹⁸Marked by FPositron probe, preparation method of the positron probe and application of the positron probe.

Background

Malignant tumors represent one of the biggest public health problems worldwide, greatly endangering human health. Malignant tumor is one of the main causes of death of residents in China. The incidence of the current tumors is high no matter in cities and towns or rural areas, wherein the first five tumors are as follows: lung cancer, gastric cancer, liver cancer, esophageal cancer, and colorectal cancer. With the increase of age, the morbidity and mortality of China gradually increase. Compared with the world, the Chinese cancer accounts for about 22 percent of the world, the standardized morbidity is 174/10 ten thousand, the world average level is 182.3/10 ten thousand, the Chinese cancer morbidity occupies 74 sites of the global morbidity, and the number of the morbidity is the first worldwide; chinese cancer deaths account for about 27% of the world, the normalized mortality rate is 122.2/10 ten thousand, the world average level is 102.4/10 ten thousand, and the Chinese cancer mortality rate is 29 in the world. At present, the incidence of cancer in China is on the rise, and the mortality is on the steady trend.

the complex pathogenesis of the tumor leads to difficult prevention of the tumor diseases. In China, the existing effective screening technology and early diagnosis technology are few, and the technical level is low, so that the time for discovering the tumor is generally late; meanwhile, the tumor treatment difficulty is higher due to poor curative effect, high recurrence and metastasis rate, large treatment side effect, poor accuracy and the like of the tumor treatment. With the development of economy and medicine, accurate medicine based on targeted therapy and accurate visual imaging provides a new idea and direction for cancer treatment.

Positron Emission Tomography (PET) is the best imaging equipment for monitoring the occurrence and development processes of tumors in living bodies at present, can realize high-resolution imaging of cell metabolism and functions, and carries out noninvasive, three-dimensional and dynamic research on physiological and biochemical processes of human bodies from a molecular level. PET examination relies on the specific metabolism and absorption of a broad-spectrum or specific targeted positron imaging agent in a target organ.

The common chemical intermediates of the polyethylene glycol di-p-toluenesulfonate or methanesulfonate compound play an important role in the fields of pharmaceutical chemistry, material chemistry and the like. Often play an important role in radiopharmaceutical chemistry as a marker "bridge" or water-soluble modifying group, e.g.¹⁸In the F-labeled PET probe, the probe was,¹⁸FC₂H₄OTs are commonly used as labelled intermediates [1.Mueller et. Synthesis of O- (2- [18F ]]fluoroethyl)-L-tyrosine based on a cartridge purification method.Nucl Med Biol.2011 Jul；38(5):653-8.doi: 10.1016/j.nucmedbio.2011.01.006.2.Prudner BC，etal.Amino Acid Uptake Measured by[18F]AFETP Increases in Response to Arginine Starvation in ASS1-DeficientSarcomas.Theranostics.2018 Mar 7；8(8):2107-2116.doi:10.7150/thno.22083.](ii) a Prepared from 1, 2-bis-methylphenoxyethane as precursor¹⁸F(C₂H₄)nC₂H₄N3 and¹⁸F(C₂H₄)nC₂C₄CCH (n ═ 0-9) is the most important mark intermediate in the mark of the click chemistry method [ Schiefferstein H, et. 18F-click labeling and registration evaluation of a new 18F-label for PET imaging. EJNMI Res.2013Sep 16; 3(1) 68.doi 10.1186/2191-219X-3-68.](ii) a Polyethylene glycol short chains are commonly used as modified fragments to increase the water solubility of probes [ Ashutosh Pal, et al, radiosynthesis and Initial In Vitro evolution [18F]F-PEG6-IPQA—A Novel PET Radiotracer for Imaging EGFR Expression-Activity in Lung Carcinoma.Mol Imaging Biol.2011 Oct；13(5):853-61.doi:10.1007/s11307-010-0408-8.]. Such chemical intermediates play an important role in the development of positron drugs.

Disclosure of Invention

The invention aims to provide a positron probe which can be used for broad-spectrum PET imaging of tumors and has clinical values of diagnosis and monitoring of treatment curative effects.

The positron probe of the invention is¹⁸An F-labeled positron probe having the structureThe formula is as follows:

Positron probe utilization of the invention¹⁸F, labeling short-chain polyethylene glycol di-p-toluenesulfonate or mesylate substances, and performing in-vivo and in-vitro evaluation to prove that the positron probe can well target tumors to perform PET imaging and is a novel efficient tumor PET imaging agent. The positron probe can be used for broad-spectrum targeted tumor imaging and has a huge application prospect as a broad-spectrum PET imaging agent for tumors.

The invention also aims to provide a preparation method of the positron probe.

The preparation method of the positron probe comprises the following steps: eluting with 1.5mL of eluent¹⁸Collecting eluate in QMA column, heating to 110 deg.C, continuously blowing high-purity nitrogen gas, and removing H by azeotropic distillation₂O; adding 1mL of mixed solution dissolved with 5mg of precursor into a reaction bottle, and reacting for 10-15min at 90-110 ℃; after cooling, the target product is obtained by semi-preparative High Performance Liquid Chromatography (HPLC) separation.

According to a further feature of the method for preparing a positron probe of the present invention, the precursor has a chemical structure of:

According to a further feature of the method for preparing a positron probe of the present invention, the solution for rinsing the QMA column comprises: 12.0mg of 4,7,13,16,21, 24-hexaoxy-1, 10-diazabicyclo [8.8.8 ]]Hexacosane was dissolved in 0.9mL acetonitrile, 3.0mgK₂CO₃Or 4.3mg KHCO₃Dissolve in 0.1mL of water.

preferably, the solvent used to dissolve the precursor is selected from: one or more of anhydrous acetonitrile, anhydrous dimethyl sulfoxide (DMSO) or anhydrous N, N-Dimethylformamide (DMF).

Preferably, the reaction temperature is 90 ℃ and the reaction time is 15 min.

according to a further feature of the method for preparing a positron probe of the present invention, the semi-preparative HPLC separation conditions are: and C-18 column, wherein the mobile phase comprises an A phase and a B phase, the A phase is aqueous solution, the B phase is acetonitrile, and the volume ratio of the A phase solution to the B phase solution is 3: 2, the total flow rate is 4 mL/min.

the preparation method of the positron probe is simple and rapid, can be automatically synthesized by a radioactive synthesis module, has high yield and high specific activity, and can meet the requirements of scientific research and clinical tests.

The invention also provides the application of the positron probe, in particular to the application of the positron probe in preparing a reagent for tumor PET imaging.

Drawings

FIG. 1 is a positron probe¹⁸FC₂H₄OC₂H₄OTs and reference Compound FC₂H₄OC₂H₄HPLC profile of OTs.

FIG. 2 is a positron probe¹⁸FC₂H₄OC₂H₄Results of in vitro stability experiments on OTs.

FIG. 3 is a drawing of example 3¹⁸FC₂H₄OC₂H₄OC₂H₄biodistribution of OTs in Balb/c mice.

FIG. 4 is a positron probe¹⁸FC₂H₄OC₂H₄OTs were visualized as PET/CT in the tumor-bearing murine A549 model.

Detailed Description

The present invention is further illustrated by the following experiments in conjunction with examples, which are provided for illustrative purposes only and do not limit the scope of the present invention.