Tumor hypoxic PET developer and precursor compound, application and preparation method thereof

Abstract

The invention relates to the technical field of tumor diagnosis, in particular to a tumor hypoxic PET developer as well as a precursor compound, application and a preparation method thereof. The precursor compound has a structure of any one of formulas I to III. The tumor hypoxia PET developer provided by the invention is used for diagnosing hypoxia tumors, and has the advantages of strong stability, good water solubility and high safety.

Description

Technical Field

[0001] The present invention relates to the technical field of tumor diagnosis, and in particular to a tumor hypoxia PET imaging agent and a precursor compound thereof, and an application and a preparation method thereof. Background Art

[0002] Hypoxia plays an important role in the progression of malignant tumors and anti-cancer treatment. Nuclear medicine imaging technology, especially PET, has unique advantages in imaging and quantitative evaluation of tumor hypoxia. Malignant tumors are one of the major diseases that seriously threaten human physical and mental health. Nearly 70% of malignant tumor patients require radiotherapy intervention during treatment, and tumor hypoxia is an important factor leading to radiotherapy resistance. How to accurately evaluate tumor hypoxia before and during radiotherapy in order to better optimize the tumor radiotherapy target dose and improve tumor hypoxia resistance has become a hot topic in current tumor research.

[0003] Positron emission tomography (PET), as a non-invasive examination method, has obvious advantages in the imaging of hypoxia and prognosis assessment of malignant tumors. Positron emission tomography (PET) is a functional imaging technology based on the molecular level. Its basic principle is that when the radioactive labeled molecular probe is injected into the body through intravenous injection, the positrons released by the nuclide collide with the free electrons. The PET instrument can obtain detailed physiological distribution and biochemical metabolism information about the radioactive probe in the body by detecting the gamma-ray photons generated in the "positron / electron annihilation" process, and obtain the in vivo imaging of the imaging agent through fusion and reconstruction. As a major breakthrough in modern nuclear medicine imaging diagnosis technology, it has the advantages of non-invasive, high-resolution, quantitative and dynamic observation of the metabolism and distribution of radionuclides in the body. It is often used in the diagnosis and treatment of diseases in different medical fields such as tumors, heart disease, and neurology.

[0004] One of the prerequisites for the application of PET technology is PET imaging drugs. With the widespread application of PET in clinical practice, the development of PET imaging agents has been promoted. PET positron imaging agents are mainly divided into tumor hypoxia imaging agents, metabolic imaging agents, receptor imaging agents, apoptosis imaging agents and inflammation imaging agents. The mechanism of tumor hypoxia provides an important basis for the diagnosis of tumors.

[0005] Tumor hypoxia is a hallmark of malignant tumors and an important feature of the tumor microenvironment. This is caused by an imbalance between oxygen delivery and consumption due to cell proliferation exceeding angiogenesis during tumor growth. Hypoxia leads to very low oxygen levels in tumors

[22] (<5 mmHg, compared to 40-60 mmHg in healthy tissue). PET is the most promising imaging technology for quantifying tumor hypoxia, but the types and quantities of its imaging agents need further research and development. Hypoxia mechanisms exist in almost all types of solid tumors. Tumor hypoxia imaging agents are used to detect and quantify the oxygen content in tumors, thereby evaluating the effectiveness of anti-tumor treatment for patients and determining the degree and extent of tumor hypoxia. This is of great significance for treatment prognosis and for selecting hypoxia-specific treatments for patients. Summary of the invention

[0006] In order to solve the above problems, the present invention provides a tumor hypoxia PET imaging agent and its precursor compound, application and preparation method. The tumor hypoxia PET imaging agent provided by the present invention is used for diagnosing hypoxic tumors and has the advantages of strong stability, good water solubility and high safety.

[0007] In order to achieve the above object, the present invention provides the following technical solutions:

[0008] The present invention provides a precursor compound of a tumor hypoxia PET imaging agent, wherein the precursor compound has a structure of any one of Formulas I to III:

[0009]

[0010] Wherein, R is a C1-8 alkyl group.

[0011] Preferably, the R is -(CH 2 ) n -, n = an integer from 1 to 4.

[0012] The present invention also provides the use of the precursor compound described in the above technical solution in the preparation of a reagent for diagnosing hypoxic tumors.

[0013] The present invention also provides a method for preparing a tumor hypoxia PET imaging agent, comprising the following steps:

[0014] 1) Reaction of 14N(p,α) and 11C to obtain [11C]CO 2 , the [11C]CO 2 Reduction to obtain [11C]CH 4 ;

[0015] 2) Reducing the [11C]CH 4 and I 2 Free radical reaction was carried out to obtain [11C]CH 3 I;

[0016] 3) Resuspending the [11C]CH 3 I and the precursor compound described in the above technical solution, K 2 CO 3 and dimethylformamide and reacted to obtain a reactant;

[0017] 4) Purifying the reactant obtained in step 3) to obtain a tumor hypoxia PET imaging agent.

[0018] Preferably, in step 1), the 14N(p,α) and 11C are reacted in a nitrogen environment containing 2.5% oxygen.

[0019] Preferably, the reduction in step 1) is carried out in a nickel / hydrogen environment at 350°C.

[0020] Preferably, the reaction conditions of step 3) include: temperature of 80° C. and reaction time of 5 min.

[0021] Preferably, the step 4) is purified by semi-preparative liquid phase and Waters Sep-Pak solid phase extraction column.

[0022] The present invention also provides a tumor hypoxia PET imaging agent prepared by the preparation method described in the above technical solution.

[0023] The present invention also provides the use of the tumor hypoxia PET imaging agent described in the above technical solution in the preparation of a drug for diagnosing hypoxic tumors.

[0024] The beneficial effects of the present invention are:

[0025] The tumor hypoxia PET imaging agent provided by the present invention is used for diagnosing hypoxic tumors, and has the advantages of strong stability, good water solubility and high safety. DETAILED DESCRIPTION

[0026] The present invention provides a precursor compound of a tumor hypoxia PET imaging agent, wherein the precursor compound has a structure of any one of Formulas I to III:

[0027]

[0028] Wherein, R is a C1-8 alkyl group.

[0029] In the present invention, the R is preferably -(CH 2 ) n -, n = an integer from 1 to 4.

[0030] The present invention also provides the use of the precursor compound described in the above technical solution in the preparation of a reagent for diagnosing hypoxic tumors.

[0031] The present invention also provides a method for preparing a tumor hypoxia PET imaging agent, comprising the following steps:

[0032] 1) Reaction of 14N(p,α) and 11C to obtain [11C]CO 2 , the [11C]CO 2 Reduction to obtain [11C]CH 4 ;

[0033] 2) Reducing the [11C]CH 4 and I 2 Free radical reaction was carried out to obtain [11C]CH 3 I;

[0034] 3) Resuspending the [11C]CH 3 I and the precursor compound according to claim 1 or 2, K 2 CO 3 and dimethylformamide and reacted to obtain a reactant;

[0035] 4) Purifying the reactant obtained in step 3) to obtain a tumor hypoxia PET imaging agent.

[0036] The present invention obtains [11C]CO by reacting 14N(p,α) with 11C. 2 , the [11C]CO 2 Reduction to obtain [11C]CH 4 In the present invention, the 14N(p, α) and 11C are preferably reacted in a nitrogen environment containing 2.5% oxygen. In the present invention, the reduction is preferably carried out in a nickel / hydrogen environment at 350°C.

[0037] The present invention obtains [11C]CH 4 and I 2 Free radical reaction was carried out to obtain [11C]CH 3 I.

[0038] The present invention obtains [11C]CH 3 I and the precursor compound described in the above technical solution, K 2 CO 3 and dimethylformamide to react to obtain a reactant. In the present invention, the reaction conditions preferably include: a temperature of 80° C. and a reaction time of 5 minutes.

[0039] The present invention purifies the obtained reactant to obtain a tumor hypoxia PET imaging agent. The present invention preferably purifies the reactant by semi-preparative liquid phase and Waters Sep-Pak solid phase extraction column.

[0040] In the present invention, the synthesis route of the tumor hypoxia PET imaging agent is as follows:

[0041]

[0042] The present invention also provides a tumor hypoxia PET imaging agent prepared by the preparation method described in the above technical solution.

[0043] The present invention also provides the use of the tumor hypoxia PET imaging agent described in the above technical solution in the preparation of a drug for diagnosing hypoxic tumors.

[0044] In order to further illustrate the present invention, the present invention is described in detail below in conjunction with embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0045] Example 1

[0046] First, [11C]CO2 was obtained by the reaction of 14N(p,α) and 11C in a TRACER lab FX-MeI synthesizer of General Electric Company in a nitrogen environment containing 2.5% oxygen by 11MeV protons (Siemens Eclipse cyclotron). Then, [11C]CO2 was reduced to [11C]CH4 in a nickel / hydrogen environment at 350°C, and finally [11C]CH3I was further obtained by free radical reaction in an oven containing I2.

[0047] The 11C-labeled radioligand was prepared by a standard methylation method under base-catalyzed conditions. First, the chemical precursor, K2CO3 and DMF were added to the reaction flask, and then the prepared [11C]CH3I was introduced. The reaction was allowed to react at 80°C for 5 minutes, and the reaction was completed. After cooling for one minute, water was added to quench the reaction, and the reaction solution was separated and purified by semi-preparative liquid phase. The radioactive product was collected in a flask and diluted with water. The final product was passed through a Waters Sep-Pak solid phase extraction column, then rinsed with water, eluted with ethanol, and diluted with saline for subsequent in vivo experiments.

[0048] Identification method: The product was identified by co-injection method.

[0049] The mice were anesthetized by inhalation with 2L / min medical oxygen as carrier, and the isoflurane content in oxygen was 3%. The scanning period was maintained under the condition of 2% isoflurane in oxygen. The mice were fixed in the center of the examination bed of the Triumph TrimodalityPET / CT scanner, prone position, and stretched limbs. The synthesized radioactive compound was injected through the tail vein and data collection began.

[0050] Experimental results: Through image analysis, it was found that the tumor hypoxia tracer accumulated in the tumor site, and its biological distribution could be analyzed.

[0051] Although the above embodiment describes the present invention in detail, it is only a part of the embodiments of the present invention, not all of the embodiments. People can also obtain other embodiments based on this embodiment without creativity, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A precursor compound of a tumor hypoxia PET imaging agent, characterized in that: The precursor compound has a structure of any one of Formula I to Formula III: Wherein, R is a C1-8 alkyl group.

2. The precursor compound according to claim 1, characterized in that The R is -(CH2) n -, n = an integer from 1 to 4.

3. Use of the precursor compound according to claim 1 in the preparation of a reagent for diagnosing hypoxic tumors.

4. A method for preparing a tumor hypoxia PET imaging agent, characterized in that: The following steps are involved: 1) reacting 14N(p,α) and 11C to obtain [11C]CO2, and reducing the [11C]CO2 to obtain [11C]CH4; 2) subjecting the [11C]CH4 obtained in step 1) to a free radical reaction with I2 to obtain [11C]CH3I; 3) mixing the [11C]CH3I obtained in step 2) with the precursor compound according to claim 1 or 2, K2CO3 and dimethylformamide, and reacting the mixture to obtain a reactant; 4) Purifying the reactant obtained in step 3) to obtain a tumor hypoxia PET imaging agent.

5. The preparation method according to claim 4, characterized in that: In the step 1), the 14N(p,α) and 11C are reacted in a nitrogen environment containing 2.5% oxygen.

6. The preparation method according to claim 4, characterized in that: The step 1) is carried out in a nickel / hydrogen environment at 350°C for reduction.

7. The preparation method according to claim 4, characterized in that: The reaction conditions of step 3) include: temperature of 80° C. and reaction time of 5 min.

8. The preparation method according to claim 4, characterized in that: The step 4) is purified by semi-preparative liquid phase and Waters Sep-Pak solid phase extraction column.

9. A tumor hypoxia PET imaging agent prepared by the preparation method according to any one of claims 4 to 8.

10. Use of the tumor hypoxia PET imaging agent according to claim 9 in the preparation of drugs for diagnosing hypoxic tumors.

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