CN118126114A - Sigma2 ligand and preparation method and application thereof - Google Patents

Sigma2 ligand and preparation method and application thereof Download PDF

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Publication number
CN118126114A
CN118126114A CN202410127294.8A CN202410127294A CN118126114A CN 118126114 A CN118126114 A CN 118126114A CN 202410127294 A CN202410127294 A CN 202410127294A CN 118126114 A CN118126114 A CN 118126114A
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sigma2
ligand
receptor
targeting
sigma
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叶佳俊
汪静
康飞
杨卫东
张明如
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Air Force Medical University of PLA
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Air Force Medical University of PLA
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Abstract

The invention relates to a Sigma2 ligand and a preparation method and application thereof. The existing Sigma2 receptor targeting probe has the problems of low specificity, high fat solubility and complex labeling. The invention provides a Sigma2 ligand which is formed by connecting a Sigma2 receptor targeting group and a bifunctional chelating agent through glycine with different lengths, and provides a radiolabeled complex which is obtained by labeling the Sigma2 ligand through a radionuclide and is used for targeting the Sigma2 receptor, and the radiolabeled complex is used for preparing human or animal tumor radiodiagnostic probes. The invention can be used as a tumor positron tracer agent, has proper physicochemical and radiological properties and ideal biological characteristics, can be used for PET imaging of tumors, is beneficial to specific diagnosis and curative effect evaluation of the tumors, and has the advantages of high specificity, low fat solubility and simple and convenient labeling.

Description

Sigma2 ligand and preparation method and application thereof
Technical Field
The invention relates to the technical field of clinical nuclear medicine, in particular to a Sigma2 ligand and a preparation method and application thereof.
Background
Sigma2 receptor plays a very important role in tumor biology, especially in cell survival, morphological changes and regulation of differentiation functions. Unlike PCNA, TK-1, DNA polyploid, which is highly expressed only in S phase, sigma2 receptor is highly expressed throughout the proliferation phase of tumor cells and at a density 10 times that of resting tumor cells, while surrounding normal cells have a lower density of Sigma2 receptor. In addition, using Sigma2 receptor fluorescent ligands, sigma2 receptor expression in many stem cell lines, including bone marrow stem cells, embryonic stem cells, hematopoietic stem cells, and amniotic fluid stem cells, was evaluated, and the fluorescence intensity was found to be significantly higher in differentiated stem cells than in normal stem cells. These results demonstrate that Sigma2 receptor is a biomarker for tumor cell proliferation, and that Sigma2 receptor can be used as a biological target for tumor imaging.
The existing Sigma2 receptor PET targeting probe has the defects. First, the Sigma2 receptor probe has a similar structure to the Sigma1 receptor probe, and the Sigma1 receptor is often highly expressed in tumor cells, and the Sigma2 receptor probe is easy to have high affinity with receptors such as acetylcholine vesicle transporter (VAChT) and the like, so that the specific imaging is influenced. For example, [ 18 F ] ISO-1 is the only Sigma2 receptor radioactive probe currently entering clinical research, can better identify the proliferation state of tumors, is consistent with the detection result of Ki-67, but has lower selectivity to limit the promotion in clinic. Secondly, most Sigma2 receptor probes have higher lipid solubility, so that liver and intestine uptake is increased, the tumor-meat ratio and the tumor-blood ratio are lower, the imaging effect is greatly influenced, and the Sigma2 receptor probes are another important factor for limiting clinical promotion. Meanwhile, the existing Sigma2 receptor probe has the defects of complicated labeling process and low labeling rate, and greatly limits the clinical application.
Therefore, there is a need to design new Sigma2 receptor targeting probes that overcome the above-mentioned drawbacks.
Disclosure of Invention
The invention aims to provide a Sigma2 ligand and a preparation method and application thereof, so as to solve the problems of low specificity, high fat solubility and complex labeling of the existing Sigma2 receptor targeting probe.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
sigma2 ligand, the Sigma2 ligand is formed by linking a Sigma2 receptor targeting group and a bifunctional chelating agent through glycine of different lengths.
Further, the Sigma2 receptor targeting group consists of 6, 7-dimethoxy-1, 2,3, 4-tetrahydroisoquinoline and naphthol linked by a pentane chain;
The difunctional chelating agent is 1,4,7, 10-tetraazacyclododecane-1, 4,7, 10-tetraacetic acid or 1,4, 7-triazacyclononane-1, 4, 7-triacetic acid;
the Sigma2 ligand had the structure:
Wherein:
n=0, 1 or 2;
m=0 or 1.
In another aspect, there is provided a method of preparing a Sigma2 ligand as described, the method comprising:
In another aspect, a radiolabeled complex targeting Sigma2 receptor is provided, said radiolabeled complex targeting Sigma2 receptor being obtained from said Sigma2 ligand by radionuclide labeling.
Further, the radionuclide is selected from 18F、68Ga、64 Cu.
Further, the structure of the radiolabeled complex targeting Sigma2 receptor is:
Or the radiolabeled complex targeting the Sigma2 receptor has the structure:
Or the radiolabeled complex targeting the Sigma2 receptor has the structure:
In another aspect, a radiolabeled complex injection is provided, comprising the radiolabeled complex targeting the Sigma2 receptor.
In another aspect, there is provided the use of a radiolabeled complex targeting the Sigma2 receptor as described in the preparation of a human or animal tumour radiodiagnostic probe.
Compared with the prior art, the invention has the following beneficial effects:
The invention provides a Sigma2 ligand, a preparation method and application thereof, wherein the Sigma2 ligand is labeled with radionuclide through a bifunctional chelating agent, and a PET molecular image probe is constructed and used as a tumor positron tracer, and experiments show that the ligand has proper physicochemical and radiological properties and ideal biological properties, can be used for PET imaging of tumors, and is beneficial to tumor specificity diagnosis and curative effect evaluation.
Compared with the existing Sigma2 receptor targeting radioactive probe, the invention constructs the Sigma2 receptor targeting probe with high specificity, low fat solubility and simple labeling. The invention selects the bifunctional chelating agent to carry out radionuclide labeling by a coordination method, has simple labeling process and high labeling rate, and is greatly convenient for clinical application. The metal chelating group is introduced into the micromolecular probe, so that the fat solubility of the probe can be greatly reduced, and simultaneously, the fat solubility of the probe can be conveniently regulated by modifying the connecting chain between the micromolecule and the chelating group, so that the method is beneficial to clinical application.
Drawings
In order to more clearly illustrate the embodiments of the invention or the technical solutions in the prior art, the drawings that are required in the embodiments or the description of the prior art will be briefly described, it being obvious that the drawings in the following description are only some embodiments of the invention, and that other embodiments of the drawings can be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 shows the chemical purity HPLC identification of Sigma2 ligand prepared in example 1. A is DOTA-SIGMA-1, B is DOTA-SIGMA-2, and C is DOTA-SIGMA-3.
FIG. 2 is the MS identification of Sigma2 ligand prepared in example 1. A is DOTA-SIGMA-1, B is DOTA-SIGMA-2, and C is DOTA-SIGMA-3.
FIG. 3 shows the result of identifying the radiochemical purity of 68 Ga-labeled probe prepared in example 2. A is 68 Ga-DOTA-SIGMA-1, B is 68 Ga-DOTA-SIGMA-2, and C is 68 Ga-DOTA-SIGMA-3.
FIG. 4 shows the results of in vitro stability HPLC identification of 68 Ga-labeled probes prepared in example 2.
FIG. 5 shows the result of the fat solubility measurement of 68 Ga-labeled probe prepared in example 2.
FIG. 6 shows the results of uptake and inhibition experiments of 68 Ga-DOTA-SIGMA-3 prepared in example 2 in different cells.
FIG. 7 shows the results of the 68 Ga-DOTA-SIGMA-3 distribution (A) and inhibition (B) experiments in C6 cell tumor-bearing mice prepared in example 2.
FIG. 8 shows the result of micro-PET imaging of 68 Ga-DOTA-SIGMA-3 prepared in example 2 in C6 cell tumor-bearing mice.
FIG. 9 shows the results of micro-PET imaging of 68 Ga-DOTA-SIGMA-3 and 18 F-FDG prepared in example 2 in an inflammation model.
Detailed Description
In order that the invention may be readily understood, a more complete description of the invention will be rendered by reference to the appended drawings. The drawings illustrate preferred embodiments of the invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
It should be noted that like reference numerals and letters refer to like items, and thus once an item is defined in one embodiment, no further definition or explanation thereof is necessary in subsequent embodiments. The particular implementation is described in terms of steps in some embodiments for clarity and accuracy of presentation and should not be construed as limiting the sequence. In addition, in the examples, the chemical used in the steps is an existing material or a commercially available product.
Positron emission computed tomography (Positron Emission Computed Tomography, PET) is a clinical examination imaging technique in the field of nuclear medicine, and involves markers in the examination process, and after the markers are injected into a human body, the situation of life metabolism activity is reflected by the accumulation of the markers in metabolism, so that the purpose of diagnosis is achieved. The coupling design method can greatly retain the biological activity of the small molecular probe on the target receptor, and the introduction of the metal chelating group into the small molecular probe can greatly reduce the fat solubility of the probe, and simultaneously, the modification of the connecting chain between the small molecule and the chelating group is also convenient for regulating the fat solubility of the probe. There is no report of labeling of positron radionuclides by a bifunctional chelator for Sigma2 ligands.
The invention constructs a ligand structure with high affinity and high selection to the Sigma2 receptor, and further carries out structural modification through a coupling design method, so as to prepare the radioactive complex with clinical application potential for targeting the Sigma2 receptor, thereby providing an alternative scheme for noninvasive accurate diagnosis of tumors.
The invention provides a Sigma2 ligand, which is formed by connecting a Sigma2 receptor targeting group and a bifunctional chelating agent through glycine with different lengths.
Sigma2 receptor targeting group consists of 6, 7-dimethoxy-1, 2,3, 4-tetrahydroisoquinoline and naphthol linked by pentane chain;
the bifunctional chelating agent is 1,4,7, 10-tetraazacyclododecane-1, 4,7, 10-tetraacetic acid (DOTA) or 1,4, 7-triazacyclononane-1, 4, 7-triacetic acid (NOTA);
the Sigma2 ligand had the structure:
Wherein:
n=0, 1 or 2;
m=0 or 1.
The synthetic route for the Sigma2 ligand described above was:
NOTA-SIGMA-1：n＝0，m＝0；
NOTA-SIGMA-2：n＝1，m＝0；
NOTA-SIGMA-3：n＝2，m＝0；
DOTA-SIGMA-1：n＝0，m＝1；
DOTA-SIGMA-2：n＝1，m＝1；
DOTA-SIGMA-3：n＝2，m＝1。
In another aspect, the present invention also provides a radiolabeled complex targeting Sigma2 receptor, which is obtained by labeling the Sigma2 ligand with a radionuclide. The radionuclide is selected from 18F、68Ga、64 Cu, preferably 18F、68 Ga.
In another aspect, the invention also provides a radiolabeled complex injection comprising a radiolabeled complex targeting Sigma2 receptor as described above.
The radiolabeled complex injection can be obtained by a wet labelling method of 68 Ga, and specifically comprises the following steps: dissolving Sigma2 ligand in a small amount of dimethyl sulfoxide, adding a proper amount of sodium acetate solution or other buffer solution, adding a fresh and leached 68GaCl3 hydrochloric acid solution into the solution, sealing the solution for reaction at 100 ℃ for 10min, diluting the reaction solution with water for injection, separating and purifying the reaction solution by a C18 reversed phase solid phase extraction column, and flushing the extraction column with the buffer solution or water for injection; and eluting the adsorbate on the C18 reversed-phase solid-phase extraction column by using ethanol and water for injection, and filtering by using a sterilizing filter to obtain the injection containing the 68 Ga-marked complex.
When m=0, the structure is as follows:
Where n=0, 1 or 2.
When m=1, the structure is as follows:
Where n=0, 1 or 2.
The radiolabeled complex injection can also be prepared by a 18 F wet labeling method, which is specifically as follows:
dissolving Sigma2 ligand (m=0) in a small amount of dimethyl sulfoxide, adding a proper amount of sodium acetate solution or other buffer solution, adding aluminum chloride and freshly prepared 18 F ion aqueous solution, sealing, reacting for 20min at 120 ℃, and cooling; diluting the reaction solution with water for injection, separating and purifying by a C18 reversed phase solid phase extraction column, and flushing the extraction column with a buffer solution or water for injection; and eluting the adsorbate on the C18 reversed-phase solid-phase extraction column by using ethanol and water for injection, and filtering by using a sterilizing filter to obtain the injection containing the 18 F-labeled complex.
The structure is as follows:
the radiolabeled complexes targeting the Sigma2 receptor can be used to prepare human or animal tumor radiodiagnostic probes.
In the wet labeling method, the buffer solution is a substance for stabilizing the pH of the reaction solution, and may be any one or a mixture of more than two of acetate, lactate, tartrate, malate, maleate, succinate, ascorbate, carbonate and phosphate.
Example 1: preparation of Sigma2 ligand
The synthetic route for Sigma2 ligand was:
DOTA-SIGMA-1：n＝0，m＝1；
DOTA-SIGMA-2：n＝1，m＝1；
DOTA-SIGMA-3：n＝2，m＝1。
The reaction reagent and conditions are specifically as follows ：(a)(Boc)2O,acetone,Et3N;(b)1,5-dibromopentane,acetonitrile,K2CO3,KI,90℃;(c)6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline,acetonitrile,K2CO3,KI,90℃;(d)CH2Cl2,TFA;(e)Gly-Boc or Gly2-Boc,CH2Cl2,HATU,Et3N;(f)CH2Cl2,TFA;(g)(i):CH2Cl2,NHS-NOTA-Boc;(ii)TFA.
The specific preparation process comprises the following steps:
(a) Compound 1 and (Boc) 2 O were dissolved in acetone at a ratio of 1:1.2 and reacted at room temperature for 4h under the action of 5eq. The reaction solution was dried under reduced pressure and purified by high performance liquid chromatography using a preparative column (Bondysil C18, 18 10nm 10um,250*30nm) under the following conditions: binary gradient elution with a mobile phase of 50% acetonitrile and 50% water (0.1% tfa). Lyophilizing to obtain compound 2;
(b) The compound 2 obtained in (a) and 1,5-dibromopentane are dissolved in acetonitrile according to the ratio of 1:1.2, and reacted for 2 hours at 90 ℃ under the action of 3eq. Potassium carbonate and trace potassium iodide. The reaction solution was dried under reduced pressure and purified by high performance liquid chromatography using a preparative column (Bondysil C18, 18 10nm 10um,250*30nm) under the following conditions: binary gradient elution with a mobile phase of 50% acetonitrile and 50% water (0.1% tfa). Lyophilizing to obtain compound 3;
(c) The compound 3 obtained in (b) and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline are dissolved in acetonitrile according to the ratio of 1:1, and reacted for 2 hours at 90 ℃ under the action of 3eq. Potassium carbonate and trace potassium iodide. The reaction solution was dried under reduced pressure and purified by high performance liquid chromatography using a preparative column (Bondysil C, 10nm10um,250 x 30 nm) under the following conditions: binary gradient elution with a mobile phase of 50% acetonitrile and 50% water (0.1% tfa). Lyophilizing to obtain compound 4;
(d) The compound 4 obtained in the step (c) is dissolved in dichloromethane and reacted for 1h at room temperature under the action of trifluoroacetic acid. The reaction solution was dried under reduced pressure and purified by high performance liquid chromatography using a preparative column (Bondysil C1810nm 10um,250 x 30 nm) under the following conditions: binary gradient elution with a mobile phase of 50% acetonitrile and 50% water (0.1% tfa). Lyophilizing to obtain compound 5;
(e) The compound 5 obtained in (d) was dissolved in methylene chloride in a ratio of 1:1.2 with Gly-Boc or Gly 2 -Boc, and reacted at room temperature for 4h under the action of 3eq. Triethylamine and 1eq. HATU. The reaction solution was dried under reduced pressure and purified by high performance liquid chromatography using a preparative column (Bondysil C18, 18 10nm 10um,250*30nm) under the following conditions: binary gradient elution with a mobile phase of 50% acetonitrile and 50% water (0.1% tfa). Lyophilizing to obtain compound 6;
(f) The compound 6 obtained in the step (e) is dissolved in dichloromethane and reacted for 1h at room temperature under the action of trifluoroacetic acid. The reaction solution was dried under reduced pressure and purified by high performance liquid chromatography using a preparative column (Bondysil C1810nm 10um,250 x 30 nm) under the following conditions: binary gradient elution with a mobile phase of 50% acetonitrile and 50% water (0.1% tfa). Lyophilizing to obtain compound 7;
(g) The compound 5 or 7 obtained in (d) or (f) and NHS-DOTA-Boc or NHS-NOTA-Boc are dissolved in methylene chloride according to the ratio of 1:1, and are reacted for 4 hours at room temperature, and then trifluoroacetic acid is added for further reaction for 1 hour. The reaction solution was dried under reduced pressure and purified by high performance liquid chromatography using a preparative column (Bondysil C18, 18 10nm 10um,250*30nm) under the following conditions: binary gradient elution with a mobile phase of 50% acetonitrile and 50% water (0.1% tfa). The white solid target compound DOTA-SIGMA-1/2/3 is obtained after freeze drying.
The chemical purity of DOTA-SIGMA-1/2/3 is respectively as follows by high performance liquid chromatography identification (figure 1): 99.32%, 99.84%, 97.14%, provided that: binary gradient elution, initial B phase concentration of 20%, 40% by 20 min, mobile phase a water (0.1% tfa) and acetonitrile (0.1% tfa). Mass spectrometry (fig. 2) identified that compound DOTA-SIGMA-1 [ M/2+H ] + was 404.5, calculated (M/z) as 806.4; the [ M/2+H ] + of the compound DOTA-SIGMA-2 was 432.9 and the calculated value (M/z) was 863.4; the [ M/2+H ] + of the compound DOTA-SIGMA-3 was 461.4 and the calculated value (M/z) was 920.5.
Example 2: preparation 68 Ga-DOTA-SIGMA-1/2/3
68 The Ga-DOTA-SIGMA-1/2/3 wet labeling method is as follows:
20 micrograms of DOTA-SIGMA-1 or DOTA-SIGMA-2 or DOTA-SIGMA-3 prepared in example 1 was dissolved in 40 microliters of dimethyl sulfoxide, approximately 18.5 to 1850 megabellum (MBq) 68GaCl3 hydrochloric acid solution (eluted from a gallium germanium generator) was added, then 0.25mol/L sodium acetate solution was added to adjust the pH to 3.0 to 4.0, and the mixture was allowed to react at 100℃for 10 minutes.
A C18 reverse phase solid phase extraction column was slowly rinsed with 5mL absolute ethanol and 10mL water for injection in sequence. Cooling to room temperature after the reaction is finished, diluting the reaction solution with 5mL of water for injection, loading the diluted reaction solution onto a C18 reversed-phase solid-phase extraction column, flushing a purification column with 5mL of water for injection, eluting adsorbate on the C18 reversed-phase solid-phase extraction column with 1.0mL of 60% ethanol and 6.0mL of water for injection in sequence, and filtering the eluted adsorbate by a sterilizing filter to obtain the injection containing 68 Ga-DOTA-SIGMA-1 or 68 Ga-DOTA-SIGMA-2 or 68 Ga-DOTA-SIGMA-3. The uncorrected mark rates were respectively: 62.3±6.8% (n=5), 55.7±8.1% (n=5) and 60.0±9.8% (n=5).
Example 3:
the following is a description of the performance of the radioactive 68 Ga-labeled probe prepared in example 2, which is given below:
1. Radio-HPLC radiochemical purity identification
Identification conditions: binary gradient elution, initial B phase concentration 5%, increasing from 5 minutes to 12 minutes to 65%, and continuing for 20 minutes, mobile phase a was water (0.1% tfa) and B was acetonitrile (0.1% tfa).
The radiochemical purity is higher than 98% by identification, and is higher than the stipulated standard (Chinese pharmacopoeia 2020 edition, two parts) for 18 F-deoxyglucose radiochemical purity of more than 90% in pharmacopoeia. The results are shown in FIG. 3.
2. Inspection of
The pH value is 4.0-7.0 (Chinese pharmacopoeia 2020 edition, two parts, appendix VI H). Bacterial endotoxin detection: taking a proper amount of the product (namely 68 Ga marked probe solution which can be used for injection after filtering by a sterilizing filter), diluting the product with water for bacterial endotoxin detection by 60 times, and detecting according to a standard method (Chinese pharmacopoeia 2020 edition, two parts, annex XI E), wherein the endotoxin content of the product per 1mL is less than 15EU. Sterile inspection: and detecting a proper amount of the product according to a standard method (Chinese pharmacopoeia 2020 edition, two parts and annex XI H), wherein the product meets the requirements.
3. Radioactivity concentration: accurately measuring a certain volume of the product, placing the product in an activity meter to measure the activity, and calculating the radioactive concentration according to the volume of the sample and the activity thereof. The radioactive concentration of the product is 1.50-150MBq/mL.
4. Validity period: and calculating 3h from the calibration time. The in vitro stability experiment shows that the stability of the probe is higher than 98% after incubation for 3 hours in physiological saline and mouse serum, which indicates that the probe has high in vitro stability. (FIG. 4)
5. Fat-solubility: the 68Ga-DOTA-SIGMA-1、68 Ga-DOTA-SIGMA-2 and 68 Ga-DOTA-SIGMA-3 have lipid solubility log D of-1.21+ -0.20, -1.35+ -0.18, -1.36+ -0.20 respectively. (FIG. 5)
6. 68 Experiments on uptake and inhibition of Ga-DOTA-SIGMA-3 in different cells
68 Ga-DOTA-SIGMA-3 injection solution prepared as in example 2. U87, F98 and C6 were seeded into 24-well plates 10 5 cells/well one day in advance. The medium was removed and washed twice with pre-chilled PBS. mu.L of serum-free medium containing 37KBq of Compound 2 was added to each well and incubated at 37℃for 15, 30, 60, 120min, respectively. At each time point, the medium was removed, washed twice with pre-chilled PBS, and cells were lysed by adding 0.2mL of 0.1M NaOH, and the cells from each well were collected for gamma counting. The experimental results show (FIG. 6) that 68 Ga-DOTA-SIGMA-3 has high uptake in all three cells, 3.19.+ -. 0.11,4.06.+ -. 0.10 and 3.38.+ -. 0.24 at 60min, respectively. Meanwhile, sigma2 receptor inhibitors ISO-1, halopoeridol and CM398 can inhibit 68 Ga-DOTA-SIGMA-3 uptake, and the inhibition rate is about 70%.
(FIG. 6)
The cell experiment shows that 68 Ga-DOTA-SIGMA-3 can specifically target Sigma2 receptor, can be used for evaluating the expression quantity of Sigma2 receptor, and has potential application in nuclide diagnosis of tumor.
7. 68 Ga-DOTA-SIGMA-3 in vivo distribution and inhibition experiments in C6 cell tumor-bearing mice
C6 cell tumor-bearing mice (n=5) were injected by tail vein with 68 Ga-DOTA-SIGMA-3 (0.1 mL, about 300 kBq) in physiological saline (containing 7% ethanol). The decapitation was sacrificed after 30 and 60min of anesthesia at the injection, respectively. Organs such as tumor, blood, whole brain, heart, liver, spleen, lung, kidney, small intestine, stomach, meat and bone were weighed and their radioactivity Counts (CPM) were measured using a gamma-counter. The percent radioactivity in each organ is expressed as percent radioactivity per gram of organ (% ID/g) and the tail count is measured for data correction. As shown in FIG. 7, 68 Ga-DOTA-SIGMA-3 has high uptake in tumor, and is 1.98+ -0.16 and 1.35+ -0.04% ID/g at 30 and 60min, respectively; the muscle uptake was low, 0.54.+ -. 0.15% ID/g and 0.34.+ -. 0.01% ID/g, and the tumor to muscle uptake ratios were 3.7 and 4.0, respectively, indicating 68 Ga-DOTA-SIGMA-3 was useful for tumor imaging.
The inhibition group was injected by tail vein with 68 Ga-DOTA-SIGMA-3 (0.1 mL, about 300 KBq) in normal saline (7% ethanol) with Sigma2 inhibitors (ISO-1, halopiridol and CM 398). The result shows that 68 Ga-DOTA-SIGMA-3 has obviously reduced tumor uptake, the inhibition rate is about 70 percent, and is similar to the result of a cell inhibition experiment, which shows that 68 Ga-DOTA-SIGMA-3 is a Sigma2 receptor specific targeting probe.
8. 68 Ga-DOTA-SIGMA-3 micro-PET imaging of C6 cell tumor-bearing mice
C6 cell tumor-bearing mice were injected by tail vein with 68 Ga-DOTA-SIGMA-3 (0.1 mL, about 10 MBq) in normal saline (7% ethanol). Dynamic imaging was performed using micro-PET after injection. The results in FIG. 8 show that 68 Ga-DOTA-SIGMA-3 can image tumors. Compared with the existing Sigma2 receptor targeting probe, the 68 Ga-DOTA-SIGMA-3 metabolism speed is obviously enhanced, and the diagnosis of abdominal tumors by the probe is facilitated mainly through kidney metabolism.
9. 68 Ga-DOTA-SIGMA-3 in micro-PET imaging of inflammation model
The identification of inflammation and tumors is one of the key points that tumor targeting probes need to elucidate. An acute inflammation model is constructed by injecting turpentine into the right hind limb of a mouse, and micro-PET imaging is carried out by using a probe 18 F-FDG and a Sigma2 receptor targeting probe 68 Ga-DOTA-SIGMA-3 which can simultaneously image tumors and inflammations. The results of FIG. 9 show that the result of constructing the inflammation model shows that 18 F-FDG can image the inflammation part, and meanwhile 68 Ga-DOTA-SIGMA-3 does not image the part, so that 68 Ga-DOTA-SIGMA-3 does not image the inflammation, is beneficial to the identification of the inflammation and the tumor and the diagnosis of clinical patients.
The radiolabeled complex provided by the invention can be used as a radioactive diagnosis probe for tumor diagnosis, has proper physicochemical and radiological properties, has ideal biological characteristics, particularly has remarkable improvement on fat solubility, and has important significance in clinical diagnosis.
The foregoing description of the invention has been presented for purposes of illustration and description, and is not intended to be limiting. Several simple deductions, modifications or substitutions may also be made by a person skilled in the art to which the invention pertains, based on the idea of the invention.

Claims (10)

  1. Sigma2 ligand characterized by:
    The Sigma2 ligand is formed by connecting a Sigma2 receptor targeting group and a bifunctional chelating agent through glycine with different lengths.
  2. 2. The Sigma2 ligand of claim 1, wherein:
    The Sigma2 receptor targeting group is formed by connecting 6, 7-dimethoxy-1, 2,3, 4-tetrahydroisoquinoline and naphthol through a pentane chain;
    The difunctional chelating agent is 1,4,7, 10-tetraazacyclododecane-1, 4,7, 10-tetraacetic acid or 1,4, 7-triazacyclononane-1, 4, 7-triacetic acid;
    the Sigma2 ligand had the structure:
    Wherein:
    n=0, 1 or 2;
    m=0 or 1.
  3. 3. The method of preparing Sigma2 ligand of claim 1, wherein:
    The method comprises the following steps:
  4. 4. a radiolabeled complex targeting Sigma2 receptor, characterized in that:
    The radiolabeled complex targeting Sigma2 receptor is obtained from the Sigma2 ligand of claim 2 by radionuclide labeling.
  5. 5. The radiolabeled complex targeting Sigma2 receptor according to claim 4, wherein:
    The radionuclide is selected from 18F、68Ga、64 Cu.
  6. 6. The radiolabeled complex targeting Sigma2 receptor according to claim 4, wherein:
    the structure of the radiolabeled complex targeting Sigma2 receptor is:
  7. 7. The radiolabeled complex targeting Sigma2 receptor according to claim 4, wherein:
    the structure of the radiolabeled complex targeting Sigma2 receptor is:
  8. 8. the radiolabeled complex targeting Sigma2 receptor according to claim 4, wherein:
    the structure of the radiolabeled complex targeting Sigma2 receptor is:
  9. 9. the radiolabeled complex injection is characterized in that:
    the radiolabeled complex injection comprising a radiolabeled complex targeting the Sigma2 receptor according to claim 4.
  10. 10. Use of a radiolabeled complex targeting Sigma2 receptor according to claim 4 for the preparation of a human or animal tumour radiodiagnostic probe.
CN202410127294.8A 2024-01-30 Sigma2 ligand and preparation method and application thereof Pending CN118126114A (en)

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