CN110743017A - Radiopharmaceutical targeting galectin-1 and preparation method thereof - Google Patents

Radiopharmaceutical targeting galectin-1 and preparation method thereof Download PDF

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CN110743017A
CN110743017A CN201911004744.XA CN201911004744A CN110743017A CN 110743017 A CN110743017 A CN 110743017A CN 201911004744 A CN201911004744 A CN 201911004744A CN 110743017 A CN110743017 A CN 110743017A
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刘昭飞
王凡
赖建豪
卢德华
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Abstract

The invention discloses a targeted galectin-1 radiopharmaceutical and a preparation method thereof, the radiopharmaceutical is a conjugate of a radionuclide, a bifunctional chelating agent and PEG4-TDGd, and the radionuclide is labeled with PEG4-TDGd through the bifunctional chelating agent. The radioactive drug delivers the radioactive nuclide to the surface of tumor cells or tumor hypoxia parts of high expression galectin-1 in vivo through the specific recognition of TDGd to galectin-1 and the modification of PEG4 to pharmacokinetics, thereby realizing the specific nuclear medicine positron emission computed tomography of tumors and tumor hypoxia areas and the monitoring of the curative effect of interventional therapy means such as tumor radiotherapy and the like.

Description

Radiopharmaceutical targeting galectin-1 and preparation method thereof
Technical Field
The invention relates to the technical field of radiopharmaceuticals for imaging and diagnosing diseases, in particular to a novel micromolecular radiopharmaceutical for nuclear medicine Positron Emission Tomography (PET) imaging and diagnosis of tumor hypoxia and a preparation method thereof.
Background
Radiotherapy is an important treatment means for various malignant tumors clinically at present. Radiotherapy is commonly applied worldwide for the treatment of 50% to 60% of patients with tumors. Radiotherapy has good curative effect in early and middle stage tumors, but obvious tolerance phenomenon can be observed in stage IV tumors and the like. Radiotherapeutic tolerance impairs the effectiveness of radiotherapy in treatment, leading to a poor prognosis of treatment failure, recurrence, etc. There is now ample evidence that radiotherapy tolerance is closely related to tumor hypoxia. In hypoxic tumors, about three times the radiation dose is required to achieve the therapeutic effect of normal oxygen level tumor tissue. Therefore, the hypoxia level is an important index for predicting the curative effect of radiotherapy. In view of the key role of tumor hypoxia in radiotherapy tolerance, if tumor hypoxia can be monitored accurately, non-invasively, quantitatively and dynamically, an effective means is provided for early warning of tumor radiotherapy tolerance or tumor recurrence after radiotherapy and making or modifying a personalized treatment scheme of a patient in a targeted manner. Thereby making it possible to prolong the survival of patients and improve prognosis.
Galectins (galectins) are members of a large family of Carbohydrate-binding lectins, and are characterized by their ability to bind tightly to β -galactoside via a conserved Carbohydrate Recognition Domain (CRD). in humans, the galectin family mainly includes the isoforms galectin-1, -2, -3, -4, -7, -8, -9, -10, -12, -13, etc., among which galectin-1 is a 14.5kD secreted protein that exhibits significantly high expression in a variety of tumors including breast cancer, lung cancer, colorectal cancer, and glioma, and is involved in the malignant progression of a variety of tumors including angiogenesis, immunosuppression, and tumor metastasis.
The tumor hypoxia condition can induce the secretion of galectin-1, and the increase of the expression level of the galectin-1 is found in various tumors (rectal cancer, prostatic cancer, Kaposi sarcoma, acute myelocytic leukemia cells and the like) under the hypoxia condition, the expression of the galectin-1 in hypoxic tumor cells is mainly regulated and controlled by HIF-1 α, the regulation and control depend on the action of Hypoxia Response Elements (HREs) positioned at the upstream of 441 423bp of the transcription initiation site of Lgals1 gene, and the design of a specific targeted small molecule radiopharmaceutical aiming at the galectin-1 highly expressed in the hypoxic region plays an important role in the early imaging diagnosis of the tumor hypoxia, the guidance and the monitoring of the curative effect of tumor radiotherapy and the like.
Disclosure of Invention
The invention aims to provide a radiopharmaceutical for galectin-1 specific nuclear medicine imaging and a preparation method thereof, and the radiopharmaceutical has low preparation cost, good stability in vivo and good tumor imaging and tumor hypoxia imaging effects.
The purpose of the invention is realized by the following technical scheme:
a radiopharmaceutical targeting galectin-1, which is a conjugate of a radionuclide, a bifunctional chelator and PEG4-TDGd, wherein the radionuclide is labeled with PEG4-TDGd through the bifunctional chelator; the PEG4-TDGd has a structure shown in a formula (1):
Figure BDA0002242397950000021
the PEG4-TDGd is PEG4 modified TDGd which is a Thiodigalactoside (TDG) derivative, the structural formula of the TDGd is shown in a formula (2), and the PEG4 is polyethylene glycol with the polymerization degree of 4. For TDGd, a triazole benzene ring modified at the C3 position is used for enhancing the binding specificity of galectin-1, and an azide modified at the C3' position is used for performing cycloaddition reaction with alkynyl to obtain triazole for connecting PEG 4. TDGd is a molecule that achieves galectin-1 targeting.
Figure BDA0002242397950000022
Further, the bifunctional chelating agent is any one of DOTA, NOTA or derivatives of both.
Further, the radionuclide is68Ga、64Cu or18F。
Further, the radioactive drug is a colorless transparent liquid injection.
The preparation method of the radiopharmaceutical for targeting galectin-1 comprises the following steps:
a. preparation of PEG 4-TDGd: dissolving TDGd in PBS buffer solution, adding alkynyl-modified PEG4(Alkyne-PEG 4-NH)2) Adding a monovalent copper ion catalyst, uniformly mixing, reacting at room temperature for 3-5 h, filtering the reaction mixed solution, separating and purifying by semi-preparative HPLC, collecting a product peak product, and freeze-drying to obtain white powder, namely NH2-PEG4-TDGd；
b. Preparation of bifunctional chelating agent-PEG 4-TDGd: NH (NH)2Dissolving PEG4-TDGd in an alkaline buffer solution, adding a bifunctional chelating agent DOTA or NOTA, uniformly mixing, reacting at room temperature for 5 hours, separating and purifying the reaction mixed solution by semi-preparative HPLC, collecting a product peak product, and freeze-drying to obtain white powder, namely DOTA-PEG4-TDGd or NOTA-PEG 4-TDGd;
c. preparation of radionuclide-bifunctional chelating agent-PEG 4-TDGd: dissolving DOTA-PEG4-TDGd or NOTA-PEG4-TDGd obtained in the step b into weak acid buffer solution, and adding radionuclide68Ga、64Cu or18F, wherein18F-labeling only reacted with NOTA-PEG4-TDGd and AlCl was added3Heating in water bath at 80-120 deg.C for 10-20 min to obtain the final product68Ga/64Cu/18F-NOTA-PEG4-TDGd or68Ga/64Cu-DOTA-PEG4-TDGd。
The medicine of the invention is prepared from galactose agglutinin-1 targeted thiodigalactoside derivative (PEG4-TDGd) connected with PEG4, bifunctional chelating agent (DOTA or NOTA) and radionuclide (B)68Ga、64Cu or18F) And (4) forming. Wherein TDGd is formed by connecting a triazole benzene ring at the C3 position on the basis of Thiodigalactoside (TDG) so as to improve half-and-half milkThe targeting affinity of the glycolectin-1, the azido is added at the C3' position to be connected with Alkyne-PEG4-NH through cycloaddition reaction with alkynyl2Synthesis of NH2-PEG4-TDGd。NH2Coupling of PEG4-TDGd with the bifunctional chelating agent DOTA, NOTA or derivatives thereof followed by radionuclide68Ga、64Cu or18F is marked on PEG4-TDGd, so that the radioactive nuclide is carried to the tumor cells or tumor hypoxia parts with high expression of the galectin-1 in vivo through the specific recognition of the TDGd and the galectin-1, and the tumor or tumor hypoxia is subjected to noninvasive imaging diagnosis and guided radiotherapy by utilizing nuclear medicine Positron Emission Tomography (PET).
The invention has the beneficial effects that:
1. according to the invention, through connecting and modifying TDGd, a conjugate of radionuclide, a bifunctional chelating agent and PEG4-TDGd is obtained, namely the targeted galectin-1 radiopharmaceutical. The medicine is a single compound component, and can be specifically combined with human galectin-1 and mouse galectin-1. The medicine can be rapidly removed from normal tissues (such as liver) and blood in vivo, and can realize high-contrast PET imaging of tumor cells or hypoxic region of tumor tissue.
2. The galectin-1 targeting TDGd is a sulfo-digalactoside structure modified by triazole at the C3 position, and the triazole benzene ring connected at the C3 position increases the affinity to galectin-1 and the in vivo stability, so that the better in vivo galectin-1 targeting is achieved. C3' is connected with azido group, and can generate cycloaddition reaction with alkynyl group to obtain triazole which is used for connecting PEG 4.
3. The number of TDGd connected with PEG is 4 (namely PEG4), thereby increasing the water solubility of TDG micromolecules, prolonging the blood circulation time and improving the metabolism condition in vivo.
4. By using the preparation method of the invention, the radioactive nuclide is processed by a bifunctional chelating agent (DOTA or NOTA)68Ga、64Cu or18F, labeling PEG4-TDGd, carrying the radionuclide to the tumor part by the specific recognition of the TDGd to the galectin-1, and utilizing the non-invasive and high-altitude methodThe nuclear medicine Positron Emission Tomography (PET) with sensitivity, high specificity and accurate quantification carries out non-invasive real-time dynamic diagnosis and development on hypoxic oxygen caused by tumors and other diseases and guides the radiotherapy of the tumors.
The invention is further explained with reference to the drawings and the embodiments.
Drawings
FIG. 1 shows the structure of radionuclide-NOTA-PEG 4-TDGd (wherein the radionuclide is68Ga、64Cu or18F)；
FIG. 2 shows the structure of radionuclide-DOTA-PEG 4-TDGd (where the radionuclide is68Ga or64Cu)；
FIG. 3,68A synthetic route of Ga-NOTA-PEG 4-TDGd;
FIG. 4, synthetic route of TDGd;
FIG. 5,18A synthetic route of F-NOTA-PEG 4-TDGd;
FIG. 6,68Ga-NOTA-PEG4-TDGd(68Binding specificity of Ga-NOTA-PTDGd) to (A) mouse galectin-1 (mGal-1) and (B) human galectin-1 (hGal-1); a, P<0.05；**,P<0.01；
FIG. 7,68Biodistribution of Ga-NOTA-PEG4-TDGd in sorafenib (sorafenib) induced 4T1 mouse breast cancer hypoxic model (n ═ 4); a, P<0.05；
FIG. 8,68Ga-NOTA-PEG4-TDGd and hypoxia imaging agent18PET imaging comparison of F-FMISO in sorafenib-induced 4T1 mouse breast cancer hypoxic model (n-4); arrows indicate hypoxic tumor sites;
FIG. 9,68PET imaging of Ga-NOTA-PEG4-TDGd in a mouse model of lotus 4T1 breast cancer predicts the curative effect of radiotherapy.
Detailed Description
The materials used in the examples of the present invention: Alkyne-PEG4-NH2Purchased from sienna millennium biotechnology limited; 1,4,7, 10-tetraazadocaine-N, N' -tetraacetic acid-N-hydroxysuccinimide (DOTA-NHS) and S-2- (4-Isothiocyanatobenzyl) -1,4,7-triazacyclononane-1,4,7-tThe RIACIC acid (p-SCN-Bn-NOTA) was purchased from Macrocyclics, USA; Sep-Pak C18 column was purchased from Waters, USA. Radionuclides64Cu is produced in nuclear medicine department of tumor hospital of Beijing university; radionuclides68Ga is composed of68Ge-68Leaching the Ga generator to obtain; radionuclides18F is produced by a medical accelerator; other conventional chemicals were purchased from Sigma-Aldrich, usa; recombinant mouse and human galectin-1 were purchased from US R&D Systems, Inc.
Example 1:
this embodiment uses radionuclides68Ga-labeled NOTA-PEG4-TDGd is exemplified.68The Ga-NOTA-PEG4-TDGd radioactive drug is prepared from TDGd, polyethylene glycol PEG4, bifunctional chelating agent NOTA and radionuclide68Ga. Wherein, the difunctional chelating agent NOTA can be replaced by DOTA,68ga radionuclides may be exchanged for64Cu or18F (shown in fig. 1 and 2). To be provided with68Ga-NOTA-PEG4-TDGd is taken as an example, and the preparation method is shown in figure 3 and comprises the following steps:
a、NH2preparation of PEG 4-TDGd: 6 mu mol of TDGd is dissolved in 500 mu L of PBS, and 36 mu mol of Alkyne-PEG4-NH is added20.6. mu. mol equivalent of CuSO4And 3 mu mol of sodium ascorbate is mixed uniformly and then placed at room temperature for reaction for 3-5 h, and then the reaction mixed solution is filtered by a microporous filter membrane and injected into semi-preparative HPLC for separation and purification. The product peak was collected, rotary evaporated to remove acetonitrile and lyophilized to a white powder by a lyophilizer. Obtaining the product NH2-PEG4A total of 2.8mg of-TDGd. MALDI-TOF-MS mass spectrometry result is that m/z ═ 742.3[ MH]+(C31H47N7O12S theoretical value 741.8).
b. Preparation of bifunctional chelating agent-PEG 4-TDGd: 2. mu. mol of NH are taken2-PEG4TDGd dissolved in 500. mu.L of 0.1mol/L NaHCO3To a buffer (pH 8.5-9.0) was added 6 μmol of p-SCN-Bn-NOTA (dissolved in DMF). After mixing uniformly, the mixture is placed at room temperature for reaction for 5 hours, and then the reaction mixture is injected into semi-preparative HPLC for separation and purification. Collecting the product peak, removing acetonitrile by rotary evaporation, and lyophilizing to obtain the final productWhite powder. The product NOTA-PEG4-TDGd was obtained in a total amount of 1.5 mg. MALDI-TOF-MS mass spectrometry analysis result shows that m/z is 1192.57[ MH []+(C51H73N11O18S2Theoretical value 1192.3).
c、68Preparation of Ga radionuclide-bifunctional chelating agent-PEG 4-TDGd: 20. mu.g of NOTA-PEG4-TDGd was dissolved in 500. mu.L of 0.1M NaOAc buffer (pH 5.5), to which 10mCi of68GaCl3Heating the leacheate in water bath at 100 ℃ for 15min to prepare the traditional Chinese medicine68Ga-NOTA-PEG4-TDGd radiopharmaceutical.
The TDGd is prepared manually, and is not limited to a preparation method, and the preparation method adopted in this example is shown in fig. 4:
firstly synthesizing a compound 1, respectively converting the compound into two structural units of glycosyl halide (a compound 3) and triisopropylsilylthioglycoside (a compound 4), then substituting isomeric bromo of a compound 2 by the compound 4 after desiliconization and activation to obtain a compound 5, and then removing an acetyl protecting group and purifying to obtain a target product compound 6.
The method comprises the following steps:
a. n equivalents of compound 1 were weighed out and dissolved in acetonitrile, and 1.5n equivalents of ethynylbenzene, 1.5n equivalents of DIPEA, 1.5n equivalents of CuI were added. The reaction mixture was stirred at 30 ℃ for 16 h. Then concentrated by filtration under reduced pressure and purified by column chromatography. N equivalents of the intermediate product were dissolved in DCM solution and 14n equivalents of HBr were added. The mixture was stirred at 25 ℃ for 4 hours. Adding NaHCO3The aqueous solution was bubbleless and extracted with DCM. The organic layer was concentrated under reduced pressure and purified by column chromatography to give compound 3.
b. Weighing n equivalents of compound 1 dissolved in DCM and EtOAc 1: 1 solution, 2n equivalents of TiBr are added4. The reaction mixture was stirred at 30 ℃ for 12 h. Adding NaHCO3The aqueous solution was bubbleless and extracted with DCM. The organic layer was concentrated under reduced pressure and subjected to column chromatography to give compound 2.
c. At n equivalents of compound 2CH3CN solution, 3n equivalents of K2CO3And 1.5n equivalents of TIPSSH. The reaction mixture is stirred at 25 ℃ 2h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography to give compound 4.
d. Dissolving n equivalents of compound 3 and n equivalents of compound 4 in CH respectively3To CN, 1.5n equivalents of TBAF were added. The mixture was stirred at 30 ℃ for 0.1 h. The reaction mixture was then concentrated under reduced pressure and purified by column chromatography to give compound 5.
e. n equivalents of compound 5 are dissolved in methanol solution and 5.6n equivalents of NaOME are added. The mixture was stirred at 30 ℃ for 3 hours. Addition of H+The pH of the resin was adjusted to 7 using Prep-HPLC (mobile phase: [ water (0.04% NH) ]3H2O+10mMNH4HCO3)-ACN]And B%: 10 to 40 percent, 10.5min) to purify the reaction solution. The purified liquid was put into a freeze dryer for concentration and freeze-dried to obtain a white powder, to obtain the objective product (Compound 6).
Example 2:
this embodiment uses radionuclides18F-labeled NOTA-PEG4-TDGd is exemplified.18The F-NOTA-PEG4-TDGd radioactive drug is prepared from TDGd, polyethylene glycol PEG4, bifunctional chelating agent NOTA and radionuclide18And F. Wherein18Radiolabelling of F with NOTA-PEG4-TDGd by AlCl3The preparation method is shown in figure 5 and comprises the following steps:
a. NOTA-PEG4-TDGd was prepared as in example 1.
b、18Preparation of F radionuclide-bifunctional chelating agent-PEG 4-TDGd: 20. mu.g of NOTA-PEG4-TDGd was dissolved in a solution containing 2mM AlCl3To 0.1M NaOAc buffer (pH 4.0), then 150 μ L of acetonitrile and 20mCi of water were added thereto18F, heating in a water bath at 110 ℃ for 15 min. After the reaction mixture was cooled to room temperature, it was diluted with 5mL of pure water and purified by Sep-Pak C18 column to obtain the product of the present invention18F-NOTA-PEG4-TDGd radiopharmaceutical.
Example 3:
this embodiment is as follows68Ga-NOTA-PEG4-TDGd exemplifies the in vivo and in vitro binding specificity identification of galectin-1 targeted radiopharmaceuticals and PET imaging applications thereof. Wherein,68Ga-NOTA-PEG4-TDGd may also be68Ga-DOTA-PEG4-TDGd、64Cu-NOTA-PEG4-TDGd、64Cu-DOTA-PEG4-TDGd or18F-NOTA-PEG4-TDGd。68Binding specificity of Ga-NOTA-PEG4-TDGd to galectin-1:
coating the recombinant mouse galectin-1 or the human galectin-1 on a high adsorption ELISA plate, and then coating the recombinant mouse galectin-1 or the human galectin-1 on the high adsorption ELISA plate68Ga-NOTA-PEG4-TDGd additions Radioactive binding experiments were performed in which the blocking group was added with excess unlabeled TDG to detect68The binding specificity of Ga-NOTA-PEG4-TDGd to galectin-1. The experimental result shows that the material is sealed by TDG68The binding of Ga-NOTA-PEG4-TDGd to mouse galectin-1 or human galectin-1 is remarkably reduced (see FIG. 6), which proves that the Ga-NOTA-PEG4-TDGd has specific binding to the mouse galectin-1 and the human galectin-1.
68Biodistribution of Ga-NOTA-PEG4-TDGd in hypoxic mouse model:
BALB/c breast cancer mice bearing 4T1 mice were divided into 2 groups of 4 mice each. One group of mice induced tumor hypoxia by gastric gavage with sorafenib (sorafenib), the other group of mice was given a blank vehicle control. Subsequent groups of mice were injected via tail vein68Ga-NOTA-PEG4-TDGd, 1h after injection, mice were sacrificed, blood, tumors and major organs were removed, their radioactivity counts were weighed and measured, and the percent injected dose per gram of tissue (% ID/g) was calculated after decay correction. The results show that it is possible to display,68uptake of Ga-NOTA-PEG4-TDGd was significantly higher in sorafenib-induced hypoxic tumors than control tumors (see figure 7). The experimental results show that the high-temperature-resistant steel,68Ga-NOTA-PEG4-TDGd has specific high uptake in hypoxic tumors.
68PET imaging of Ga-NOTA-PEG4-TDGd in hypoxic mouse tumor models:
in a sorafenib-induced hypoxic 4T 1-loaded breast cancer BALB/c mouse model, hypoxic imaging agents are respectively injected18F-FMISO and68Ga-NOTA-PEG 4-TDGd. The best imaging time after injection is that a NanoScan PET/CT imaging instrument (Mediso, Hungary) scans and acquires PET images, and the tumor hypoxia imaging characteristics of the two images are compared. As shown in fig. 8, compared with the current clinical anaerobic imaging agent18Compared with the F-FMISO method, the method has the advantages that,68the Ga-NOTA-PEG4-TDGd has low background in the abdominal cavity and high contrast of hypoxic tumor imaging.
68The Ga-NOTA-PEG4-TDGd mouse PET imaging predicts the curative effect of radiotherapy:
19 hypoxic-induced-sorafenib-induced, 4T 1-charged, breast cancer BALB/c mice were divided into 2 groups, a control group and a radiation-treated group, respectively. Among them, 6 mice were used as a blank control group and 13 mice were used as a radiation treatment group. On day 3, mice in the radiation treatment group were injected via tail vein68Ga-NOTA-PEG4-TDGd, PET images were scanned by a NanoScan PET/CT imager 1h after injection, and tumor uptake was quantitatively analyzed. According to the quantitative68SUV value of Ga-NOTA-PEG4-TDGd uptake in tumors is SUV>0.15 (high uptake) and SUV<Group 0.15 (low intake). Then, local radiotherapy was performed on the tumors of the radiotherapy group by an X-ray irradiator (RS2000 PRO, Radsource, usa) on days 6, 8 and 10, respectively. Observation channel68Ga-NOTA-PEG4-TDGd distinguishes high tumor uptake (high hypoxic degree) and low tumor uptake (low hypoxic degree) tumor radiotherapy curative effects. As can be seen from the experimental results,68the tumor treatment effect of the Ga-NOTA-PEG4-TDGd low-uptake radiotherapy group is obviously higher than that of the Ga-NOTA-PEG4-TDGd low-uptake radiotherapy group68The tumor treatment effect of the Ga-NOTA-PEG4-TDGd high-uptake radiotherapy group (see FIG. 9). The result indicates that68Ga-NOTA-PEG4-TDGd noninvasive PET imaging evaluation of tumor hypoxia state, thereby early predicting the curative effect of radiotherapy.
In this embodiment, the galectin-1 targeting radiopharmaceutical can be used for hypoxia imaging of tumors and predicting the efficacy of tumor radiotherapy. The radiopharmaceutical of the invention specifically binds to the galectin-1 at the hypoxic part, so that the radiopharmaceutical can realize specific PET imaging diagnosis in other hypoxic-related diseases such as stroke and the like.

Claims (5)

1. A galectin-1 targeting radiopharmaceutical which comprises: the radionuclide is a conjugate of radionuclide, a bifunctional chelating agent and PEG4-TDGd, and the radionuclide is marked with PEG4-TDGd through the bifunctional chelating agent; the PEG4-TDGd has a structure shown in a formula (1):
Figure FDA0002242397940000011
2. the galectin-1 targeting radiopharmaceutical of claim 1, wherein: the radionuclide is68Ga、64Cu or18F。
3. The galectin-1 targeting radiopharmaceutical of claim 1, wherein: the bifunctional chelating agent is any one of DOTA, NOTA or derivatives of the DOTA and the NOTA.
4. The galectin-1 targeting radiopharmaceutical of claim 1, wherein: the radioactive drug targeting the galectin-1 is a colorless transparent liquid injection.
5. The method for preparing the galectin-1 targeting radiopharmaceutical of any one of claims 1 to 4, comprising the steps of:
a、NH2preparation of PEG 4-TDGd: dissolving TDGd in PBS buffer solution, adding alkynyl-modified PEG4, adding a monovalent copper ion catalyst, uniformly mixing, reacting at room temperature for 3-5 hours, filtering the reaction mixture, separating and purifying by semi-preparative HPLC, collecting a product peak product, and freeze-drying to obtain white powder, namely NH2-PEG4-TDGd；
b. Preparation of bifunctional chelating agent-PEG 4-TDGd: NH (NH)2Dissolving PEG4-TDGd in an alkaline buffer solution, adding a bifunctional chelating agent, uniformly mixing, reacting at room temperature for 5 hours, separating and purifying the reaction mixed solution by semi-preparative HPLC, collecting a product peak product, and freeze-drying to obtain white powder, namely the bifunctional chelating agent-PEG 4-TDGd;
c. preparation of radionuclide-bifunctional chelating agent-PEG 4-TDGd: dissolving a bifunctional chelating agent-PEG 4-TDGd in a weak acid buffer solution, adding a radionuclide, heating in a water bath at 80-120 ℃ for 10-20 min to prepare the radionuclide-bifunctional chelating agent-PEG 4-TDGd, namely the radiopharmaceutical for targeting the galectin-1.
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CN111808161A (en) * 2020-06-01 2020-10-23 北京大学 Method for radiolabeling biological compounds
CN111991570A (en) * 2020-07-24 2020-11-27 北京大学 FAP-alpha specific tumor diagnosis SPECT imaging agent
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CN113861254A (en) * 2021-09-16 2021-12-31 复旦大学附属中山医院 Tumor PET imaging agent68Ga-NOTA-ADG and preparation method and application thereof
CN113861254B (en) * 2021-09-16 2023-10-27 复旦大学附属中山医院 Tumor PET imaging agent 68 Ga-NOTAN-aDG, and preparation method and application thereof
CN114028590A (en) * 2021-11-18 2022-02-11 北京大学 Granzyme B targeting complex, radiopharmaceutical, preparation methods and applications thereof
US11964948B2 (en) 2022-06-07 2024-04-23 Actinium Pharmaceuticals, Inc. Bifunctional chelators and conjugates
US11975081B2 (en) 2022-06-07 2024-05-07 Actinium Pharmaceuticals, Inc. Bifunctional chelators and conjugates

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