CN114805499A - PET molecular probe with PD-L1 pathway as target spot and application thereof - Google Patents
PET molecular probe with PD-L1 pathway as target spot and application thereof Download PDFInfo
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Abstract
The invention relates to the technical field of imaging molecular probes, in particular to a PET molecular probe taking a PD-L1 passage as a target spot and application thereof. The PET molecular probe can well carry out in-vivo imaging on the expression level of the PD-L1 pathway in various tumor microenvironments. In animal experiments, the tumor position of a mouse can be clearly observed by using the probe within 30 minutes, which shows that the probe can be rapidly accumulated at the tumor part, the accumulation condition of tumor cells can be observed within a long time, and the targeting property of the probe is good and the contrast is high. The kit can be used for detecting the PD-L1 pathway expression in various tumor microenvironments, can assist the curative effect evaluation of an immunosuppressant in immunotherapy, and provides real-time reference for the therapy. The invention can be used for non-invasive detection after being applied to an imaging agent, can realize real-time imaging of the whole body of a living body, has simple marking, high contrast, high specificity and high sensitivity, and has better clinical transformation prospect.
Description
Technical Field
The invention relates to the technical field of imaging molecular probes, in particular to a PET molecular probe taking a PD-L1 passage as a target spot and application thereof.
Background
Programmed death receptor 1 (PD-1) is a transmembrane receptor on lymphocytes, and PD-1 is expressed predominantly on activated T cells and B cells. PD-1 and its ligands (Programmed Death-Ligand 1; PD-L1) are important mechanisms by which tumor cells evade immune surveillance by the body. PD-L1 molecules are highly expressed on a plurality of tumor cell membranes, and after the PD-L1 molecules are combined with PD-1 on immune cells such as T cells, the tumor cells send inhibition signals, so that the T cells can not effectively recognize and kill the tumor cells, and the tumor immune escape is generated. Blocking the interaction between PD-1 and its ligand PD-L1 has become a promising immunotherapy for the treatment of cancer.
Drugs currently on the market directed to the PD-1/PD-L1 pathway include monoclonal antibodies as well as small molecule inhibitors. Among the reported peptides and peptidomimetics, AUNP-12 is one of the most active polypeptides. Studies have shown that AUNP-12 inhibits the proliferation of mouse B16 melanoma and mouse 4T1 breast cancer tumor cells in preclinical models. Immunotherapy based on Immune Checkpoints (Immune Checkpoints) has become an important tool for tumor therapy and antibody therapy against PD-1 or PD-L1 and other Immune Checkpoints, such as anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4), is currently under clinical investigation.
In vivo shows that the expression level of PD-L1 in a tumor microenvironment can provide important reference for selecting patients with suppressive drugs taking PD-L1 as a target spot, and simultaneously, the expression condition of PD-L1 in vivo can be detected in real time, so that the treatment scheme can be adjusted clinically in time. Therefore, the molecular probe capable of efficiently and accurately performing in-vivo imaging on the expression level of PD-L1 in various tumor microenvironments has important clinical application value. In view of the current poor response of immunotherapy based on the PD1/PD-L1 pathway to multiple tumors in the clinic, patient P was found to be a studyThe expression level of D1/PD-L1 is inconsistent or the expression of PD1/PD-L1 fluctuates in the immunotherapy process, so that the real-time noninvasive accurate imaging of PD1/PD-L1 expression of a patient in advance by means of PET imaging is the hotspot of the current research. However, the current imaging of the PD1/PD-L1 pathway is mainly based on a single-antibody PET molecular probe, and although the PET molecular probe has certain imaging capability, the antibody source cost is high, and nuclides are adopted 64 Cu、 89 Not only is Zr very difficult to obtain, but it is also extremely expensive and difficult for both research and patient to tolerate. The PET molecular probe of PD1/PD-L1 polypeptide is the key direction of research at present because of small molecule, low cost and convenient labeling, and only one has 68 Ga-WL12 is used clinically, but the imaging effect is difficult to meet the clinical requirement, the defects of low targeting property and poor contrast exist, and because the aggregation condition of tumor cells cannot be observed in a long-lasting period, real-time reference cannot be provided for treatment selection; the real-time whole-body imaging cannot be realized, the curative effect evaluation of an immunosuppressant in the immunotherapy cannot be assisted, the detectable tumor types are few, the labeling is difficult, and the imaging effect on tumors is poor.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide a PET molecular probe targeting the PD-L1 pathway and its application. By taking the PDL-1 pathway as a target point, the in-vivo imaging method can efficiently and accurately carry out in-vivo imaging on the activation degree of the PDL-1 pathway in various tumor microenvironments.
The invention provides a compound shown in a formula I,
wherein R is a chelating group selected from NOTA, DOTA or DTPA.
The invention also provides a PET molecular probe taking a PD-L1 passage as a target spot, which comprises a compound shown in the formula I and a radioactive isotope;
wherein R is a chelating group selected from NOTA, DOTA or DTPA.
In the embodiment of the invention, NOTA is taken as a chelating group and is marked as NOTA-AUNP 12. The structure is as follows:
the PET molecular probe has a structure shown in a formula II:
wherein R is a chelating group selected from NOTA, DOTA or DTPA;
x is a radioisotope selected from the group consisting of 68 Ga、Al 18 F、 177 Lu、 89 Zr、 64 Cu or 99 mTc。
In some embodiments, the PET molecular probe comprises a NOTA as a chelating group and a radioisotope 68 Ga, notation 68 Ga-NOTA-AUNP12。
The invention also provides a preparation method of the PET molecular probe, which comprises the step of reacting the compound shown in the formula I with a radioactive isotope in an acid environment to prepare the PET molecular probe.
The acidic environment of the present invention includes a hydrochloric acid environment.
The reaction solution also comprises an aqueous solution formed by weak acid salts such as acetic acid ions.
In the invention, the preparation method of the PET molecular probe provided by the invention comprises the following steps: dissolving the compound of formula I in NaOAc aqueous solution to obtain solution A, dissolving 68 And leaching Ga to be solution A through HCl solution, and reacting to obtain the PET molecular probe.
In some embodiments, the concentration of the NaOAc aqueous solution is 0.1 to 0.5M; the concentration of the HCl solution is 0.01-0.1M. In some embodiments, the concentration of the NaOAc aqueous solution is 0.25M; the concentration of the HCl solution was 0.05M.
In some embodiments, the concentration of the compound of formula I in solution A is 10-50 μ g/mL; and washing until the radioactivity is 10 mCi-55 mCi. In some embodiments, the concentration of the compound of formula I in solution A is 30 μ g/mL; and washing until the radioactivity is 30 mCi-35 mCi.
The reaction conditions include: the pH value is 3.5-4.5, the temperature is 80-100 ℃, and the reaction time is 10-15 min. In some embodiments, the conditions of the reaction include: the pH value is 4.0-4.5, the temperature is 90-1.00 ℃, and the reaction time is 8-10 min. In some embodiments, the conditions of the reaction include: the pH value is 4.0-4.5, the temperature is 90 ℃, and the reaction time is 10 min.
The invention provides an application of the PET molecular probe in preparing an imaging agent.
The PET molecular probe provided by the invention can well carry out in-vivo imaging on PDL-1 pathway expression levels in various tumor microenvironments, can be used for PDL-1 pathway expression detection in various tumor microenvironments, can assist in curative effect evaluation of an immunosuppressant during immunotherapy, and provides real-time reference for treatment selection.
The invention also provides an imaging agent which comprises the PET molecular probe.
The invention also provides application of the imaging agent in preparing a diagnostic reagent for diseases related to the PD-L1 pathway.
The application of the invention, wherein the PD-L1 pathway related diseases comprise melanoma, liver cancer, colon cancer, pancreatic cancer and/or lymphoma.
The application of the invention, wherein the PD-L1 pathway related diseases also comprise other tumors which can affect the expression change of the PD-L1 pathway.
The invention also provides a reagent for non-invasively detecting the expression level of the PD-L1 pathway, which comprises the PET molecular probe.
The invention provides a reagent for assisting an immunosuppressant to evaluate the curative effect of immunotherapy, which comprises the PET molecular probe.
The invention also provides application of the PET molecular probe in evaluating the effect of an immune drug on treating PD-L1 pathway related diseases.
The invention also provides a method for detecting, diagnosing or evaluating the curative effect of the PD-L1 channel-related diseases, which comprises imaging by using the PET molecular probe.
The NOTA-AUNP12 is derived on the basis of the structure of an immunosuppressant AUNP12, the targeting of the NOTA-AUNP12 to a PD1/PD-L1 channel is definite, and a pre-experiment result also shows that the PET molecular probe is simple in labeling, has a good imaging effect on various tumors and has a good clinical transformation prospect.
The PET molecular probe provided by the invention can well carry out in-vivo imaging on the expression level of the PD-L1 pathway in various tumor microenvironments. In animal experiments, the PET molecular probe can be used for clearly observing the tumor position of a mouse within 30 minutes, which shows that the molecular probe can be rapidly aggregated at the tumor part, has good targeting property and high contrast, can observe the aggregation condition of tumor cells within a long time, and shows that the targeting property of the probe to the tumor is very good. The kit can be used for detecting the PD-L1 pathway expression in various tumor microenvironments, can assist the curative effect evaluation of an immunosuppressant in immunotherapy, and provides real-time reference for treatment selection. The PET imaging agent can be used for non-invasive detection after being applied to the PET imaging agent, can perform real-time imaging on the whole body of a living body, has simple marking and better imaging effect on various tumors, has the characteristics of high contrast, high specificity, high sensitivity and the like, and has better clinical transformation prospect.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts according to the drawings:
FIG. 1 shows 68 A radiochemical purity HPLC profile of Ga-NOTA-AUNP 12;
FIG. 2 shows 68 Imaging of mouse PET with Ga-NOTA-AUNP12 molecular probe;
FIG. 3 shows a mass spectrum of NOTA-AUNP 12;
FIG. 4 shows a probe 68 The ratio of target costs of Ga-NOTA-AUNP12 in different tumors.
Detailed Description
The invention provides a PET molecular probe taking a PD-L1 passage as a target spot and application thereof. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of this invention without departing from the spirit and scope of the invention.
NOTA-AUNP12 the molecular structure is derived on the basis of the structure of an immunosuppressant AUNP12 and is used for PET in vivo imaging research in the field of nuclear medicine diagnosis, and the synthesis is customized and synthesized by a company.
The compounds of formula I according to the invention (mass spectrum see fig. 3) were purchased from: gill Biochemical (Shanghai) Co., Ltd
The effect of targeting and contrast in the scheme has two expression modes, one is animal visualization (as shown in figure 2), and the other is tumor uptake value SUV, wherein the higher the value is, the better the visualization effect is. In addition, there is a map of the ratio of tumor to muscle targets (as shown in figure 4).
Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
Example 1
1) To an EP tube containing 30. mu.g of the precursor compound (NOTA-AUNP12), 1mL of 0.25M aqueous NaOAc solution was added and mixed;
2) the NOTA-AUNP12 solution was transferred to a 20mL reaction tube;
3) 4mL of 0.05M HCl 68 Leaching Ga into a reaction tube, wherein the radioactivity is about 30 mCi-35 mCi;
4) reacting for 10min at 90 ℃ in a reaction tube;
5) adding 10mL of deionized water to quench the reaction;
6) enriching the reaction system by using a C18 Plus column, and washing the C18 Plus column by using 10mL of deionized water;
7) rinsing the product with 1mL of ethanol and 10mL of physiological saline in sequence into a vial of filter-equipped product to form 68 The Ga-NOTA-AUNP12 product injection has the radioactivity of 24.8 mCi;
8) 68 and (3) carrying out HPLC purity analysis on the Ga-NOTA-AUNP12 product injection: mobile phase a was distilled water containing 0.1% TFA, mobile phase B was acetonitrile containing 0.1% TFA, and the column was ZORBAX SB-C18. The elution mode is gradient elution (0 min-2 mm: 5% acetonitrile; 3 min-20 min: 90% acetonitrile), the product peak time is 10.32min, and the purity is more than 99%.
The HPLC results of the obtained PET molecular probe for the purification by amplification are shown in FIG. 1.
Example 2 animal imaging
1. 40C 57 mice were purchased and randomly divided into four groups of 10 mice, one group was used as a control group and cultured normally, the other three groups were used as experimental groups, subcutaneous melanoma B16 model, pancreatic cancer PANC02 model and colorectal cancer CT26 model were respectively constructed in the experimental groups, and the mice were used as model mice when the tumor size was about 0.5 cm.
2. Model rat tail intravenous injection 68 Ga-NOTA-AUNP12(0.1mCi~0.2mCi)。
3. After 30min, the PET/CT imaging of the small animal is carried out, and the result is shown in figure 1, and the tumor position of the mouse can be cleaned and observed within 30min, which shows that the molecular probe can be rapidly gathered at the tumor part, has high contrast, can observe the gathering condition of tumor cells within a long time, and shows that the targeting of the probe to the tumor is better.
4. Data analysis to obtain SUV value of tumor part, wherein 68 The tumor uptake SUV values of the Ga-NOTA-AUNP12 probe in the melanoma B16 model, the pancreatic cancer PANC02 model and the colorectal cancer CT26 model were 5.6. + -. 1.2, 4.5. + -. 0.9 and 3.9. + -. 1.2, respectively, indicating that 68 Ga-NOTA-AUNP12 can better perform quantitative analysis and detection on PD-L1 pathway activity in various tumor models, and has higher contrast (figure 4).
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (10)
4. The method for preparing a PET molecular probe according to claim 2 or 3, wherein the compound of formula I is reacted with a radioisotope in an acidic environment to prepare the PET molecular probe.
5. The method of claim 4, wherein the acidic environment comprises a hydrochloric environment.
6. The preparation method according to claim 4, wherein in the preparation method, the pH is 3.5-4.5, the temperature is 80-100 ℃, and the reaction time is 10-15 min.
7. Use of the PET molecular probe of claim 2 or 3 for the preparation of an imaging agent.
8. An imaging agent comprising the PET molecular probe of claim 2 or 3.
9. Use of the imaging agent of claim 8 for the preparation of a diagnostic agent for a disease associated with the PD-L1 pathway.
10. The use of claim 9, wherein the disease associated with the PD-L1 pathway comprises melanoma, liver cancer, colon cancer, pancreatic cancer and/or lymphoma.
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