Labeled precursor, probe, preparation method therefor, and use thereof

Abstract

Provided are a labeled precursor, a probe, a preparation method therefor, and use thereof. The structure of the provided labeled precursor is: Cyclo(Ac-Ala-Arg-L-2-aminoheptanoic acid-Tyr-His-Asp-Arg-Val-Leu-Bip(4,4)-L-2-aminoheptanoic acid-Asp-Cys). The provided probe has good stability, excellent pharmacokinetic properties, good binding specificity to tumor CD38, a relatively high tumor uptake, a relatively high tumor-to-muscle uptake ratio, and good in vivo metabolic performance.

Description

Labeling precursors, probes, their preparation methods and applications

[0001] This application claims priority to Chinese Patent Application No. 202410485947X, filed on April 22, 2024, entitled “Labeling Precursor, Probe and Preparation Method and Application Thereof”, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention relates to the field of imaging, and particularly to labeled precursors, probes, their preparation methods, and applications. Background Technology

[0003] Lymphoma is a collective term for a group of cancerous diseases originating from lymphocytes. As a heterogeneous cancer, many lymphoma subtypes have proven to be highly aggressive, with extremely poor prognoses for patients. Multiple myeloma (MM) is the second most common hematologic malignancy in adults and remains incurable. In the era of precision medicine, monoclonal antibodies have provided a powerful therapeutic tool for cancer treatment. Currently, almost all treatments and research focus on anti-CD20 antibody therapy for CD20-positive lymphomas. However, some lymphoma patients do not express or express very little CD20, and therefore cannot benefit from these anti-CD20 antibodies. With the development of monoclonal antibodies for cancer treatment, the identification of tumor-specific biomarkers has become a prerequisite for pre- and post-treatment evaluation.

[0004] CD38 is a 45kDa multifunctional transmembrane glycoprotein receptor with dual enzymatic and receptor functions. CD38 is abnormally highly expressed in 95%-100% of malignant plasma cells, while its expression level is relatively low in normal cells. It is a promising biomarker for various types of lymphoma, especially multifocal lymphoma (MM). Daratumumab (Dara) is a monoclonal antibody targeting CD38 and has been approved for the treatment of newly diagnosed or relapsed / refractory MM patients. However, the efficacy of daratumumab is influenced by the tumor's CD38 expression level.

[0005] In clinical practice, flow cytometry and microscopy are routinely used to detect CD38 expression in bone marrow biopsy samples. However, biopsies are invasive and prone to false negatives in heterogeneous or minimally invasive lesion samples. In contrast, whole-body imaging methods can non-invasively assess target expression. 18 F]-Fluorodeoxyglucose ([ 18 Positron emission tomography (PET / CT) is one of the most commonly used imaging techniques for lymphoma. However, [ 18The application of FDG PET / CT in the diagnosis of multiple myeloma (MM) is limited by false negatives caused by low expression of hexokinase 2 in MM cells. It also cannot accurately provide molecular information, such as the expression of CD38 in MM cells. However, immunoPET is an emerging imaging technique that uses radiolabeled monoclonal antibodies to non-invasively assess the expression of specific biomarkers. Dara, a well-known anti-CD38 antibody, is likely to become an immunoPET imaging probe targeting CD38. Currently reported... 89 Zr-labeled Dara imaging probes can be used for immunoPET of CD38 in lymphoma models. Tumor uptake occurs during injection. 89 Zr-labeled Dara reaches its peak 5 days after administration, while background radioactivity in the blood remains high for up to 4 days after administration, resulting in poor contrast in early tumors and requiring patients to return for scans several days later. This may limit the effectiveness of the treatment. 89 Clinical applications of Zr-labeled Dara. Furthermore... 89 Zr's long half-life (78.4 h) and relatively high energy (average 0.389 MeV) can cause excessive radiation doses to patients. Unbound... 89 Zr is a radioactive metallic nuclide that tends to accumulate in bones, which may reduce... 89 The accuracy of Zr-labeled antibody detection in metastatic multiple myeloma (MM).

[0006] In view of this, there is an urgent clinical need to develop smaller and more stable molecular imaging probes to non-invasively visualize CD38 expression and monitor the response to CD38-targeted therapy in real time, which would also be more conducive to clinical translation. Summary of the Invention

[0007] In view of this, the present invention provides a labeled precursor, a probe, a method for preparing the probe, and its applications. The probe provided by the present invention has good stability, excellent pharmacokinetics, good specificity for binding to tumor CD38, high tumor uptake and a high tumor-to-muscle uptake ratio, good in vivo metabolic performance, and good clinical application prospects.

[0008] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0009] This invention provides a cyclic peptide with the structure: Cyclo(Ac-Ala-Arg-L-2-aminoheptanoic acid-Tyr-His-Asp-Arg-Val-Leu-Bip(4,4)-L-2-aminoheptanoic acid-Asp-Cys).

[0010] The present invention also provides a labeling precursor having a structural formula as shown in formula (1):

[0011] Where: X is selected from equations (2) to (7):

[0012] R is selected from equations (8) to (10):

[0013] In equations (8) to (10), a is an integer from 1 to 8, b is an integer from 1 to 24, and c is an integer from 1 to 12.

[0014] In some embodiments of the present invention, in the above-mentioned marker precursor, a is an integer from 1 to 3, b is an integer from 4 to 24, c is an integer from 4 to 12, and d is an integer from 1 to 3.

[0015] In some embodiments of the present invention, in the above-mentioned marker precursor, a is 2, b is 4, 12 or 24, c is 12 or 24, and d is 1 or 3.

[0016] In some embodiments of the present invention, X in the above-mentioned marking precursor is formula (2) or formula (5):

[0017] In some embodiments of the present invention, the above-mentioned marking precursor has a structural formula as shown in any of formulas (11) to (16):

[0018] The present invention also provides a method for preparing the above-mentioned labeled precursor, wherein the labeled precursor is obtained by using the required amino acids and DOTA as raw materials and the Fmoc solid-phase synthesis method.

[0019] In some embodiments of the present invention, the required amino acids in the above preparation method include any one of formulas (8) to (10), and Boc-cysteine, S-triphenylmethyl-L-cysteine, aspartic acid, L-diaminoheptanoic acid, 4-phenylphenylalanine, leucine, valine, arginine, aspartic acid, histidine, tyrosine, L-diaminoheptanoic acid, arginine and alanine.

[0020] The present invention also provides a probe comprising: the labeled precursor described above and / or the labeled precursor and radionuclide obtained by the above preparation method.

[0021] In some embodiments of the present invention, the radionuclide in the probe includes: 67 Ga、 68 Ga、 64 Cu、 18 F, 86 Y、 90 Y、 89 Zr、111 In、 99 mTc, 11 C 123 I, 125 I, 124 I, 131 I, 177 Lu、 211 At、 153 Sm、 186 Re、 188 Re、 212 Pb, 225 Ac、 213 Bi、 212 Any one of Bi.

[0022] In some embodiments of the present invention, the radionuclide in the probe includes: 68 Ga or 18 F.

[0023] The present invention also provides a method for preparing the above-mentioned probe, wherein the radionuclide is mixed with the labeled precursor and reacted to obtain the probe.

[0024] The present invention also provides the application of the above-described labeling precursor, the labeling precursor obtained by the above-described preparation method, the above-described probe, and / or the probe obtained by the above-described preparation method in any of the following:

[0025] (I) Preparation of products for detecting CD38 expression levels; and / or

[0026] (II) Preparation of products for detecting non-solid tumors; and / or

[0027] (III) Detecting CD38 expression levels; and / or

[0028] (IV) Detection of non-solid tumors.

[0029] In some embodiments of the present invention, the non-solid tumors described above include hematologic malignancies and / or multiple myeloma.

[0030] The present invention also provides a method for detecting non-solid tumors, wherein the above-described probe and / or the probe obtained by the above-described preparation method are applied to the analyte, and after imaging, the detection result is obtained.

[0031] The present invention also provides a product comprising: the above-described labeling precursor, the labeling precursor obtained by the above-described preparation method, the above-described probe, and / or the probe obtained by the above-described preparation method.

[0032] In some embodiments of the present invention, the above-mentioned products include one or more of the following: reagents, kits, drugs, and imaging agents.

[0033] This invention provides a cyclic peptide with the structure: Cyclo(Ac-Ala-Arg-L-2-aminoheptanoic acid-Tyr-His-Asp-Arg-Val-Leu-Bip(4,4)-L-2-aminoheptanoic acid-Asp-Cys).

[0034] The probe provided by this invention has good stability, excellent pharmacokinetics, good specificity for binding to tumor CD38, high tumor uptake and high tumor to muscle uptake ratio, good in vivo metabolic performance, and good clinical application prospects. Attached Figure Description

[0035] Figure 1 shows the mass spectra of the cyclic peptides CP001, CP002, CP003, CP004, CP005 and CP006 targeting CD38;

[0036] Figure 2 shows 68 Ga-labeled CP001, CP002, CP003, CP004, CP005 and CP006 structural formula (A) and Al 18 F marks the structural formulas (B) for CP001, CP002, CP003, and CP005;

[0037] Figure 3 shows 68 Ga-labeled CP001, CP002, CP003, CP004, CP005 and CP006(A)-(F) and Al 18 The detection results for F-labeled CP001, CP002, CP003, and CP005(G)-(J) labels are shown; where: (A) shows 68 Ga-CP001; (B) shown 68 Ga-CP002; (C) shows 68 Ga-CP003; (D) shown 68 Ga-CP004; (E) shown 68 Ga-CP005; (F) indicates 68 Ga-CP006; (G) indicates Al 18 F-CP001; (H) indicates Al 18 F-CP002; (I) indicates Al 18 F-CP003; (J) shows Al 18 F-CP004; (K) indicates Al 18 F-CP005; (L) indicates Al 18 F-CP006;

[0038] Figure 4 shows 68micro-PET / CT images of Ga-labeled CP001, CP002, CP003, CP004, CP005 and CP006 in tumor-bearing mice;

[0039] Figure 5 shows 68 Radioactive uptake of Ga-labeled CP001, CP002, CP003, CP004, CP005 and CP006 in tumors, liver, kidneys, heart, lungs and tumors / muscles in tumor-bearing mice;

[0040] Figure 6 shows 68 Micro-PET / CT imaging of Ga-CP003 in tumor-bearing mice under 800x blockade; (A) is... 68 Ga-CP003 is a micro-PET / CT imaging image; (B) is... 68 Ga-CP003-800x blocking group micro-PET / CT imaging;

[0041] Figure 7 shows 68 Ga-CP003 and 68 The change in tumor radioactive uptake of Ga-CP003 over time in tumor-bearing mice under 800-fold blocking conditions;

[0042] Figure 8 shows 68 Micro-PET / CT imaging of Ga-CP004 in tumor-bearing mice under 800x blockade; (A) is... 68 Ga-CP004 is a micro-PET / CT imaging image; (B) is... 68 Ga-CP004-800x blocking group micro-PET / CT imaging;

[0043] Figure 9 shows 68 Ga-CP004 and 68 The change in tumor radioactive uptake of Ga-CP004 over time in tumor-bearing mice under 800-fold blocking conditions;

[0044] Figure 10 shows Al 18 F-labeled CP001, CP002, CP003, CP004, CP005 and CP006 micro-PET / CT images in tumor-bearing mice;

[0045] Figure 11 shows Al 18 Radioactive uptake of F-labeled CP001, CP002, CP003, CP004, CP005, and CP006 in tumor, liver, lung, and kidney tissues in tumor-bearing mice. Detailed Implementation

[0046] This invention discloses a labeling precursor, a probe, its preparation method, and its application. Those skilled in the art can refer to the content of this document and appropriately modify the process parameters to achieve the desired results. It is particularly important to note that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included in this invention. The methods and applications of this invention have been described through preferred embodiments. Those skilled in the art can clearly modify or appropriately change and combine the methods and applications described herein without departing from the content, spirit, and scope of this invention to realize and apply the technology of this invention.

[0047] The first aspect of this invention provides a labeled precursor for a tumor-targeting CD38 polypeptide radionuclide probe as shown in formula (1), with the structure Cyclo(Ac-Ala-Arg-L-2-aminoheptanoic acid-Tyr-His-Asp-Arg-Val-Leu-Bip(4,4)-L-2-aminoheptanoic acid-Asp-Cys), which can be synthesized with diagnostic and / or therapeutic radionuclides for integrated diagnosis and treatment of CD38-overexpressing tumors. It has the structure shown in formula (1):

[0048] Wherein, X is at least one of the groups shown in formulas (2) to (7) below:

[0049] R is at least one of the groups shown in formulas (8) to (10): wherein R is a group shown in formulas (8), (9) and (10).

[0050] Wherein, a is an integer from 1 to 4, preferably an integer from 1 to 3; b is an integer from 1 to 24, preferably an integer from 4 to 24; c is an integer from 1 to 12, preferably an integer from 4 to 12; and d is an integer from 1 to 4, preferably an integer from 1 to 3.

[0051] Furthermore, a is an integer from 3 to 8, b is an integer from 1 to 3, and c is an integer from 4 to 12.

[0052] Further, X is a group as shown in formula (2) or formula (5); R is a group as shown in formula (8) or formula (9), where a is 4 and b is 2.

[0053] Furthermore, the precursor is labeled with a structure as shown in formula (11), formula (12), formula (13), formula (14), formula (15) or formula (16), and the corresponding compounds are numbered CP001, CP002, CP003, CP004, CP005, and CP006, respectively.

[0054] Thirdly, the present invention provides a cyclic peptide nuclide probe targeting tumor CD38, wherein the nuclide probe is a radiolabeled precursor of the cyclic peptide nuclide probe targeting tumor CD38.

[0055] Furthermore, the radionuclide is a diagnostic radionuclide or a therapeutic radionuclide; preferably, the diagnostic radionuclide is selected from... 67 Ga、 68 Ga、 64 Cu、 18 F, 86 Y、 9 0 Y、 89 Zr、 111 In、 99 mTc, 11 C 123 I, 125 I and 124 At least one of the following: Class I; preferably, the therapeutic radionuclide is selected from... 177 Lu、 125 I, 131 I, 211 At、 111 In、 153 Sm、 186 Re、 188 Re、 67 Cu、 212 Pb, 225 Ac、 213 Bi、 212 Bihe 212 At least one of Pb, etc. However, the radionuclides applicable to the present invention are not limited thereto, but may include, without limitation, alpha-ray and beta-ray radionuclides as therapeutic radioisotopes for treating cancer, etc., and positron-emitting and gamma-ray radionuclides as diagnostic radioisotopes for diagnosis.

[0056] Fourthly, the present invention provides a method for preparing a cyclic peptide nuclide probe labeled precursor targeting tumor CD38 as shown in Formula (1).

[0057] Fifthly, the present invention provides the use of a labeled precursor of a cyclic peptide nuclide probe targeting tumor CD38 as shown in formula (1).

[0058] Sixthly, the present invention provides, as follows 68 Ga / [ 18 Application of F]AlF-labeled cyclic peptide nuclide probes targeting tumor CD38 as shown in formula (1).

[0059] Furthermore, CD38 is highly expressed in most tumors, including any one or more of the following non-solid tumors: multiple myeloma, chronic lymphocytic leukemia, Waldenström macroglobulinemia, primary systemic amyloidosis, mantle cell lymphoma, acute myeloid leukemia, acute lymphoblastic leukemia, natural killer cell leukemia, NK / T cell lymphoma, etc., preferably multiple myeloma.

[0060] In Examples 1 to 6 of this invention, all raw materials and reagents used can be purchased from the market.

[0061] The present invention will be further illustrated below with reference to the embodiments:

[0062] Example 1

[0063] The synthesis method of CD38-targeted cyclic peptide CP003 is as follows: Using Fmoc-amine resin, following the Fmoc solid-phase synthesis strategy, the following components were sequentially coupled: Nota, Boc-cysteine, R chain, S-triphenylmethyl-L-cysteine, aspartic acid, L-diaminoheptanoic acid, 4-phenylphenylalanine, leucine, valine, arginine, aspartic acid, histidine, tyrosine, L-diaminoheptanoic acid, arginine, and alanine. 2-Bromoacetic acid was then used for coupling and cyclization. After the entire synthesis was completed, BOC hydrolysis was performed, and the peptide was cleaved from the resin to obtain crude cyclic peptide. This crude peptide was purified by preparative liquid chromatography and lyophilized to obtain the target ligands (CP001, CP002, CP003, CP004, CP005, and CP006). The ligand structures were identified by mass spectrometry, as shown in Figure 1.

[0064] Example 2 68 Preparation of Ga-CP001 / CP002 / CP003 / CP004 / CP005 / CP006

[0065] (1) Take 68 Add 1 mL of Ga eluent and 180 μL of sodium acetate (1 M) to adjust the pH to 4-5;

[0066] (2) Add 50 μg (1 mg / mL) of the precursor and react at 37 °C for 10 min;

[0067] (3) Radio-TLC detection of product labeling rate.

[0068] After labeling, the peak area ratio of the products under Radio-TLC detection was all above 99%, indicating that the labeling rate of the products was above 99% (Figures 3A-F).

[0069] Example 3 Al 18 Preparation of F-CP001 / CP002 / CP003 / CP004 / CP005 / CP006

[0070] (1) Produced by a cyclotron [ 18 F] Fluoride ions, take 200 μL of fluoride ions for approximately 30 mCi;

[0071] (2) Add 50 μg (1 mg / mL) of the precursor, 6 μL of 2 mM AlCl3 solution and 1 mL of anhydrous acetonitrile, and mix thoroughly.

[0072] (3) Add 12 μL of glacial acetic acid to adjust the pH to 3 and mix thoroughly;

[0073] (4) Place the mixture in a 100°C constant temperature metal heater and incubate for 10 minutes. After the reaction is complete, remove it and cool it to room temperature.

[0074] (5) Radio-TLC detection of product labeling rate;

[0075] (6) Use Sep-Pak C18 purification column for separation and purification to make the radiochemical purity of the target compound greater than 99%;

[0076] (7) Radio-TLC testing of the radiochemical purity of the product;

[0077] After purification by Sep-Pak C18 column, the peak area ratio of the labeled product was above 99% as detected by Radio-TLC, indicating that the radiochemical purity of the product was above 99% (Figure 3G-L).

[0078] Example 4 68 Imaging of six Ga-labeled cyclic peptides in tumor-bearing mice

[0079] (1) Place the molp8 tumor mass in PBS and use tweezers to divide it into small clumps of 2mm×2mm;

[0080] (2) Tumor blocks were inoculated under the armpit of 5-week-old male NSG mice using a cannula;

[0081] (3) When the tumor volume reaches 100-150 mm 3 When used for Micro-PET imaging;

[0082] (4) In the molp8 tumor-bearing mouse model, 5.34 MBq was injected via the tail vein. 68 Ga-CP001、 68 Ga-CP002, 68 Ga-CP003, 68 Ga-CP004 68 Ga-CP005 and 68Ga-CP006 was used to perform Micro PET / CT scans at 30 min, 1 h, 2 h and 4 h after injection. The animals were placed prone on the scanning table and anesthetized with 1-2% isoflurane and oxygen flow rate of 300 mL / min. The scan time was 15 min.

[0083] Micro PET / CT imaging: As shown in Figures 4 and 5 and Tables 1-6, PET / CT imaging shows that 30 minutes after drug administration, 68 Ga-labeled cyclic peptides are mainly concentrated in tissues such as tumors, lungs, and kidneys. 68 The tumor uptake value of Ga-CP004 was the highest at 9.09 ± 0.55% ID / g, which was higher than that of other tumors. 68 Ga-CP001 (3.15±0.52%ID / g), 68 Ga-CP002 (2.86±0.49%ID / g), 68 Ga-CP003 (4.53±0.44%ID / g), 68 Ga-CP005 (4.09±0.52%ID / g), 68 Ga-CP006 (5.17±0.96% ID / g) group; and, 68 The highest hepatic uptake value of Ga-CP003 was 0.80±0.07%ID / g (30 min), which was lower than that of other drugs. 68 Ga-CP001、 68 Ga-CP002 and 68 Ga-CP005 group; more importantly... 68 All six Ga-labeled cyclic peptides showed low uptake in the kidneys (<15% ID / g), which can reduce radiation-induced kidney damage.

[0084] Table 1 68 Tumor uptake values ​​of six Ga-labeled peptides at different time points (unit: %ID / g)

[0085] Table 2 68 Liver uptake values ​​of six Ga-labeled peptides at different time points (unit: %ID / g)

[0086] Table 3 68 Renal uptake values ​​of six Ga-labeled peptides at different time points (unit: %ID / g)

[0087] Table 4 68 Cardiac uptake values ​​of six Ga-labeled peptides at different time points (unit: %ID / g)

[0088] Table 5 68 Lung uptake values ​​of six Ga-labeled peptides at different time points (unit: %ID / g)

[0089] Table 6 68 Tumor / muscle ratio of six Ga-labeled peptides at different time points (unit: %ID / g)

[0090] Example 5 68 Ga-CP003 and 68 Imaging of Ga-CP004 in tumor-bearing mice under 800x blocking conditions.

[0091] Experimental steps (1) to (4) are the same as in Example 4; subsequently, in the molp8 tumor-bearing mouse model, the administration method for the blocking group was as follows: first, 40 mg (800 times the blocking dose) of unlabeled CP003 or CP004 was injected via the tail vein, and half an hour later, 5.34 MBq was injected via the tail vein. 68 Ga-CP003 or 68 Ga-CP004, in injection 68 Ga-CP003 or 68 Micro PET / CT scans were performed at 30 min, 1 h, and 2 h after Ga-CP004 administration. The animals were placed prone on the scanning table and anesthetized with 1-2% isoflurane and oxygen at a flow rate of 300 mL / min. The scan time was 15 min.

[0092] Micro PET / CT Imaging: As shown in Figures 6 and 7 and Table 7, PET / CT imaging reveals: during injection... 68 Ga-CP003 1h and 2h, 68 The Ga-CP003-800x blocking group showed significantly lower uptake at tumor tissue compared to the non-blocking group. 68 Ga-CP003 (p<0.05). This indicates... 68 Ga-CP003 has specific tumor targeting properties.

[0093] As shown in Figures 8 and 9 and Table 8, PET / CT imaging reveals: during injection... 68 Ga-CP004 1h and 2h, 68 The Ga-CP004-800x blocking group showed significantly lower uptake at tumor tissue compared to the non-blocking group. 68 Ga-CP004 (p<0.01). This indicates... 68 Ga-CP004 has specific tumor targeting properties.

[0094] Table 7 68Ga-CP003 and 68 Tumor uptake values ​​at different time points in the Ga-CP003 800-fold blockade group (unit: %ID / g)

[0095] Table 8 68 Ga-CP004 and 68 Tumor uptake values ​​at different time points in the Ga-CP004 800-fold blockade group (unit: %ID / g)

[0096] Example 6 A1 18 Imaging of six F-labeled cyclic peptides in tumor-bearing mice

[0097] (1) Place the mm1s tumor mass in PBS and use tweezers to divide it into small clumps of 2mm×2mm;

[0098] (2) Tumor blocks were inoculated under the armpit of 5-week-old male NSG mice using a cannula;

[0099] (3) When the tumor volume reaches 100-150 mm 3 When used for Micro-PET imaging;

[0100] (4) In the mm1s tumor-bearing mouse model, 7.48 MBq Al was injected via the tail vein. 18 F-CP003 was used to perform Micro PET / CT scans at 30 min, 1 h, and 2 h after injection. The animals were placed prone on the scanning bed and anesthetized with 1-2% isoflurane and oxygen at a flow rate of 300 mL / min. The scan time was 15 min.

[0101] Micro PET / CT imaging: As shown in Figures 10 and 11 and Tables 9-12, PET / CT imaging shows that 1 hour after drug administration, Al 18 F-labeled cyclic peptides are mainly concentrated in tissues such as tumors, lungs, and kidneys. Among them, Al 18 The highest tumor uptake value of F-CP004 was 4.45 ± 0.57% ID / g (30 min), which was higher than that of Al. 18 F-CP001, Al 18 F-CP002, Al 18 F-CP003, Al 18 F-CP005 and Al 18 Group F-CP006;

[0102] Table 9 Al 18 Tumor uptake values ​​of six F-labeled peptides at different time points (unit: %ID / g)

[0103] Table 10 Al 18 Liver uptake values ​​of six F-labeled peptides at different time points (unit: %ID / g)

[0104] Table 11 Al 18 Renal uptake values ​​of four F-labeled peptides at different time points (unit: %ID / g)

[0105] Table 12 Al 18 Lung uptake values ​​of six F-labeled peptides at different time points (unit: %ID / g)

[0106] The labeling precursor, probe, preparation method, and application of the present invention have been described in detail above. Specific examples have been used to illustrate the principles and implementation methods of the present invention. The descriptions of the above embodiments are only for the purpose of helping to understand the method and core ideas of the present invention. It should be noted that those skilled in the art can make several improvements and modifications to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A cyclic peptide, characterized in that, Its structure is: Cyclo(Ac-Ala-Arg-L-2-aminoheptanoic acid-Tyr-His-Asp-Arg-Val-Leu-Bip(4,4)-L-2-aminoheptanoic acid-Asp-Cys).

2. A marker precursor, characterized in that, It has the structural formula shown in equation (1): Where: X is selected from equations (2) to (7): R is selected from equations (8) to (10): In equations (8) to (10), a is an integer from 1 to 8, b is an integer from 1 to 24, and c is an integer from 1 to 12.

3. The labeling precursor as described in claim 2, characterized in that, The marker precursor has a structural formula as shown in any of formulas (11) to (16):

4. The method for preparing the labeled precursor as described in claim 2 or 3, characterized in that, The labeled precursor was obtained using the required amino acids and DOTA as raw materials via the Fmoc solid-phase synthesis method.

5. The preparation method according to claim 4, characterized in that, The required amino acids include any one of formulas (8) to (10), and Boc-cysteine, S-triphenylmethyl-L-cysteine, aspartic acid, L-diaminoheptanoic acid, 4-phenylphenylalanine, leucine, valine, arginine, aspartic acid, histidine, tyrosine, L-diaminoheptanoic acid, arginine, and alanine.

6. A probe, characterized in that, include: The cyclic peptide as described in claim 1, the labeled precursor as described in claim 2 or 3, and / or the labeled precursor and radionuclide obtained by the preparation method as described in claim 4 or 5.

7. The probe as described in claim 6, characterized in that, The radionuclides include: 67 Ga、 68 Ga、 64 Cu、 18 F, 86 Y、 90 Y、 89 Zr、 111 In、 99 mTc, 11 C 123 I, 125 I, 124 I, 131 I, 177 Lu、 211 At、 153 Sm、 186 Re、 188 Re、 212 Pb, 225 Ac、 213 Bi、 212 Any one of Bi.

8. The method for preparing the probe as described in claim 6 or 7, characterized in that, The probe is obtained by mixing the radionuclide with the labeled precursor and reacting the mixture.

9. The use of the cyclic peptide of claim 1, the labeling precursor of claim 2 or 3, the labeling precursor obtained by the preparation method of claim 4 or 5, the probe of claim 6 or 7, and / or the probe obtained by the preparation method of claim 8 in any of the following: (I) Preparation of products for detecting CD38 expression levels; and / or (II) Preparation of products for detecting non-solid tumors; and / or (III) Detecting CD38 expression levels; and / or (IV) Detection of non-solid tumors.

10. A method for detecting non-solid tumors, characterized in that, The probe as described in claim 6 or 7 and / or the probe prepared by the method described in claim 8 are applied to the analyte, and after imaging, the detection result is obtained.

11. The product, characterized in that, include: The cyclic peptide as described in claim 1, the labeling precursor as described in claim 2 or 3, the labeling precursor obtained by the preparation method as described in claim 4 or 5, the probe as described in claim 6 or 7, and / or the probe obtained by the preparation method as described in claim 8.

Images