CN117945993A - Glutamic acid-urea dimer derivative containing L-aspartic acid connector and application thereof - Google Patents

Glutamic acid-urea dimer derivative containing L-aspartic acid connector and application thereof Download PDF

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CN117945993A
CN117945993A CN202410107111.6A CN202410107111A CN117945993A CN 117945993 A CN117945993 A CN 117945993A CN 202410107111 A CN202410107111 A CN 202410107111A CN 117945993 A CN117945993 A CN 117945993A
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glutamic acid
tumor
derivative containing
dgah
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张俊波
李作杰
阮晴
江雨豪
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Beijing Normal University
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Beijing Normal University
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Abstract

The invention relates to the technical fields of radiopharmaceuticals and clinical nuclear medicine, in particular to a glutamic acid-urea dimer derivative containing an L-aspartic acid connector and application thereof. The radioactive preparation obtained by labeling the glutamic acid-urea dimer derivative containing the L-aspartic acid connector with 99m Tc has high uptake in tumors, very low uptake in non-target tissues, good tumor/non-target ratio, and specific binding with prostate specific membrane antigen, and can be used as a novel tumor radioactive drug for diagnosing prostate cancer with popularization and application values.

Description

Glutamic acid-urea dimer derivative containing L-aspartic acid connector and application thereof
Technical Field
The invention relates to the technical fields of radiopharmaceuticals and clinical nuclear medicine, in particular to a glutamic acid-urea dimer derivative containing an L-aspartic acid connector and application thereof.
Background
Prostate Specific Membrane Antigen (PSMA) is a transmembrane glycoprotein located on the cell membrane and is specifically highly expressed in prostate cancer (PCa). In addition, the expression level is related to tumor invasiveness, and is an important target for PCa detection and treatment.
Small molecule inhibitors containing glutamate-urea units bind specifically to PSMA on the surface of prostate cancer cells. Radionuclide-labeled inhibitors containing glutamate-urea units that target PSMA are now a focus of international radiopharmaceuticals. 99m Tc is the most common Single Photon Emission Computed Tomography (SPECT) imaging nuclide, can be obtained from a 99Mo/99m Tc generator, and the 99m Tc marked medicine can be prepared through medicine box, so that the method is easy to clinically popularize and use, and therefore, the development of a novel PSMA-targeted 99m Tc tumor radiopharmaceutical has important clinical application value.
In radiopharmaceuticals studies, increasing the number of targeting groups in the radiolabeled molecule is a viable strategy to further increase the accumulation of probes within the tumor. In 2023, literature reports 68 Ga-PSMA-D5 (containing two glutamate-urea pharmacophores) tumor-bearing mice biodistribution showed that higher tumor uptake and higher tumor/kidney ratio (Chen Y,Zhang X,Ni M,et al.Synthesis,Preclinical Evaluation,and First-in-Human PET Study of[68Ga]-Labeled Biphenyl-Containing PSMA Tracers.J Med Chem.2023;66(18):13332-13345.). compared to 68Ga-PSMA-617,68 Ga-PSMA-D5 and that the linker (linker) linked the targeting group and the chelating group linked to the radionuclide, played an important role in modulating the pharmacodynamics and pharmacokinetics of the radiopharmaceuticals. Based on the background, the L-aspartic acid is used as a connecting agent to synthesize the derivative containing two glutamic acid-urea targeting groups, and the derivative is subjected to 99m Tc labeling under the participation of other co-ligands to search for a novel tumor radiopharmaceutical specifically targeting PSMA, so that the preparation method has important scientific significance and wide clinical application prospect.
Disclosure of Invention
The invention provides a glutamic acid-urea dimer derivative containing an L-aspartic acid connector and application thereof, and the derivative has the advantages of good stability, simple and convenient preparation, high tumor uptake and good target/non-target ratio after radiolabeling, and has important scientific significance and application prospect in the field of tumor diagnosis and treatment.
Specifically, the invention provides the following technical scheme:
Glutamic acid-urea dimer derivative containing L-aspartic acid connector and application thereof, wherein the structural formula is as follows:
The corresponding 99m Tc complex prepared by the derivative is specifically combined with PSMA, has very low uptake in non-target organs, has high tumor uptake value and tumor/non-target ratio, and can achieve very good effect on tumor diagnosis and treatment.
The invention also provides a radioactive preparation comprising the glutamic acid-urea dimer derivative containing the L-aspartic acid linker and the application thereof, wherein the glutamic acid-urea dimer derivative is marked by radionuclide.
Preferably, in the above-mentioned radioactive preparation, the radionuclide moiety is a metal radionuclide.
Preferably, in the above radioactive preparation, the metal radionuclide is 99mTc、99Tc、94mTc、94Tc、52Mn、186 Re or 188 Re.
Most preferably, in the above radioactive preparation, the radionuclide is 99m Tc, and the structural formula of the radioactive preparation is (II):
the invention also provides application of the radioactive preparation in preparing tumor radiopharmaceuticals.
The invention has the beneficial effects that: the invention provides a glutamic acid-urea dimer derivative containing an L-aspartic acid connector and application thereof, and a radioactive preparation obtained by labeling the glutamic acid-urea dimer derivative with a radioactive nuclide has high uptake in tumors, and meanwhile, the ratio of the tumors to non-target is good, so that the glutamic acid-urea dimer derivative is a novel tumor radioactive drug with popularization significance.
Drawings
FIG. 1: 99m Tc-DGAH-EDDA was visualized in a control SPECT 2h after injection in mice with 22RV1 tumor Balb/c model.
Fig. 2: after 30min ahead injection of PSMA inhibitor 2-PMAP, 99m Tc-DGAH-EDDA was used to inhibit SPECT imaging in the group 2h after injection in mice with 22RV1 tumor Balb/c model.
Detailed Description
The invention provides a glutamic acid-urea dimer derivative containing an L-aspartic acid connector and application thereof, and in a preferred embodiment, the invention provides a radioactive preparation with a structural general formula of 99m Tc-DGAH-EDDA:
The preparation method comprises the following steps:
Synthesis of ligand DGAH:
Dissolving 6-chloronicotinic acid (compound 1) in 80% hydrazine hydrate (hydrazine hydrate), refluxing and stirring for 4 hours, cooling to room temperature, filtering the precipitate, washing a filter cake, and vacuum drying to obtain a compound 2; dissolving the compound 2 and Di-tert-butyl dicarbonate (Di-tert-butyl dicarbonate) in N, N-Dimethylformamide (DMF), stirring at room temperature for 12h, and purifying by column chromatography to obtain a compound 3; weighing a proper amount of L-glutamic acid di-tert-butyl ester hydrochloride (compound 4) in a round-bottom flask, adding a proper amount of Dichloromethane (DCM) for dissolution, then sequentially adding triphosgene (Triphosgene), N-E-benzyloxycarbonyl-L-lysine tert-butyl ester hydrochloride (H-Lys (Z) -OtBu. HCl) and Triethylamine (TEA), reacting for 4 hours at room temperature, and separating and purifying by column chromatography to obtain a compound 5; dissolving the compound 5 in methanol, and reducing palladium carbon (Pd/C) and hydrogen (H 2) to obtain a compound 6; hydrolysis of di-tert-butyl L-aspartate hydrochloride (compound 7) with NaOH to give compound 8; the compound 8 reacts with benzyl chloroformate (Cbz-Cl) for 6 hours at low temperature to obtain a compound 9; dissolving a compound 6, a compound 9, 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) and TEA in DMF, stirring at room temperature for 12h, and purifying by column chromatography to obtain a compound 10; dissolving the compound 10 in methanol, and reducing Pd/C, H 2 to obtain a compound 11; dissolving the compound 3 and the compounds 11, HATU and TEA in DMF, stirring at room temperature for 12h, and purifying by column chromatography to obtain a compound 12; compound 12 was dissolved in DCM, added with equal volume of trifluoroacetic acid (TFA), reacted for 3h at room temperature, and purified by column chromatography to give the final product DGAH.
The specific synthetic route is as follows:
Preparation of 99m Tc-DGAH-EDDA Complex:
Weighing N-tris (hydroxymethyl) methylglycine (Tricine) and ethylenediamine-N, N' -diacetic acid (EDDA), dissolving in normal saline, adding succinate buffer solution with pH of 7.0, adjusting the pH of the solution to 7.0-8.0 by NaOH, sequentially adding ligand DGAH, snCl 2·2H2 O and freshly leached Na 99mTcO4, and reacting at 100 ℃ for 20-30min to obtain the 99m Tc-DGAH-EDDA complex.
The 99m Tc-DGAH-EDDA complex prepared by the method has radiochemical purity of more than 90 percent, is hydrophilic substance and has good in vitro stability. The imaging result shows that the PSMA inhibitor has very high uptake and good retention at the tumor part of a tumor-bearing mouse, the non-target tissue uptake is low, the tumor uptake is obviously reduced after the PSMA inhibitor is injected for inhibition, the PSMA specific uptake is shown in the tumor, and the PSMA inhibitor is a novel SPECT molecular probe with excellent performance and can be used for tumor imaging.
The following examples are illustrative of the invention and are not intended to limit the scope of the invention. The specific techniques or conditions are not identified in the examples and are described in the literature in this field or are carried out in accordance with the product specifications.
The invention is illustrated by the following examples: a 99m Tc labeled glutamic acid-urea dimer derivative containing an L-aspartic acid connector can be used for SPECT/CT imaging of targeted PSMA, and has a structural general formula of 99m Tc-DGAH-EDDA.
The preparation method is as follows, but is not limited to the illustrated complexes:
1. preparation of 99m Tc-DGAH-EDDA
Synthesis of DGAH
Synthesis of Compound 2. Compound 1 (2.0 g,12.7 mmol) was dissolved in 20mL of ethanol and hydrazine hydrate (1.48 mL,31.7 mmol) was added. Refluxing the mixture overnight, cooling to room temperature to obtain solid, filtering, collecting, washing with petroleum ether/ethyl acetate (2:1) to obtain yellow solid as compound 2(1.60g,81.0％).1H NMR(400MHz,DMSO-d6):δ8.520(d,J＝2.3Hz,1H),7.88(dd,J＝8.9,2.3Hz,1H),6.63(d,J＝9.0Hz,1H).
Synthesis of Compound 3. Compound 2 (2.0 g,13.2 mmol) and di-tert-butyl dicarbonate (3.18 g,14.59 mmol) were dissolved in DMF (10 mL), 2.76mL TEA was added, stirring was performed at room temperature for 12h, TLC monitored the progress of the reaction, and the filtrate was concentrated. Purifying by column chromatography, [ DCM/MeOH=50/1 (v/v) ], and finally obtaining white solid, namely the compound 3(2.5g,74.5％).1H NMR(600MHz,Methanol-d4)δ8.63(d,J＝1.0Hz,1H),8.04(s,1H),6.68(s,1H),1.96(s,1H),1.46(s,9H),1.27(s,6H).
Synthesis of Compound 5. Triphosgene (2.0 g,6.74 mmol) was weighed into a round bottom flask, dissolved in 20mL of DCM, then added compound 4 (5.98 g,20.22 mmol), TEA (9.37 mL,67.4 mmol) and stirred at room temperature for 1h, then added N-E-benzyloxycarbonyl-L-lysine tert-butyl hydrochloride (7.54 g,20.22 mmol) and TEA (2.81 mL,20.22 mmol) and reacted at room temperature for 2h. After the reaction, the solvent was distilled off under reduced pressure, followed by purification by column chromatography to give [ DCM/MeOH=100/1 (v/v) ], and an oily substance was obtained as the compound 5(8.0g,64.0％).1H NMR(600MHz,DMSO-d6)δ7.52-7.14(m,5H),6.27(d,J＝23.8Hz,2H),5.00(s,1H),4.07-3.88(m,2H),2.98(d,J＝6.3Hz,2H),2.22(d,J＝16.8Hz,2H),1.87(d,J＝6.8Hz,2H),1.67(s,2H),1.45-1.35(m,27H),1.30-1.15(m,3H),0.86(s,1H).
Synthesis of Compound 6. Compound 5 (3.0 g,4.82 mmol) was weighed into a round bottom flask, dissolved in 5mL of methanol, then palladium on carbon (340 mg,1.74 mmol) was added, the reaction was carried out at room temperature under hydrogen pressure for 12h, and tlc monitored the progress of the reaction. After the reaction, the mixture was filtered through celite, the solvent was removed by distillation under reduced pressure, and the mixture was purified by column chromatography to give [ DCM/MeOH=30/1 (v/v) ], to give an oily substance as a compound 6(2.0g,85％).1H NMR(600MHz,Chloroform-d)δ5.20(s,1H),4.34(d,J＝5.0Hz,2H),4.12(d,J＝7.2Hz,1H),2.68(d,J＝1.3Hz,1H),2.33(d,J＝9.7Hz,2H),2.05(s,2H),1.81(d,J＝58.4Hz,2H),1.60(s,2H),1.45(d,J＝16.6Hz,27H),1.26(s,2H).
Synthesis of Compound 8. Compound 7 (2.0 g,7.10 mmol) was weighed into a round bottom flask, 5mL dioxane was added for dissolution, then 5mL NaOH (1 mol/L) was added, the reaction was carried out at room temperature for 12h, and TLC monitored the progress of the reaction. After the reaction, the pH was adjusted to weak acidity, the solvent was distilled off under reduced pressure, and ether and petroleum ether were washed several times to obtain a white powder, which was crude compound 8 (0.86 g, 91%). 1H NMR(600MHz,Methanol-d4 ) Delta 4.18-3.92 (m, 1H), 2.86-2.57 (m, 2H).
Synthesis of Compound 9. Compound 8 (2.5 g,18.78 mmol) was dissolved in 25mL of water, K 2CO3 (5.2 g,37.6 mmol) was added and the mixture was cooled in an ice bath. Benzyl chloroformate (3.9 mL,26.3 mmol) was then added dropwise to the mixture, stirring was continued at room temperature for 18h, and TLC monitored the progress of the reaction. The mixture was extracted with diethyl ether, the pH was adjusted to 1 with hydrochloric acid and the acidified solution was extracted with ethyl acetate. Drying with anhydrous MgSO 4, concentrating to obtain compound 9(3.5g,87％).1H NMR(600MHz,Methanol-d4)δ7.52-7.16(m,5H),5.08(d,J＝0.8Hz,2H),4.62(d,J＝9.1Hz,1H),2.79-2.48(m,2H).
Synthesis of Compound 10. Compound 9 (1.0 g,3.74 mmol), HATU (3.56 g,9.35 mmol) and Compound 6 (4.56 g,9.35 mmol) were weighed into a round bottom flask and dissolved in 15mL of DMF followed by TEA (1.3 mL,9.35 mmol) and reacted at room temperature for 12h and TLC monitored the progress of the reaction. Cooling to room temperature, removing solvent under reduced pressure, purifying by column chromatography, [ DCM/MeOH=80/1 (v/v) ], to obtain a colorless oily substance, namely the compound 10(2.9g,64％).1H NMR(400MHz,Methanol-d4)δ7.41-7.22(m,5H),5.10(s,2H),4.52(m,1H),4.29-4.08(m,3H),3.72(s,1H),3.26-2.93(m,4H),2.81(s,7H),2.31(d,J＝7.4Hz,13H),1.56-0.88(m,56H).
Synthesis of Compound 11. Compound 10 (2.0 g,1.65 mmol) was weighed into a round bottom flask, dissolved in 5mL of methanol, then palladium on carbon (219 mg,1.12 mmol) was added, the reaction was carried out at room temperature under hydrogen pressure for 12h, and tlc monitored the progress of the reaction. After the reaction, the mixture was filtered through celite, the solvent was removed by distillation under reduced pressure, and the mixture was purified by column chromatography to give [ DCM/MeOH=30/1 (v/v) ], to give a white powder as a compound 11(1.5g,88％).1H NMR(600MHz,Chloroform-d)δ4.31-4.09(m,6H),3.81(d,J＝6.3Hz,1H),3.10(m,4H),2.65-2.26(m,6H),2.12-1.98(m,4H),1.81-1.65(m,4H),1.41-0.95(m,62H).
Synthesis of Compound 12. Compound 3 (100 mg,0.40 mmol), HATU (165.40 mg,0.44 mmol), compound 11 (635.90 mg,0.60 mmol) were weighed into a round bottom flask, dissolved in 5mL DMF, then TEA (82.49 ul,0.60 mmol) was added, reacted at room temperature for 12h, tlc monitored the progress of the reaction. Cooling to room temperature, removing solvent under reduced pressure, purifying by column chromatography, [ DCM/MeOH=40/1 (v/v) ], to obtain a colorless oily substance, namely the compound 12(0.30g,58.1％).1H NMR(400MHz,Methanol-d4)δ8.56(d,J＝2.4Hz,1H),8.01(d,J＝7.0Hz,1H),7.70(s,1H),5.47(s,1H),4.31-3.98(m,4H),3.06(d,J＝80.8Hz,5H),2.79(s,3H),2.38-2.20(m,4H),1.94(d,J＝36.8Hz,3H),1.43(m,74H).
Synthesis of Compound DGAH. Compound 12 (200 mg,0.15 mmol) was weighed into 2mL DCM and then 2mL TFA was added and reacted at room temperature for 3h with TLC monitoring the progress of the reaction. Cooling to room temperature, removing solvent under reduced pressure, purifying by column chromatography, [ DCM/MeOH=5/1 (v/v) ], to obtain a colorless oily substance, namely the compound DGAH(110mg,84.6％).1H NMR(600MHz,Methanol-d4)δ8.44(s,1H),8.12(d,J＝1.8Hz,1H),6.88(s,1H),4.64(s,1H),4.23(d,J＝7.2Hz,3H),3.63(d,J＝30.3Hz,4H),3.30-3.07(m,3H),2.95-2.51(m,3H),2.37(s,3H),1.95(s,6H),1.67-0.77(m,8H).MS-ESI:calcd for[M+H]+:871(M＝C34H50N10O17),found:871.
The synthetic route is as follows:
b. preparation of 99m Tc-DGAH-EDDA Complex
20Mg Tricine and 10mg EDDA are weighed and dissolved in 0.5mL physiological saline, succinate buffer with pH of 7.0 is added, the pH of the solution is adjusted to 7.0-8.0 by NaOH (1 mol/L), 20 mug ligand DGAH, 100 mug SnCl 2·2H2 O and 0.5mL freshly leached Na 99mTcO4 (about 370 MBq) are sequentially added, and the 99m Tc-DGAH-EDDA complex is obtained after 20min reaction at 100 ℃.
Performance measurement of 99m Tc-DGAH-EDDA complexes according to the invention:
1. Identification of complexes
A. High Performance Liquid Chromatography (HPLC) method identification:
With a C18 reverse column, a SCL-10AVP type high pressure liquid chromatograph, wherein the A phase is water (containing 0.1% trifluoroacetic acid), the B phase is acetonitrile (containing 0.1% trifluoroacetic acid), the gradient is 0-2min, the B phase is 10%, the B phase is 2-10min, the B phase is changed from 10% to 90%, the B phase is 10-20min, the B phase is 90%, and the B phase is changed from 90% to 10% in 20-25 min. The sample injection amount was 10. Mu.L, and the flow rate was 1mL/min. The retention time (R t) was determined as: 99m Tc-DGAH-EDDA for 13.11min.
B. Thin Layer Chromatography (TLC) identification
The unfolding system is as follows: polyamide film as a support, ammonium acetate (L mol/L)/methanol=2:1 (V/V) as a developing agent, and the R f values of the respective radioactive components under the system are shown in Table 1 below
Table 1 results of chromatography of the components of the Complex (R f values)
The radiochemical purity of the markers identified by both methods is greater than 90%
2. Determination of the lipid partition coefficient of the Complex
0.9ML of phosphate buffer (0.025 mol/L) at pH 7.4 was taken in a 5mL centrifuge tube, 1mL of n-octanol and 0.1mL 99m Tc-DGAH-EDDA solution were added to the centrifuge tube, capped, vortexed, and centrifuged for 5min (5000 r/min). Then 3×0.1mL were removed from the organic and aqueous phases, respectively, the radioactivity counts of the two phases were determined and the partition coefficient D (d=radioactivity of the organic phase/radioactivity of the aqueous phase) was calculated, and three groups were repeated. The lipid partition coefficient (log D) of 99m Tc-DGAH-EDDA complex was measured to be-2.72.+ -. 0.13, indicating that it is a hydrophilic substance.
3. Stability determination of Complex
The 99m Tc-DGAH-EDDA complex is placed at room temperature and placed in the whole blood of a mouse at 37 ℃ for 8 hours, and the radiochemical purity of the complex is measured, so that the radiochemical purity of the complex is more than 90% after the complex is placed at room temperature and placed in the whole blood of the mouse at 37 ℃ for 8 hours, and the in-vitro stability of the complex is good.
4. Biodistribution experiments of complexes in normal Kunming mice
The mice were sacrificed 2h after injection with isoflurane gas for anesthesia by injecting 0.10mL 99m Tc-DGAH-EDDA marker fluid (about 3.7x10 5 Bq) into the tail vein of normal Kunming mice. In addition, mice in vivo inhibition experiments were performed on 99m Tc-DGAH-EDDA using PSMA inhibitor (2-PMPA) as follows: 0.20mL of physiological saline containing 500. Mu.g of 2-PMAP was injected into the tail vein, after 30min, 0.10mL 99m Tc-DGAH-EDDA marker fluid (about 3.7X10 5 Bq) was injected, and after 2h mice were anesthetized with isoflurane gas and then sacrificed. The heart, liver, spleen, lung, kidney, muscle, bone, stomach, large intestine, small intestine, blood and other relevant tissues and organs were taken, cleaned, weighed, and their radioactivity counts were measured on a gamma Counter to calculate the percent injection dose per gram (% ID/g) of each tissue, with 5 mice per group. The results are shown in Table 2.
TABLE 2 biological distribution (% ID/g) in normal Kunming mice 2h after 99m Tc-DGAH-EDDA injection
As can be seen from Table 2, the kidney was used as an organ with higher PSMA expression, and 99m Tc-DGAH-EDDA was taken very little in other non-target organs, except for a certain basal uptake in the kidney.
5. SPECT imaging of complexes in tumor-bearing mice
From the tail vein of the Balb/c model mice with 22RV1 tumor, 0.5mL (about 37 MBq) of 99m Tc-DGAH-EDDA solution was injected, and after 2 hours, anesthetized with isoflurane gas. Mice were fixed prone and subjected to control SPECT/CT imaging. 0.20mL of physiological saline containing 500. Mu.g of 2-PMAP was injected from the tail vein into a Balb/c model mouse with 22RV1 tumor, 30min later, 0.50mL 99m Tc-DGAH-EDDA marker fluid (about 3.7X10 7 Bq) was injected, and after 2h, the mice were anesthetized with isoflurane gas. Mice were fixed prone and subjected to inhibition group SPECT/CT imaging. SPECT imaging results showed that 99m Tc-DGAH-EDDA was evident in the tumor in the control group (shown in FIG. 1) and was very low in other non-target tissues. And in the inhibition group (shown in figure 2), the uptake of the tumor is obviously inhibited, which shows that the uptake of the PSMA in the tumor has specificity, and the PSMA can be used as a novel PSMA-targeted SPECT molecular probe with excellent performance.
While the invention has been described in detail in the foregoing general description and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that modifications and improvements can be made thereto. Thus, various linkers such as D-aspartic acid and other amino acids, peptide chains, polyethylene glycol (PEG) chains, fatty chains, etc., or radionuclides labeled with Tricine and triphenylphosphine sodium tri-m-sulfonate (TPPTS), tricine and diphenylphosphinobenzene-3-sulfonate sodium (TPPMS), tricine and 3,3' - (phenylphosphinediyl) disodium (benzene-1-sulfonate), tricine and nicotinic acid (NIC), tricine and isonicotinic acid (ISONIC), tricine and 3, 5-pyridinedicarboxylic acid (PDA), tricine and 3-pyridinesulfonic acid (PSA), tricine and glucoheptonate, tricine and glucosamine, tricine and mannitol, tricine and diphenylphosphinobenzoic acid, etc., are all within the scope of the present invention.

Claims (5)

1. A glutamic acid-urea dimer derivative containing an L-aspartic acid linker, characterized in that the glutamic acid-urea dimer derivative containing an L-aspartic acid linker has the structural formula (I):
2. A radioactive preparation comprising a glutamic acid-urea dimer derivative containing an L-aspartic acid linker according to any one of claims 1 labeled with a radionuclide.
3. The radioactive preparation according to claim 2, wherein the radionuclide is 99mTc、99Tc、94mTc、94Tc、52Mn、186 Re or 188 Re.
4. The radioactive preparation according to claim 3, wherein the radioactive preparation has a structural formula (II):
5. Use of a radioactive preparation according to any one of claims 2-4 for the preparation of a tumor imaging agent.
CN202410107111.6A 2024-01-25 2024-01-25 Glutamic acid-urea dimer derivative containing L-aspartic acid connector and application thereof Pending CN117945993A (en)

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