Difunctional chelating agent, PSMA ligand compound thereof, radiolabeled compound and application of difunctional chelating agent and PSMA ligand compound

Abstract

The invention discloses a bifunctional chelating agent, a PSMA ligand compound thereof, a radiolabeled compound and application thereof, and relates to the technical field of radiopharmaceuticals. Wherein the structure of the bifunctional chelating agent is shown in the specification, and R is targeted peptide. The bifunctional chelating agent can form a stable complex with various radionuclides such as 68Ga, Al18F, 177Lu and the like, so that the bifunctional chelating agent can be applied to integrated tumor diagnosis and treatment of 68Ga / Al18F / 177Lu. The PSMA ligand compound based on the bifunctional chelating agent has good PSMA binding capacity, and compared with a tracer agent or a therapeutic agent in the prior art, a radiolabeled compound composed of the PSMA ligand compound and radionuclide has equivalent or even higher uptake value on tumors expressed by a prostate specific membrane antigen receptor, so that the PSMA ligand compound can be used for preparing a prostate specific membrane antigen receptor. In addition, the in-vivo inhibition effect is remarkable, and a new strategy is provided for diagnosis and treatment of tumors with prostate specific membrane antigen receptor expression.

Description

Technical Field

[0001] This invention relates to the field of radiopharmaceutical technology, and particularly to bifunctional chelating agents and their PSMA ligand compounds, radiolabeled compounds and their applications. Background Technology

[0002] Prostate cancer (PCa) is the most common malignant tumor in men, with high incidence and mortality rates, making precision diagnosis and treatment urgently needed. Theranostics employs a "same target ligand + different radionuclides" strategy, enabling diagnosis and treatment on the same molecular platform, significantly improving the accuracy of radioimmunotherapy dose estimation. Prostate-specific membrane antigen (PSMA) is highly expressed on the surface of most PCa cells and has become a core target for radionuclide-targeted therapy. Currently, the most clinically mature... 68 Ga / 177 There are two major bottlenecks in the diagnosis and treatment of Lu-PSMA-617: (1) 68 Ge / 68 The Ga generator can only meet the needs of 1-3 patients per elution, with low throughput and high quality control frequency; (2) 68 Ga's half-life is too short (67.7 minutes), and its imaging window is far from sufficient to cover the image. 177 Lu (half-life 6.65 days) labels the pharmacokinetics of drugs over hours to days, thus limiting the accuracy of individualized dose estimation.

[0003] Fluorine-18 ( 18 F;t 1 / 2 =109.8min) can be mass-produced in multiple doses, automatically, and at a GMP level using a hospital cyclotron accelerator. The positron yield (96.7%) and average energy (0.635MeV) are both superior to 68 Ga can provide higher spatial resolution and lower radiation dose. However, constructing Al... 18 F / 177 Lu's "diagnosis and treatment pair" faces a key chemical bottleneck: Al 3+ With Lu 3+ The ionic radii differ by approximately 20 pm, resulting in significantly different coordination geometry preferences; existing chelate systems (DOTA, HBED, DATA, NOA, etc.) cannot simultaneously satisfy Al within the same molecular framework. 18 F complex and 177 The demanding coordination conditions of Lu. Therefore, to date, no universal chelating agent can simultaneously achieve... 68 Ga, Al 18 F and 177 The high stability and high radiochemical purity of Lu for labeling, the development of novel bifunctional chelators and their conjugation with PSMA-targeting ligands to form therapeutic radiopharmaceuticals, are crucial for treating prostate cancer.68 Ga / Al 18 F / 177 The core technical issues that need to be addressed in Lu-integrated diagnostic and therapeutic drugs are as follows.

[0004] Therefore, existing technologies still need improvement and development. Summary of the Invention

[0005] In view of the shortcomings of the prior art, the purpose of this invention is to provide bifunctional chelating agents and their PSMA ligand compounds, radiolabeled compounds and their applications, aiming to solve the problem that existing chelating systems cannot simultaneously satisfy Al within the same molecular backbone. 18 F complex and 177 Lu's coordination prevents prostate cancer from being achieved. 68 Ga / Al 18 F / 177 The issue of integrated diagnosis and treatment for Lu.

[0006] The technical solution of the present invention is as follows: Firstly, a bifunctional chelating agent is provided, the structural formula of which is as follows: Where R is the target peptide.

[0007] Specifically, this invention designs a novel bifunctional chelating agent that can, on the one hand, bind to… 68 Ga, Al 18 F, 177 It can form stable complexes with various radionuclides such as Lu, and can also couple with target peptides through amide condensation. Therefore, it can be used to connect radionuclides and target molecules for applications based on... 68 Ga / Al 18 F / 177 In Lu's integrated tumor diagnosis and treatment, technical effects that existing radiopharmaceuticals do not possess are achieved.

[0008] Secondly, a PSMA ligand compound or its ester or pharmaceutically acceptable salt is provided, the PSMA ligand compound having the following structural formula: ; or .

[0009] Specifically, the present invention designs a bifunctional chelator based on the first aspect, and conjugates it with a PSMA targeting ligand to design a PSMA ligand compound. This type of PSMA ligand compound has good PSMA binding ability and can be applied to the diagnosis and treatment of PSMA-expressing tumors.

[0010] Thirdly, the use of bifunctional chelating agents as described in the first aspect, or PSMA ligand compounds or their esters or pharmaceutically acceptable salts as described in the second aspect, in the preparation of radiolabeled compounds.

[0011] Fourthly, a radiolabeled compound is provided, comprising: a PSMA ligand compound as described in the second aspect, or an ester or pharmaceutically acceptable salt thereof, and a radionuclide, wherein the radionuclide binds to a chelating group of the PSMA ligand compound via coordination.

[0012] In a preferred embodiment, the radioactive nuclide includes 18 F, 225 Ab、 225 Ac、 198 Au、 199 Ag、 32 P, 44 Sc、 47 Sc、 165 Dy、 169 Er、 177 Lu、 142 Pr, 159 Gd, 72 As、 72 Se、 97 Ru、 109 Pd, 105 Rh、 101m Rh、 119 Sb、 128 Ba、 197 Hg, 211 At、 151 Eu、 153 Eu、 169 Eu、 203 Pb, 212 Pb, 175 Yb、 139 La、 140 La、 166 Ho、 51 Cr 43 Sc、 44 Sc、 51 Mn, 52 Mn, 55 Co、 64 Cu、 67 Ga、 68 Ga、 152 Tb, 155 Tb, 161 Tb, 86 Y、 89 Y、 90 Y、 89 Sr、 89Zr、 94m Tc, 99m Tc, 111 In、 114m In、 117m Sn、 153 Sm、 149 Pm, 152 Tb, 155 Tb, 201 Tl、 203 Pb, 32 P, 18 F, 76 Br、 77 Br、 123 I, 124 I, 125 I, 169 Er、 177 Lu、 186 Re、 188 Re、 211 At、 212 Pb, 212 Bi、 213 Bi、 223 Ra、 224 Ra、 186 Re、 188 Re、 225 Ab、 64 Cu、 67 Cu、 67 Ga、 68 Ga、 212 Bi、 213 Bi、 223 Ra、 224 Ra or 227 Th, preferably 177 Lu、 68 Ga、 86 Y、 90 Y, 64 Cu、 67 Cu、 213 Bi、 225 Ac or 89 Y.

[0013] In a preferred embodiment, the structure of the radiolabeled compound is selected from one of the following: .

[0014] Fifthly, a composition is provided comprising: a PSMA ligand compound as described in the second aspect, or an ester or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0015] In a preferred embodiment, the pharmaceutically acceptable excipient includes at least one of pharmaceutically acceptable excipients, pharmaceutically acceptable additives, and pharmaceutically acceptable adjuvants.

[0016] Sixthly, the use of a PSMA ligand compound as described in the second aspect, or an ester or pharmaceutically acceptable salt thereof, a radiolabeled compound as described in the fourth aspect, or a composition as described in the fifth aspect, in the preparation of a medicament for diagnosing and / or treating tumors having prostate-specific membrane antigen (PSMA) receptors.

[0017] In a preferred embodiment, the tumor with prostate-specific membrane antigen receptor includes one or more of the following: prostate cancer, renal cell carcinoma, glioma, thyroid cancer, breast cancer, and lung cancer.

[0018] Beneficial effects: Compared with the prior art, the advantages of this invention are: (1) The PSMA ligand compound prepared using the bifunctional chelating agent of the present invention has good binding ability with PSMA, and the IC50 of NOTAPY-PSMA-NP is [missing information]. 50 At 7.89nm, it is 1.2 times stronger than DOTA-PSMA-617; the IC of NOTAPY-PSMA-tNP 50 It has a clock speed of 4.95nM, which is 1.9 times stronger than DOTA-PSMA-617.

[0019] (2) Compared to existing tracers or therapeutic agents, such as DOTA-PSMA-617 or its radiolabeled compounds, the radiolabeled compounds provided by this invention (e.g., […]) 18 F]AlF-PSMA-tNP, [ 68 Ga]Ga-PSMA-tNP or [ 177 Lu]Lu-PSMA-tNP has a comparable or even higher uptake value for PSMA-expressing tumors.

[0020] (3) The radiolabeled compounds provided by this invention (e.g., [ 18 F]AlF-PSMA-tNP, [ 68 Ga]Ga-PSMA-tNP, [ 18 F]AlF-PSMA-NP or [ 68 Ga]Ga-PSMA-NP) uptake gradually increases over time in tumors with high PSMA expression, while uptake gradually decreases in other non-specific expression organs (such as the heart, muscle, and liver).

[0021] (4) The radiolabeled compound provided by this invention [18 F]AlF-PSMA-tNP, [ 68 Ga]Ga-PSMA-tNP, [ 18 F]AlF-PSMA-NP, [ 68 Ga-PSMA-NP exhibits good stability in both in vitro saline and in vitro serum. In in vitro saline, the degradation rate is ≤5% for at least 2 hours, and in in vitro serum, the degradation rate is ≤5% for at least 2 hours. 177 Lu]Lu-PSMA-tNP and [ 177 The degradation rate of Lu]Lu-PSMA-NP in in vitro serum was ≤5% for at least 48 hours.

[0022] (5) After the addition of competitively binding DOTA-PSMA-617, PSMA highly expresses tumors against the radiolabeled compounds provided by this invention (e.g., […]). 68 Ga]Ga-PSMA-tNP and [ 68 The uptake value of Ga[Ga-PSMA-NP] was significantly reduced, and the in vivo inhibitory effect was significant, indicating that the compound provided by the present invention has high specificity in vivo. Attached Figure Description

[0023] Figure 1 The different concentrations of NOTPY-PSMA-NP, NOTPY-PSMA-tNP, and DOTA-PSMA-617 in Example 9 [ 177 Statistical chart of inhibition results of Lu-PSMA-617 and 22RV1 cells.

[0024] Figure 2 In Example 10 [ 68 Ga]Ga-PSMA-NP, [ 68 Ga]Ga-PSMA-tNP and [ 68 Statistical chart showing the uptake values ​​of Ga-PSMA-617 in 22RV1 cells with high PSMA expression (PSMA(+) uptake group) after incubation for 5 minutes, 15 minutes, 30 minutes, 60 minutes, and 120 minutes.

[0025] Figure 3 In Example 10 [ 68 Ga]Ga-PSMA-NP, [ 68 The statistical results of Ga]Ga-PSMA-tNP uptake values ​​after 60 minutes of incubation with competitively binding DOTA-PSMA-617 (22RV1(+) inhibition group) in 22RV1 cells with high PSMA expression (PSMA(+) uptake group).

[0026] Figure 4In Example 10 [ 18 F]AlF-PSMA-NP and [ 18 Statistical chart of uptake values ​​of F]AlF-PSMA-tNP in PSMA-high-expressing 22RV1 cells (PSMA(+) uptake group) after incubation for 5 minutes, 15 minutes, 30 minutes, 60 minutes and 120 minutes.

[0027] Figure 5 In Example 10 [ 177 Lu]Lu-PSMA-NP and [ 177 Statistical chart showing the uptake values ​​of Lu]Lu-PSMA-tNP in PSMA-high-expressing 22RV1 cells (PSMA(+) uptake group) after incubation for 0.5 hours, 1 hour, 4 hours, 8 hours and 24 hours.

[0028] Figure 6 In Example 11 [ 68 Ga]Ga-PSMA-NP and [ 68 Statistical graph showing the percentage of intracellular radioactivity retained in 22RV1 cells after incubation for 5, 15, 30, 60, and 120 minutes (i.e., the results of the cell endogenization experiment).

[0029] Figure 7 In Example 11 [ 18 F]AlF-PSMA-NP and [ 18 Statistical graph showing the percentage of intracellular radioactivity retained in 22RV1 cells after incubation for 5, 15, 30, 60, and 120 minutes (i.e., the results of the cell endogenization experiment).

[0030] Figure 8 In Example 11 [ 177 Lu]Lu-PSMA-NP and [ 177 The statistical graph shows the percentage of intracellular radioactivity retained in 22RV1 cells after incubation for 0.5 hours, 1 hour, 4 hours, 8 hours, and 24 hours (i.e., the results of the cell endogenization experiment).

[0031] Figure 9 This is a statistical chart of cell efflux rates from Example 12; where, [ 68 Ga]Ga-PSMA-NP and [ 68After incubating Ga]Ga-PSMA-tNP in 22RV1 cells with high PSMA expression (PSMA(+) uptake group) for 1 hour, the uptake values ​​were recorded after culturing in radioactive-free medium for 5 minutes, 15 minutes, 30 minutes, 60 minutes, and 120 minutes, respectively, and the cell efflux rate was plotted based on these values.

[0032] Figure 10 This is a statistical chart of cell efflux rates from Example 12; where, [ 18 F]AlF-PSMA-NP and [ 18 After incubating F]AlF-PSMA-tNP in PSMA-high-expressing 22RV1 cells (PSMA(+) uptake group) for 1 hour, the uptake values ​​were recorded after culturing in radioactive-free medium for 5 minutes, 15 minutes, 30 minutes, 60 minutes, and 120 minutes, respectively, and a statistical graph of cell efflux rate was plotted based on this.

[0033] Figure 11 This is a statistical chart of cell efflux rates from Example 12; where, [ 177 Lu]Lu-PSMA-NP and [ 177 After incubating Lu]Lu-PSMA-tNP in PSMA-high-expressing 22RV1 cells (PSMA(+) uptake group) for 1 hour, the uptake values ​​were measured after culturing in radioactive-free medium for 0.5 hours, 1 hour, 4 hours, 8 hours and 24 hours, respectively, and the cell efflux rate was plotted based on these values.

[0034] Figure 12 This is a Radio-HPLC chromatogram of the in vitro stability of the compound in Example 13; it is [ 68 Ga]Ga-PSMA-NP, [ 68 Ga]Ga-PSMA-tNP, [ 18 F]AlF-PSMA-NP, [ 18 F]AlF-PSMA-tNP, [ 177 Lu]Lu-PSMA-NP and [ 177 The in vitro stability of Lu-PSMA-tNP was determined by Radio-HPLC; among which, [ 68 Ga]Ga-PSMA-NP, [ 68 Ga]Ga-PSMA-tNP, [ 18 F]AlF-PSMA-NP and [ 18 F]AlF-PSMA-tNP remained in its original form after incubation at 37°C for 2 hours in PBS and in vitro in mouse serum (original degradation rate ≤5%).

[0035] Figure 13This is a Radio-HPLC chromatogram of the in vitro stability of the compound in Example 13; wherein, [ 177 Lu]Lu-PSMA-NP and [ 177 The degradation rate of Lu]Lu-PSMA-tNP in mouse serum after incubation at 37°C for 24 hours was ≤5%, and the degradation rate after 72 hours was ≤20%.

[0036] Figure 14 It is in Example 14 [ 68 Ga]Ga-PSMA-NP, [ 68 Ga]Ga-PSMA-tNP and [ 68 Uptake PET images of Ga-PSMA-617 at 10, 30, 60, 90, and 120 minutes in the 22RV1 tumor model (PSMA(+) uptake group), and [ 68 Ga]Ga-PSMA-NP and [ 68 Ga]Ga-PSMA-tNP uptake bars for liver, heart and muscle over 2 hours.

[0037] Figure 15 It is in Example 14 [ 68 Ga]Ga-PSMA-NP and [ 68 Inhibition PET images of Ga]Ga-PSMA-tNP at 1 hour in a 22RV1 tumor model (Blocking (PSMA(+) inhibition group)).

[0038] Figure 16 It is in Example 14 [ 18 F]AlF-PSMA-NP and [ 18 Uptake PET images of F]AlF-PSMA-tNP at 10, 30, 60, 90 and 120 minutes in the 22RV1 tumor model (PSMA(+) uptake group).

[0039] Figure 17 In Example 15 [ 177 Lu]Lu-PSMA-NP and [ 177 Biodistribution of Lu]Lu-PSMA-tNP in 22RV1 tumor-bearing nude mice after 1 hour. Detailed Implementation

[0040] This invention provides bifunctional chelating agents and their PSMA ligand compounds, radiolabeled compounds and their applications. To make the objectives, technical solutions and effects of this invention clearer and more explicit, the invention will be further described below through specific embodiments.

[0041] In the embodiments, unless otherwise stated, all reagents used are commercially available or can be prepared by the methods described in this invention. 68 Ga represents gallium-68; 177 Lu represents lutetium-177; 86 Y represents Yttrium-86; 90 Y represents Yttrium-90; 64 Cu indicates copper-64; 67 Cu indicates copper-67; 213 Bi represents bismuth-213; 225 Ac indicates Actinium-225; 89 Y represents yttrium-89, and so on. pip represents piperidine; pH represents acidity / alkalinity; nmol / ml represents nanomoles per milliliter; mg represents milligrams; DMSO represents dimethyl sulfoxide; PBS represents phosphate-buffered saline solution; min represents minutes; %ID / g represents the percentage of the injected dose taken up by each gram of tissue; %ID / 1 mio cells represents the percentage of the injected dose taken up by each million cells; μM represents micromoles per liter; mmol represents millimoles; GBq / µmol represents 10 9 Becker per micromolar; MBq represents megabecq (10 6 (Beck); μCi represents the radioactivity unit microcurie; mio cells / well represents millions of cells per well; SDS represents sodium dodecyl sulfate; NaOH represents sodium hydroxide; 22RV1 cells represent human prostate cancer cells with high PSMA expression. Final concentration represents the concentration of the substance in the solution after addition at the end of the sample and reagent addition operations; Radio-HPLC represents radioactive high-performance liquid chromatography; PSMA-Positive represents PSMA-highly expressing cells.

[0042] The structures or Chinese names of some compounds are listed in Table 1 below.

[0043] Table 1: Abbreviations or Chinese names of compounds in the examples

[0044] Example 1: Preparation of compound NOTAPY-PSMA-NP 1) Preparation of compound of formula (1)

[0045] 1,4,7-triazacyclononane trihydrochloride (60 mmol) was dissolved in 100 mL of anhydrous acetonitrile, and N,N-diisopropylethylamine (180 mmol) was slowly added. After mixing, tert-butyl bromoacetate (120 mmol) was dissolved in 50 mL of anhydrous acetonitrile and added dropwise using a constant pressure dropping funnel. The reaction was allowed to proceed overnight to obtain compound (1).

[0046] 2) Preparation of compound (2)

[0047] Compound (1) (30 mmol) was dissolved in 100 mL of anhydrous DCM, and methyl 6-formyl-2-pyridinecarboxylate (30 mmol) was added. Sodium triacetoxyborohydride (60 mmol) was dissolved in 20 mL of anhydrous dichloromethane and slowly added to the mixed solution. The reaction was carried out at room temperature for 3 hours. After collection and drying, sodium hydroxide (60 mmol) was added and the reaction was carried out at room temperature for 60 minutes. Compound (2) was then collected and dried to obtain compound (2). An appropriate amount of compound (2) was analyzed by mass spectrometry and high-performance liquid chromatography. The mass spectrometry results showed that the molecular formula was C 25 H 40 N4O6([M + H)) + The purity was 493.29, measured by mass spectrometry, and 493.32; the high performance liquid chromatography result showed a purity >98%.

[0048] 3) Preparation of compound of formula (3)

[0049] H-Glu(OtBu)-OtBu·HCl and N,N'-disuccinimidyl carbonate were dissolved in 3 mL of DCM, and 1.5 mL of DIPEA was slowly added. The reaction was carried out overnight at room temperature, and the compound of formula (3) was obtained by column chromatography purification.

[0050] 4) Preparation of compound of formula (4)

[0051] Repeat step 3) of the coupling process to couple the compound (3 mmol) of formula (3) with H-Lys(Z)-OtBu·HCl. Then deprotect with palladium on carbon to obtain the compound of formula (4).

[0052] 5) Preparation of compound of formula (5)

[0053] Repeat step 4) of the coupling process, and sequentially couple the compound of formula (4) (3 mmol) prepared in step 4) with the following amino acids (3 mmol each): [[benzyloxycarbonyl]amino]-2-naphthylpropionic acid and (trans-4-(N-fluorenylmethoxycarbonylaminomethyl)cyclohexanecarboxylic acid. Then deprotect with 20% (v / v) pip / DMF (1:4, 3 ml, 2~20 min) to obtain compound (5).

[0054] 6) Preparation of Nota-PSMA-NP

[0055] Under nitrogen atmosphere, the compound of formula (2) prepared in step 2) was dissolved in 3 mL of anhydrous DCM, and DIPEA (8 mmol) and TSTU (4 mmol) were added. After reacting at room temperature for 1 h, the mixture was transferred to the compound of formula (5) and reacted at room temperature with shaking for 2 h to form N-terminal coupling. After evaporation, 3 mL of a trifluoroacetic acid / water / triisopropylsilane (volume ratio 95:2.5:2.5) mixture was added and reacted at 0 °C in an ice bath for 2 h before filtration. The filtrate was poured into cold diethyl ether, and the solid initial product precipitated. The Nota-PSMA-NP compound was then separated by a semi-preparative separation method. An appropriate amount of the Nota-PSMA-NP compound was analyzed by mass spectrometry and high performance liquid chromatography. The mass spectrometry results showed that the molecular formula was C 50 H 67 N9O 14 ([M + H)) + ), 1017.48, mass spectrometry measured 1018.50; high performance liquid chromatography results: purity >98%.

[0056] Example 2: [ 18 Preparation of F]AlF-PSMA-NP compounds (1) In manual labeling, the NOTAPY-PSMA-NP compound prepared in Example 1 was used as a precursor, and a cyclotron was used to obtain... 18 F - Manually mark to [ 18 The preparation of the F]AlF-PSMA-NP compound includes the following steps: 1) Add 0.3 mL of DMSO containing 40 nmol of compound NOTAPY-PSMA-NP to the reaction flask; 2) Add 10 μL of AlCl3 solution (0.2 M, pH=4.0) to the reaction flask and shake thoroughly for one minute; 3) 18 After eluting F- into the QMA column, use sodium acetate solution (0.5M, pH=3.9, 0.3mL) to... 18 F -The elution is transferred to the reaction flask from step 2); 4) After heating the reaction flask to 105℃ and reacting for 15-20 minutes, a reaction solution containing the product is obtained; 5) Add 3 mL of water to dilute and obtain the diluted reaction solution; 6) The diluted reaction solution was passed through a Sep-Pak C18 column (Waters, USA) to adsorb the product onto the Sep-Pak C18 column; 7) Rinse the Sep-Pak C18 column twice with 10 mL of water each time to remove any residue remaining in the Sep-Pak C18 column. 18 F - ion; 8) Elute the product from the Sep-Pak C18 column into a transfer bottle with 2 mL of ethanol and dilute with physiological saline; 9) The product in the transfer bottle was filtered through a sterile membrane to obtain the compound [ 18 F]AlF-PSMA-NP.

[0057] From preparation 18 F - Starting with ions, the compound was successfully prepared within 30-40 minutes. 18 F]AlF-PSMA-NP, decay-corrected yield 25%, radiochemical purity >98%, specific activity 22 GBq / µmol.

[0058] (2) In the automated labeling of modules, using the NOTAPY-PSMA-NP compound as a precursor, a cyclotron was used to obtain... 18 F - Use the Tracerlab FN module for automated tagging [ 18 The preparation of the F]AlF-PSMA-NP compound includes the following steps: 1) Production using a cyclotron 18 F - After being transferred to the module, it is rinsed into the QMA column; 2) Elute with 0.5 mL of 0.9% (w / v) sodium chloride solution. 18 F - Pour the solution into a reaction flask containing 188 nmol of compound NOTAPY-PSMA-NP, 12 μL of AlCl3 solution (10 mM, pH=4.0), 288 μL of sodium acetate solution (0.1 M, pH=4.0), and 520 μL of anhydrous acetonitrile; 3) After heating the reaction flask to 105℃ and reacting for 15-20 minutes, add 10mL of water to adsorb onto the Sep-Pak C18 column; 4) Rinse the Sep-Pak C18 column twice with 10 mL of water each time to remove any residue remaining in the Sep-Pak C18 column. 18 F - ion; 5) Elute the product from the Sep-Pak C18 column into a transfer bottle with 2 mL of ethanol and dilute with physiological saline; 6) The product in the transfer bottle is filtered through a sterile membrane to obtain the compound [ 18 F]AlF-PSMA-NP.

[0059] From preparation 18 F - Starting with ions, the compound was successfully prepared within 30-40 minutes. 18 F]AlF-PSMA-NP, decay-corrected yield 45%, radiochemical purity >98%, specific activity 84 GBq / µmol.

[0060] Example 3: [ 68 Preparation of Ga]Ga-PSMA-NP Using the NOTAPY-PSMA-NP compound prepared in Example 1 as a precursor, a germanium-gallium generator was used to obtain... 68 GaCl3 was manually labeled for […] 68 The preparation of Ga]Ga-PSMA-NP includes the following steps: 1) Add a sodium acetate solution containing 10 nmol of compound NOTAPY-PSMA-NP to the reaction flask (sodium acetate concentration: 0.25M, pH=5.5, 1mL). 2) Rinse the germanium-gallium generator with 0.5M hydrochloric acid solution (pH=3.0, 4mL). 68 Ga - The mixture is transferred to a reaction flask, heated to 105°C, and reacted for 10-20 minutes to obtain a reaction solution containing the product. The solution is then cooled to room temperature. 3) Add 3 mL of water to dilute and obtain the diluted reaction solution; 4) The diluted reaction solution was passed through a Sep-Pak C18 column to adsorb the product onto the column; 5) Rinse the Sep-Pak C18 column twice with 10 mL of water each time to remove any residue remaining in the Sep-Pak C18 column. 68 Ga - ion; 6) Elute the product from the Sep-Pak C18 column into a transfer bottle with 2 mL of ethanol and dilute with physiological saline; 7) The product in the transfer bottle was filtered through a sterile membrane to obtain the compound [ 68 Ga]Ga-PSMA-NP.

[0061] From preparation 68 Ga - Ions were introduced, and successful preparation was achieved within 30-40 minutes. 68 Ga]Ga-PSMA-NP, with a decay-corrected yield of 70%, radiochemical purity >98%, and specific activity of 30 GBq / µmol, has the same retention time as its standard in HPLC.

[0062] Example 4: [ 177 Preparation of Lu-PSMA-NP Using the NOTAPY-PSMA-NP compound prepared in Example 1 as a precursor, manual labeling was performed. 177 The preparation of the Lu]Lu-PSMA-NP compound includes the following steps: 1) Purchased 177 Sodium acetate solution (0.4M, pH=5.5, 0.4mL) and gentianic acid (4mg) were added to LuCl3 solution (370~740MBq) to obtain a mixed solution; 2) Add the mixed solution obtained in step 1) to the compound NOTAPY-PSMA-NP (73.6 μg, 50 nmol), heat to 90~100℃ and react for 15~20 minutes to obtain the reaction solution containing the product, and cool to room temperature; 3) Add 3 mL of water to dilute and obtain the diluted reaction solution; 4) The diluted reaction solution was passed through a Sep-Pak C18 column to adsorb the product onto the column; 5) Rinse the Sep-Pak C18 column with 3 mL of water to remove any residue remaining in the column. 177 Lu ions; 6) Elute the product from the Sep-Pak C18 column to a transfer flask with 2 mL of ethanol, and dilute with physiological saline to obtain [ 177 Lu]Lu-PSMA-NP. HPLC analysis showed radiochemical purity >95%. It can be used directly after dilution with physiological saline.

[0063] Example 5: Preparation of the NOTAPY-PSMA-tNP compound 1) Preparation of compound of formula (6)

[0064] Repeat step 4) of Example 1, coupling process, and sequentially couple the compound of formula (4) (3 mmol) prepared in Example 1 with the following amino acids (all 3 mmol): N-benzyloxycarbonyl-L-tryptophan, [[benzyloxycarbonyl]amino]-2-naphthylpropionic acid and (trans-4-(N-fluorenylmethoxycarbonylaminomethyl)cyclohexanecarboxylic acid. Then deprotection was performed with 20% (v / v) pip / DMF (1:4, 3 ml, 2~20 min) to obtain compound of formula (6).

[0065] 2) Preparation of Nota-PSMA-tNP

[0066] Under nitrogen atmosphere, the compound of formula (2) prepared in step 2) of Example 1 was dissolved in 3 mL of anhydrous DCM. DIPEA (8 mmol) and TSTU (4 mmol) were added, and the mixture was reacted at room temperature for 1 h. The solution was then transferred to the compound of formula (6), and the mixture was shaken at room temperature for 2 h to form N-terminal coupling. After rotary evaporation, a mixture of trifluoroacetic acid / water / triisopropylsilane (volume ratio 95:2.5:2.5) was added, and the mixture was reacted at 0°C in an ice bath for 2 h before filtration. The filtrate was poured into cold diethyl ether, and the solid initial product precipitated. The Nota-PSMA-tNP compound was then separated using a semi-preparative separation method. An appropriate amount of the Nota-PSMA-tNP compound was analyzed by mass spectrometry and high-performance liquid chromatography. The mass spectrometry results showed that the molecular formula was C 48 H 66 N 10 O 14 ([M + 2H] 2+ ), 1009.49, mass spectrometry measured 1007.51; high performance liquid chromatography results: purity >98%.

[0067] Example 6: [ 18 Preparation of F]AlF-PSMA-tNP compound (1) In manual labeling, the preparation process is the same as in Example 2, except that: the NOTAPY-PSMA-tNP compound prepared in Example 5 is used as a precursor, and the cyclotron is used to obtain... 18 F - Manually mark to [ 18 Preparation of F]AlF-PSMA-tNP compound.

[0068] From preparation 18 F - Starting with ions, the compound was successfully prepared within 30-40 minutes. 18 F]AlF-PSMA-tNP, decay-corrected yield 20%, radiochemical purity >98%, specific activity 20 GBq / µmol.

[0069] (2) In the automated labeling module, the preparation process is the same as in Example 2, except that the NOTAPY-PSMA-tNP compound prepared in Example 5 is used as a precursor, and a cyclotron is used to obtain... 18 F - Use the TracerlabFN module for automated tagging [ 18 Preparation of F]AlF-PSMA-tNP compound.

[0070] From preparation 18 F - Starting with ions, the compound was successfully prepared within 30-40 minutes. 18 F]AlF-PSMA-tNP, decay-corrected yield 46%, radiochemical purity >98%, specific activity 80 GBq / µmol.

[0071] Example 7: [ 68 Preparation of Ga]Ga-PSMA-tNP The preparation process is the same as in Example 3, except that the NOTAPY-PSMA-tNP compound prepared in Example 5 is used as a precursor, and a germanium-gallium generator is used to obtain... 68 GaCl3 was manually labeled for […] 68 Preparation of Ga]Ga-PSMA-tNP.

[0072] From preparation 68 Ga - Ions were introduced, and successful preparation was achieved within 30-40 minutes. 68 Ga]Ga-PSMA-tNP, after decay correction, has a yield of 60%~70%, radiochemical purity >98%, and specific activity of 25~30 GBq / µmol, consistent with the retention time of its standard in HPLC.

[0073] Example 8: [ 177 Preparation of Lu]Lu-PSMA-tNP The preparation process is the same as in Example 4, except that: the NOTAPY-PSMA-tNP compound prepared in Example 5 is used as a precursor, and commercially available... 177 LuCl3 solution was manually labeled for […] 177 Preparation of Lu]Lu-PSMA-tNP.

[0074] Successfully prepared within 30-40 minutes. 177 Lu]Lu-PSMA-tNP, HPLC analysis showed radiochemical purity >95%, and it can be used directly after dilution with physiological saline.

[0075] Example 9: Combination Ability Test 22RV1 cells were seeded in 24-well plates containing culture medium (cell count using a cell counting chamber, 0.40 million cells / well) and cultured for 2 days. The culture medium was then removed, leaving the cultured 22RV1 cells. Fresh culture medium without fetal bovine serum was added, and radioactive tracers were added to different wells of the cell plate. 177 Lu]Lu-PSMA-617 (0.5 μCi / well) and compound DOTA-PSMA-617 (10 μCi / well) with different concentrations were added respectively. -5 ~ 10 -12 mol / L (4 wells per group), NOAPY-PSMA-NP (10 mol / L) -5 ~ 10 - 12 mol / L (4 wells per group), NOAPY-PSMA-tNP (10 mol / L) -5 ~ 10 -12 Cells were incubated at 37°C for 60 minutes with 0.2% (w / v) SDS (4 wells per group) for 60 minutes. After incubation, the radioactive culture medium was removed, and the cells were washed twice with PBS (0.5 mL). The cells were then lysed with NaOH solution (0.5 mL, 1 M) containing 0.2% (w / v) SDS. The lysate was counted using a gamma counter.

[0076] Table 2: Results of Combined Ability Tests

[0077] Result: As Figure 1 As shown, different concentration groups (10 -5 ~ 10 -12 Count and plot the IC50 of NOTAPY-PSMA-NP, NOTAPY-PSMA-tNP, and DOTA-PSMA-617 using mol / L (4 wells per group) and calculate the IC50 of NOTAPY-PSMA-NP, NOTAPY-PSMA-tNP, and DOTA-PSMA-617 respectively. 50 As shown in Table 1 above, the affinity of NOTAPY-PSMA-NP for the PSMA receptor is 1.2 times stronger than that of DOTA-PSMA-617, and the affinity of NOTAPY-PSMA-tNP for the PSMA receptor is 1.9 times stronger than that of DOTA-PSMA-617.

[0078] Example 10: Cell Uptake and Inhibition Experiment PSMA-overexpressing 22RV1 cells were seeded into 12-well plates (cell count using a cell counting chamber, 0.38–0.40 million cells / well) and cultured in fresh culture medium without fetal bovine serum. [The following data are collected:] 68 Ga]Ga-PSMA-NP, [ 68 Ga]Ga-PSMA-tNP, [ 18 F]AlF-PSMA-NP, [18 F]AlF-PSMA-tNP, [ 177 Lu]Lu-PSMA-NP、 [ 177 Lu]Lu-PSMA-tNP and DOTA-PSMA-617 (1 μCi / well) were processed and grouped according to Table 3. Incubation was performed at 37°C at the corresponding time points. 68 Ga]Ga-PSMA-NP, [ 68 Ga]Ga-PSMA-tNP, [ 18 F]AlF-PSMA-NP or [ 18 F]AlF-PSMA-tNP: 5, 15, 30, 60 and 120 minutes; 177 Lu]Lu-PSMA-NP or [ 177 Lu]Lu-PSMA-tNP: 0.5, 1, 2, 4 and 12 hours; 4 wells per group), after removing the radioactive culture medium, the cells were washed twice with PBS (1 mL) and then lysed with NaOH solution (1 mL, 1 M) containing 0.2% (w / v) SDS. The lysate was counted using a gamma counter.

[0079] Table 3: Experimental treatments and results of cell uptake and inhibition experiments

[0080] result: Figure 2 This invention provides [ 68 Ga]Ga-PSMA-NP and [ 68 The uptake values ​​of Ga-PSMA-tNP in PSMA-high expressed 22RV1 cells at 5 min, 15 min, 30 min, 60 min, and 120 min compared with known tracers [Ga]Ga-PSMA-tNP uptake values ​​at 5 min, 15 min, 30 min, 60 min, and 120 min. 68 Ga]Ga-PSMA-617 equivalent. Figure 3 This indicates that the uptake was significantly inhibited after 1 hour following the addition of the competitively binding DOTA-PSMA-617. Figure 4 This invention provides [ 18 F]AlF-PSMA-NP and [ 18 F]AlF-PSMA-tNP was continuously uptaken in 22RV1 cells with high PSMA expression after incubation at different time points of 5 minutes, 15 minutes, 30 minutes, 60 minutes and 120 minutes. Figure 5 This invention provides [ 177 Lu]Lu-PSMA-NP or [ 177 Lu]Lu-PSMA-tNP was continuously uptaken in 22RV1 cells with high PSMA expression at different incubation times of 0.5 hours, 1 hour, 4 hours, 8 hours and 24 hours.

[0081] Example 11: Cell Endogenization Experiment Endogenization assay: PSMA-overexpressing 22RV1 cells were seeded in 24-well plates (cell count using a cell counting chamber, 0.13 million cells / well), cultured in 0.5 mL of fresh culture medium without fetal bovine serum, and 0.5 μCi of radioactive [protein] was added to each well. 68 Ga]Ga-PSMA-NP, [ 68 Ga]Ga-PSMA-tNP, [ 18 F]AlF-PSMA-NP, [ 18 F]AlF-PSMA-tNP, [ 177 Lu]Lu-PSMA-NP or [ 177 Lu]Lu-PSMA-tNP. Incubate at 37℃ at the corresponding time points ([ 68 Ga]Ga-PSMA-NP, [ 68 Ga]Ga-PSMA-tNP, [ 18 F]AlF-PSMA-NP or [ 18 F]AlF-PSMA-tNP: 5, 15, 30, 60 and 120 minutes; 177 Lu]Lu-PSMA-NP or [ 177 Lu-PSMA-tNP: 0.5, 1, 2, 4, and 12 hours; 4 wells per group). At each time point, after removing the radioactive culture medium, the cells were washed twice with cold PBS (0.5 mL), followed by the addition of 0.5 mL of glycine hydrochloride solution (0.1 M). The cells were incubated at 37°C for 10 minutes, and the glycine hydrochloride solution was collected. The cells were then washed twice with cold PBS (0.5 mL). After lysing the cells with NaOH solution (0.5 mL, 1 M) containing 0.2% (w / v) SDS, the radioactivity of the glycine hydrochloride solution and the NaOH solution containing 0.2% SDS was measured using a gamma counter.

[0082] result: Figure 6 show,[ 68 Ga]Ga-PSMA-NP or [ 68 After incubating Ga]Ga-PSMA-tNP in 22RV1 cells for 120 minutes, [ 68 Ga]Ga-PSMA-NP, [ 68 The internalization rate of Ga-PSMA-tNP reached over 60%. Among them, [ 68 Ga]Ga-PSMA-tNP and [ 68 Similar to Ga]Ga-PSMA-617 endogenization. Figure 7 show,[ 18F]AlF-PSMA-NP or [ 18 After incubating F]AlF-PSMA-tNP in 22RV1 cells for 120 minutes, [ 18 F]AlF-PSMA-NP and [ 18 The endogenization of F]AlF-PSMA-tNP reached over 50%. Figure 8 show,[ 177 Lu]Lu-PSMA-NP or [ 177 [Lu]Lu-PSMA-tNP showed a continuous increase in internalization rate in 22RV1 cells within 24 hours of incubation, reaching over 70% within 24 hours, which was higher than [ 177 Lu]Lu-PSMA-617.

[0083] Example 12: Cell Effluent Experiment PSMA-overexpressing 22RV1 cells were seeded into 12-well plates (cell count using a cell counting chamber, 0.38–0.40 million cells / well), and […]. 68 Ga]Ga-PSMA-NP, [ 68 Ga]Ga-PSMA-tNP, [ 18 F]AlF-PSMA-tNP, [ 177 Lu]Lu-PSMA-NP or [ 177 Lu-PSMA-tNP (1 μCi / well) was added to 22RV1 cells and incubated at 37°C for 1 hour. After removing the radioactive culture medium, the cells were washed twice with PBS (1 mL) and then incubated at 37°C at the corresponding time points. 68 Ga]Ga-PSMA-NP, [ 68 Ga]Ga-PSMA-tNP, [ 18 F]AlF-PSMA-NP or [ 18 F]AlF-PSMA-tNP: 5, 15, 30, 60 and 120 minutes; 177 Lu]Lu-PSMA-NP or [ 177 Lu]Lu-PSMA-tNP: 0.5, 1, 2, 4 and 12 hours; 4 wells per group). At each time point, cells were washed with PBS (1 mL) and lysed with NaOH solution (1 mL, 1 M) containing 0.2% (w / v) SDS. The lysates were counted using a gamma counter.

[0084] result: Figure 9 show[ 68 Ga]Ga-PSMA-NP and [ 68 The efflux rate of Ga-PSMA-tNP in PSMA-highly expressed 22RV1 was lower than that of [Ga-PSMA-tNP].68 Ga]Ga-PSMA-617. This indicates the cell's response to [ 68 Ga]Ga-PSMA-NP and [ 68 Ga]Ga-PSMA-tNP has a longer retention time in cells. Figure 10 show[ 18 F]AlF-PSMA-NP ratio[ 18 The efflux rate of F]AlF-PSMA-tNP was lower in 22RV1 cells with high PSMA expression. Figure 11 show[ 177 Lu]Lu-PSMA-NP or [ 177 The efflux rate of Lu-PSMA-tNP in PSMA-highly expressed 22Rv1 was lower than that of [ 177 Lu]Lu-PSMA-617.

[0085] Example 13: Stability Experiment [ 68 Ga]Ga-PSMA-NP, [ 68 Ga]Ga-PSMA-tNP, [ 18 F]AlF-PSMA-NP, [ 18 F]AlF-PSMA-tNP, [ 177 Lu]Lu-PSMA-NP and [ 177 In vitro stability experiment of Lu]Lu-PSMA-tNP: Pick[ 68 Ga]Ga-PSMA-NP, [ 68 Ga]Ga-PSMA-tNP, [ 18 F]AlF-PSMA-NP and [ 18 F]AlF-PSMA-tNP (20 μL, 600 μCi) was placed in 200 μL of mouse serum and incubated at 37 °C for 2 hours. The radiochemical purity was then determined by Radio-HPLC.

[0086] Pick[ 177 Lu]Lu-PSMA-NP and [ 177 Lu]Lu-PSMA-tNP (20 μL, 500 μCi) was placed in 200 μL of mouse serum at 37 °C. After incubation for 4 hours, 24 hours and 48 hours, its radiochemical purity was determined by Radio-HPLC.

[0087] Result: As Figure 12 As shown, after incubation in PBS and mouse serum at 37°C for 2 hours in vitro, [ 68 Ga]Ga-PSMA-NP, [ 68Ga]Ga-PSMA-tNP, [ 18 F]AlF-PSMA-NP or [ 18 The degradation rates of [F]AlF-PSMA-tNP (30 μL, 600 μCi) were all ≤5%. Figure 13 As shown, [ 177 Lu]Lu-PSMA-NP, [ 177 Lu]Lu-PSMA-tNP and [ 177 The degradation rate of Lu]Lu-PSMA-617 in mouse serum after incubation at 37°C for 48 hours was ≤5%.

[0088] Example 14: Small Animal PET-CT Imaging (1) PSMA (+) intake group [ 68 Ga]Ga-PSMA-NP uptake group: 200 μCi of [ 68 Ga]Ga-PSMA-NP was injected via the tail vein into nude mice bearing 22RV1 tumors with high PSMA expression; dynamic scanning was performed on small animals using PET-CT for 2 hours.

[0089] [ 68 Ga]Ga-PSMA-tNP uptake group: 200 μCi of [ 68 Ga]Ga-PSMA-tNP was injected via the tail vein into nude mice bearing 22RV1 tumors with high PSMA expression; dynamic scanning was performed on the small animals using PET-CT for 2 hours.

[0090] [ 18 F]AlF-PSMA-NP uptake group: 200 μCi of [ 18 F]AlF-PSMA-NP was injected via the tail vein into nude mice bearing 22RV1 tumors with high PSMA expression; dynamic scanning was performed on small animals using PET-CT for 2 hours.

[0091] [ 18 F]AlF-PSMA-tNP uptake group: 200 μCi of [ 18 F]AlF-PSMA-tNP was injected via the tail vein into nude mice bearing 22RV1 tumors with high PSMA expression; dynamic scanning was performed on small animals using PET-CT for 2 hours.

[0092] (2) PSMA(+) inhibition group (Blocking) [ 68 Ga]Ga-PSMA-NP suppression group: Take [ 68Ga]Ga-PSMA-NP (200 μCi) was added to DOTA-PSMA-617 (50 μg / mouse) and injected via the tail vein into 22RV1 tumor-bearing nude mice with high PSMA expression; static scanning was performed using small animal PET-CT for 1 hour.

[0093] [ 68 Ga]Ga-PSMA-tNP inhibition group: Take [ 68 Ga]Ga-PSMA-tNP (200 μCi) was added to DOTA-PSMA-617 (50 μg / mouse) and injected via the tail vein into 22RV1 tumor-bearing nude mice with high PSMA expression; static scanning was performed using small animal PET-CT for 1 hour.

[0094] result: (1) From Figure 14 It can be seen that in the PSMA(+) intake group, [ 68 Ga]Ga-PSMA-NP and [ 68 Ga-PSMA-tNPs specifically and highly accumulated in 22RV1 tumor sites with high PSMA expression, and uptake gradually increased over time. In 22RV1 tumors... 68 Ga]Ga-PSMA-NP or [ 68 The uptake value of Ga]Ga-PSMA-tNP and [ 68 Compared to Ga-PSMA-617, the uptake value was significantly increased. 68 Ga]Ga-PSMA-NP and [ 68 Ga]Ga-PSMA-tNP is rapidly metabolized in organs other than the kidneys (such as the liver and heart).

[0095] (2) From Figure 14 and Figure 15 As can be seen from the data, in the PSMA(+) inhibition group, the addition of DOTA-PSMA-617 to 22RV1 tumors significantly reduced the incidence of […]. 68 Ga]Ga-PSMA-NP and [ 68 The Ga]Ga-PSMA-tNP uptake value was significantly reduced, and the in vivo inhibitory effect was significant, indicating that both have high specificity in vivo.

[0096] (3) From Figure 16 It can be seen from this that, 18 F]AlF-PSMA-NP or [ 18 [F]AlF-PSMA-tNP specifically and highly accumulated at 22RV1 tumor sites with high PSMA expression, and uptake gradually increased over time. 18 F]AlF-PSMA-NP and [ 18F]AlF-PSMA-tNP is rapidly metabolized in organs other than the kidneys (such as the liver, heart, and muscles).

[0097] Example 15: Biodistribution Take 0.2 mL of the compound [ 177 Lu]Lu-PSMA-NP、 [ 177 Lu]Lu-PSMA-tNP or [ 177 Lu-PSMA-617 (1.48 MBq) was injected intravenously into 22RV1 tumor-bearing nude mice (n=3 per group) with high PSMA expression. One hour after injection, the eyeballs of the tumor-bearing mice were removed, blood was collected, and they were euthanized by cervical dislocation. Tissue samples were collected from the heart, liver, lungs, kidneys, femur, muscles, small intestine, tumor, blood, pancreas, spleen, stomach, gallbladder, and brain. The samples were weighed, and the radioactivity count was measured using a gamma counter. All measurements were adjusted for background and decay time, and then averaged. The data are expressed as the percentage of the injected dose taken up per gram of tissue (%ID / g).

[0098] Result: As Figure 17 As shown, [ 177 Lu]Lu-PSMA-NP、 [ 177 The tumor uptake of Lu-PSMA-tNP was higher than that of [[ 177 Lu]Lu-PSMA-617, no significant difference; while kidney significantly lower than [ 177 Lu]Lu-PSMA-617.

[0099] The following conclusions can be drawn from the above embodiments: (1) In vitro cell experiments showed that [ 68 Ga]Ga-PSMA-NP, [ 68 Ga]Ga-PSMA-tNP, [ 18 F]AlF-PSMA-NP and [ 18 F]AlF-PSMA-tNP both exhibit high specificity for PSMA.

[0100] (2) [ 68 Ga]Ga-PSMA-NP, [ 68 Ga]Ga-PSMA-tNP, [ 18 F]AlF-PSMA-NP and [ 18 F]AlF-PSMA-tNP exhibits good stability in vitro. 177 Lu]Lu-PSMA-NP and [ 177 The degradation rate of Lu]Lu-PSMA-tNP in mouse serum within 48 hours was [ 177The degradation rate is ≤5%, consistent with Lu-PSMA-617.

[0101] (3) Small-animal PET / CT imaging showed that the tumor responded to the compound [ 68 Ga]Ga-PSMA-NP or [ 68 The uptake values ​​of Ga]Ga-PSMA-tNP were significantly higher than those of known compounds. 68 Ga]Ga-PSMA-617.

[0102] (4) [ 177 Lu]Lu-PSMA-NP and [ 177 Lu]Lu-PSMA-tNP is a simple therapeutic radiopharmaceutical to prepare.

[0103] (5) This invention introduces novel bifunctional chelating agents, screening out those with stable structures, simple preparation methods, and high efficiency, which can be used to introduce... 68 Ga nuclides and 18 F nuclide preparation of compounds [ 68 Ga]Ga-PSMA-NP, [ 68 Ga]Ga-PSMA-tNP, [ 18 F]AlF-PSMA-NP and [ 18 F]AlF-PSMA-tNP can be used as a tracer, and can also introduce 177 Lu nuclide preparation of compounds [ 177 Lu]Lu-PSMA-NP and [ 177 Lu]Lu-PSMA-tNP is a radiotherapy drug that uses two PSMA ligands to achieve integrated diagnosis and treatment.

[0104] (6) In summary, compared to DOTA-PSMA-617, NOTAPY-PSMA-NP and NOTAPY-PSMA-tNP can perform [further actions] by introducing NOTAPY. 18 F / 177 Lu tag. 68 Ga]Ga-PSMA-NP and [ 68 Ga]Ga-PSMA-tNP both exhibit higher uptake of PSMA in lesions. 18 F]AlF-PSMA-NP and [ 18 [F]AlF-PSMA-tNP also exhibits good PSMA lesion monitoring capabilities and good stability. Furthermore... 177 Lu]Lu-PSMA-NP and [ 177 Lu]Lu-PSMA-tNP successfully conducted 177The compounds labeled with Lu showed a degradation rate of ≤5% in mouse serum within 48 hours, and all of the compounds provided by this invention have good application prospects.

[0105] It should be understood that the application of the present invention is not limited to the examples above. Those skilled in the art can make improvements or modifications based on the above description, and all such improvements and modifications should fall within the protection scope of the appended claims.

Claims

1. A bifunctional chelating agent, characterized in that, The structural formula of the bifunctional chelating agent is as follows: ； Where R is the target peptide.

2. A PSMA ligand compound or its ester or pharmaceutically acceptable salt, characterized in that, The structural formula of the PSMA ligand compound is: ； or .

3. The use of the bifunctional chelating agent of claim 1, or the PSMA ligand compound of claim 2, or its ester or pharmaceutically acceptable salt, in the preparation of radiolabeled compounds.

4. A radiolabeled compound, characterized in that, include: The PSMA ligand compound of claim 2, or its ester or pharmaceutically acceptable salt and radionuclide, wherein the radionuclide binds to the chelating group of the PSMA ligand compound through coordination.

5. The radiolabeled compound according to claim 4, characterized in that, The radionuclides include 18 F, 225 Ab、 225 Ac、 198 Au、 199 Ag、 32 P, 44 Sc、 47 Sc、 165 Dy、 169 Er、 177 Lu、 142 Pr、 159 Gd, 72 As、 72 Se、 97 Ru、 109 Pd, 105 Rh、 101m Rh、 119 Sb, 128 Ba、 197 Hg, 211 At、 151 Eu、 153 Eu、 169 Eu、 203 Pb, 212 Pb, 175 Yb、 139 La、 140 La、 166 Ho、 51 Cr 43 Sc、 44 Sc、 51 Mn, 52 Mn, 55 Co、 64 Cu、 67 Ga、 68 Ga、 152 Tb, 155 Tb, 161 Tb, 86 Y、 89 Y、 90 Y、 89 Sr、 89 Zr、 94m Tc, 99m Tc, 111 In、 114m In、 117m Sn、 153 Sm、 149 Pm, 152 Tb, 155 Tb, 201 Tl、 203 Pb, 32 P, 18 F, 76 Bro 77 Bro 123 I 124 I 125 I 169 Err 177 sun 186 Re 188 Re 211 And 212 Pb、 212 Hello 213 Hello 223 Ra 224 Ra 186 Re 188 Re 225 Ab 64 Cu、 67 Cu、 67 Ga 68 Ga 212 Hello 213 Hello 223 Ra 224 Day or 227 Th.

6. The radiolabeled compound according to claim 4, characterized in that, The structure of the radiolabeled compound is selected from one of the following: 。 7. A composition, characterized in that, include: The PSMA ligand compound as described in claim 2, or its ester or pharmaceutically acceptable salt, and pharmaceutically acceptable excipients.

8. The composition according to claim 7, characterized in that, The pharmaceutically acceptable excipients include at least one of pharmaceutically acceptable excipients, pharmaceutically acceptable additives, and pharmaceutically acceptable adjuvants.

9. The use of the PSMA ligand compound of claim 2 or its ester or pharmaceutically acceptable salt, the radiolabeled compound of any one of claims 4 to 6, or the composition of claims 7 to 8 in the preparation of a medicament for the diagnosis and / or treatment of tumors having prostate-specific membrane antigen receptors.

10. The application according to claim 9, characterized in that, The tumors possessing prostate-specific membrane antigen receptors include one or more of the following: prostate cancer, renal cell carcinoma, glioma, thyroid cancer, breast cancer, and lung cancer.

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