Heterocycle-containing chelating ligand, derivative thereof, preparation method of derivative, conjugate and application of conjugate

Abstract

The invention particularly relates to a heterocyclic chelating ligand, a derivative thereof, a preparation method of the derivative, a conjugate and application of the conjugate. The chelating ligand disclosed by the invention is a macrocyclic chelating ligand with a five-membered heterocyclic ring. The spatial configuration of the chelating ligand is different from the configuration of a chelating ligand only containing phenyl or also containing a six-membered ring with similar properties to the phenyl, and is also different from the molecular configuration connected through a straight chain or a straight chain. When the chelating ligand disclosed by the invention is complexed with metal, a complex with higher stability can be formed through the unique spatial configuration of the five-membered heterocycle, so that the stability of the chelate is improved, and metal nuclide in a body is prevented from escaping. Meanwhile, after the chelate ligand disclosed by the invention forms a conjugate and a metal complex, distribution and metabolism in a body can be influenced, the chelate ligand is higher in targeting property, damage to other tissues is remarkably reduced, and hepatotoxicity is remarkably reduced, so that a basis is provided for preparing diagnosis and treatment medicines.

Description

Technical Field

[0001] The present invention relates to the research field of chelating ligand compounds capable of chelating with metal ions, especially radionuclides, and specifically relates to heterocyclic-containing chelating ligands, their derivatives, their preparation methods, conjugates and applications. Background Art

[0002] Radioactive chelates or targeted compounds with radioactive labels have been widely used in diagnostics, which generally need to include at least several parts such as a chelating ligand for complexing radionuclides, a linker, a targeting molecule or a crosslinking group.

[0003] The selection of different radioactive chelates or targeted compounds with radioactive labels is based on evaluations of different parameters, including but not limited to parameters such as relaxivity, toxicity, distribution and metabolism in the human body, etc.

[0004] The complexing property of the chelating ligand with the metal radionuclide, the binding sites on the chelating ligand that can be provided for binding to the targeting molecule, and the morphology of the overall molecular structure after the chelating ligand binds to the metal radionuclide and / or the targeting molecule will all affect the above parameters.

[0005] In view of this, the present invention is specifically proposed. Summary of the Invention

[0006] One of the invention objects of the present invention is to provide a heterocyclic-containing chelating ligand, so as to improve the performance of the chelating ligand, enhance its chelating property with metals or metal radionuclides, and provide more expected binding sites for target molecules or crosslinking groups.

[0007] Another invention object of the present invention is derivatives and conjugates of the aforementioned heterocyclic-containing chelating ligand, so that they can have better targeting and biological properties after chelating with radionuclides as chelating ligands.

[0008] Meanwhile, the present invention also provides a preparation method for the above-mentioned heterocyclic-containing chelating ligand compound and its derivatives.

[0009] Finally, the present invention also discloses the application of the above-mentioned heterocyclic-containing chelating ligand compound, its derivatives and its conjugates in the preparation of radioactive drugs, and the radioactive drugs can be used for the diagnosis and treatment of related diseases.

[0010] In order to achieve the above invention objects, the present invention first discloses a heterocyclic-containing chelating ligand, and the chelating ligand compound includes a chelating group containing multiple nitrogen atoms and at least one linker connected to the nitrogen atoms on the chelating group:

[0011]

[0012] Wherein:

[0013] Z is a chelating group containing multiple nitrogen atoms and has the following structure:

[0014]

[0015] Wherein:

[0016] K is a five-membered heterocyclic group;

[0017] R1 and R2 are substituents on the benzene ring, and the substituents do not contain residues that react with the target molecule; R1 and R2 can be the same or different; further preferably, R1 = R2; more preferably, both R1 and R2 are methyl groups;

[0018] L is a linker part connected to the N atom in the chelating group Z, and the linker part L has a terminal group X for connecting to the target molecule or the targeting group.

[0019] The linker part L connects the chelating group and the target molecule by connecting to the N atom on the chelating group and the target molecule respectively. Therefore, for the linker L, as long as both ends can be connected to the N atom (—NH) and the target molecule respectively.

[0020] According to the connection requirements of different target molecules or targeting groups, different terminal groups X can be connected, so that the connection with the target molecule can be achieved through covalent bond connection, ligand connection or through hydrophobic bonds and electrostatic interactions, etc.

[0021] Sometimes we may need several identical or different terminal groups X, and these terminal groups X can be designed on one linker part L or on different linker parts L. The specific design ideas and methods can refer to the connection methods between the targeting molecule or targeting group and the linker part L in the prior art.

[0022] Preferably, the heterocyclic-containing chelating ligand compound further includes a group Q, and the group Q is a heteroatom group with a lone pair of electrons;

[0023] There are two connection methods between the group Q and the chelating group Z,

[0024] One is that the group Q is connected between the chelating group Z and the linker part L,

[0025]

[0026] The other is that the group Q is directly connected to the N atoms in the chelating group Z that are not connected to the linker part L,

[0027]

[0028] It should be noted that two connection methods between the group Q and the chelating group Z are provided here, but it does not mean that in a specific embodiment, the group Q can only adopt one of the two mutually exclusive connection methods. On the contrary, in a technical solution, for the group Q, there may be two different connection methods with the chelating group Z at the same time, and these groups Q can be the same or different.

[0029] Further preferably, the group Q is selected from the groups having the following formula:

[0030] Q m -X Q ;

[0031] Wherein:

[0032] Q m is a substituted or unsubstituted alkyl group, preferably, Q m is a substituted or unsubstituted C0-C3 alkyl group;

[0033] X Q is a heteroatom group with a lone pair of electrons, including but not limited to —COOH, —H2PO3, —H2PO4 or —H2PO2.

[0034] In a preferred technical solution, the linker part L is selected from the groups having the following formula:

[0035] L m -X,

[0036] Wherein:

[0037] X is —COOH, —OH, —CO, —SH, —CO—N(CH3)OH, —NH2,

[0038] —H2PO3, —H2PO4, —H2PO2 or halogen;

[0039] L m is a substituted or unsubstituted alkyl group, preferably, L m is a substituted or unsubstituted C0-C3 alkyl group.

[0040] Preferably, the K is a substituted or unsubstituted furyl group, a substituted or unsubstituted thiophenyl group, a substituted or unsubstituted pyrrolyl group, a substituted or unsubstituted thiazolyl group, a substituted or unsubstituted oxazolyl group, a substituted or unsubstituted imidazolyl group, a substituted or unsubstituted tetrahydrofuryl group, a substituted or unsubstituted tetrahydrothiophenyl group.

[0041] Further preferably, the heterocyclic chelating ligand compound is selected from:

[0042]

[0043]

[0044] Furthermore, the present invention also discloses derivatives of the chelating ligand, and the derivatives are compounds having the structure shown by the following formula or salts formed by them and inorganic acids or organic acids:

[0045]

[0046] In this formula, the definition of K is as described above, that is, K is a five-membered heterocyclic group; preferably, the K is a substituted or unsubstituted furyl group, a substituted or unsubstituted thienyl group, a substituted or unsubstituted pyrrolyl group, a substituted or unsubstituted thiazolyl group, a substituted or unsubstituted oxazolyl group, a substituted or unsubstituted imidazolyl group, a substituted or unsubstituted tetrahydrofuryl group, or a substituted or unsubstituted tetrahydrothienyl group.

[0047] Furthermore, the present invention also discloses a conjugate formed after the chelating ligand compound is conjugated with a target molecule.

[0048] The target molecule can be selected from biomacromolecules, or can be selected from drugs or small molecule compounds, and the target molecule and the targeting group include but are not limited to antibodies, proteins, peptides, carbohydrates, nucleotides, oligonucleotides, oligosaccharides, vitamins, liposomes, small molecule drugs or fragments or derivatives, etc.

[0049] Furthermore, in the present invention, there is also provided a method for preparing a heterocyclic-containing chelating ligand compound using substituted or unsubstituted 2,6-diformylphenol and as raw materials.

[0050] Finally, in the present invention, there is also disclosed a metal complex, and the metal complex is formed by complexing a chelating ligand compound or its conjugate with a metal element.

[0051] In the present invention, there is also disclosed the application of the chelating ligand compound and its derivatives in the preparation of radiopharmaceuticals, as well as the application of the conjugate and metal complex of the chelating ligand compound in radiopharmaceuticals.

[0052] In this application, the metal is a metal nuclide, and the nuclide can be 89 Zr, 47 Sc, 55 Co, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 66 Ga, 67 Ga, 68 Ga, 82 Rb,86 Y, 87 Y, 90 Y, 97 Ru, 105 Rh, 109 Pd, 111 In, 117m Sn, 149 Pm, 52 Mn, 149 Tb, 152 Tb, 153 Sm, 177 Lu, 186 Re, 188 Re, 199 Au, 201 Tl, 203 Pb, 212 Pb, 212 Bi, 213 Bi, 225 Ac, 223 Ra and 227 Th, etc.

[0053] The radiopharmaceuticals prepared from the compounds formed by combining different target molecules and different radionuclides can be used for the diagnosis and treatment of different diseases.

[0054] The chelating ligand disclosed in the present invention is a chelating ligand with a heterocyclic ring, specifically a macrocyclic chelating ligand with a five-membered heterocyclic ring, thus forming a macrocyclic chelating ligand structure with two phenyl groups and two five-membered heterocyclic groups. The stereoconfiguration of this chelating ligand is different from that of the chelating ligand containing only phenyl groups or also containing six-membered rings with similar properties to phenyl groups, and is also different from the molecular configuration connected by a straight chain or a straight chain. When the chelating ligand disclosed in the present invention complexes with a metal, through the unique stereoconfiguration of the five-membered single heterocyclic ring, it can form a more stable complex, thereby improving the stability of the chelate and preventing the escape of metal radionuclides in the body. At the same time, after the chelating ligand disclosed in the present invention forms a conjugate and a metal complex, it can affect the distribution and metabolism in the body, has stronger targeting, significantly reduces the damage to other tissues, and significantly reduces hepatotoxicity, thus providing a basis for the preparation of diagnostic and therapeutic drugs. Brief Description of the Drawings

[0055] Figure 1 It is a diagram of the iTLC analysis result of the Ga-68 radiolabeled product of the chelating ligand R1.

[0056] Figure 2 It is a diagram of the iTLC analysis result of the Ga-68 radiolabeled product of the chelating ligand R2.

[0057] Figure 3The iTLC analysis result diagram of the Ga-68 radiolabeled product of the chelating ligand R3.

[0058] Figure 4 The HPLC analysis result diagram of the Ga-68 radiolabeled product of the compound R1-1.

[0059] Figure 5 The HPLC analysis result diagram of the Ga-68 radiolabeled product of the compound R1-2.

[0060] Figure 6 The HPLC analysis result diagram of the Ga-68 radiolabeled product of the compound R1-3.

[0061] Figure 7 The HPLC analysis result diagram of the Ga-68 radiolabeled product of the compound R1-4.

[0062] Figure 8 The HPLC analysis result diagram of the Ga-68 radiolabeled product of the compound F1.

[0063] Figure 9 The HPLC analysis result diagram of the Ga-68 radiolabeled product of the compound F2.

[0064] Figure 10 The HPLC analysis result diagram of the Ga-68 radiolabeled product of the compound F3.

[0065] Figure 11 The HPLC analysis result diagram of the Ga-68 radiolabeled product of the compound F4.

[0066] Figure 12 For the injected compound 68 The PET scan diagram of nude mice injected with Ga-R1-2.

[0067] Figure 13 For the injected compound 68 The PET scan diagram of nude mice injected with Ga-F2. Detailed implementation mode

[0068] To better understand the present invention, the following will further elaborate on the present invention in combination with specific embodiments.

[0069] Example 1

[0070]

[0071] Dissolve 2,6-diformyl-4-methylphenol (164 mg, 1 mmol) in 30 ml of methanol and heat to 60 °C. At 60 °C, add dropwise a 30 ml methanol solution of 2,5-bis(aminomethyl)furan (138 mg, 1.1 mmol). After the addition is complete, continue the reaction for 2 hours. Then concentrate the reaction solution to half its volume to obtain a methanol solution of Compound 1.

[0072] While stirring, add sodium borohydride (228 mg, 6 mmol) to the methanol solution of Compound 1 and stir the reaction for 3 hours. Remove the solvent under reduced pressure. The residue is extracted and washed with ethyl acetate / water and dried over anhydrous sodium sulfate. Filter, add 1 ml of a dioxane solution of hydrogen chloride (4 M) to the filtrate, filter the precipitated solid, and dry to obtain the hydrochloride salt of Compound 2 (211 mg).

[0073] LC-MS: 517.3 (M+1)

[0074] H-NMR (300M, D2O): δ 2.29 (s, 6H), 4.28 - 4.30 (d, 16H), 6.67 (s, 4H), 7.26 (s, 4H)

[0075] Mix the hydrochloride salt of Compound 2 (199 mg, 0.3 mmol), tert-butyl bromoacetate (585 mg, 3 mmol), DIEA (465 mg, 3.6 mmol), and 5 ml of acetonitrile and react at room temperature for 3 hours. Concentrate to dryness, extract with ethyl acetate / water, dry and concentrate to obtain the crude product, and purify to obtain Compound 3 (233 mg).

[0076] Dissolve Compound 3 (97.3 mg, 0.1 mmol) in 4 M hydrochloric acid (2 ml) and react at 45 °C for 2 hours. Concentrate to dryness under reduced pressure, and prepare and purify to obtain the target compound R1 (23 mg).

[0077] LC-MS: 749.3 (M+1), 375.1 (M / 2+1)

[0078] H-NMR (300M, D2O): δ 2.29 (s, 6H), 3.96 (s, 8H), 4.30 - 4.32 (m, 16H), 6.67 (s, 4H), 7.26 (s, 4H).

[0079] Example 2

[0080] In this example, we prepared compounds R1-1, R1-2, R1-3, and R1-4 by coupling Compound 4 with Compound X.

[0081]

[0082] At room temperature, dissolve compound R1 (150 mg, 0.2 mmol) in N,N-dimethylformamide (2.5 ml), add DIEA (155 mg, 1.2 mmol) and HATU (228 mg, 0.6 mmol). After stirring for 10 minutes, add compound X (146 mg, 0.6 mmol) and continue the reaction for 2 hours. Extract with ethyl acetate / water to obtain a mixed product containing R1-1, R1-2, R1-3, and R1-4. After separation and purification, compounds R1-1, R1-2, R1-3, and R1-4 are obtained respectively:

[0083] R1-1 (12 mg), LC-MS: 609.1 (M / 2 + 1), 406.4 (M / 3 + 1);

[0084] R1-2 (15 mg), LC-MS: 843.9 (M / 2 + 1), 562.3 (M / 3 + 1);

[0085] R1-3 (22 mg), LC-MS: 718.3 (M / 3 + 1), 539.0 (M / 4 + 1);

[0086] R1-4 (11 mg), LC-MS: 874.6 (M / 3 + 1).

[0087] Its structure is as follows:

[0088]

[0089]

[0090] Example 3

[0091] Referring to the preparation method in Example 1, only replace 2,5-bis(aminomethyl)furan with cis-2,5-bis(aminomethyl)oxolane to synthesize compound R2.

[0092]

[0093] LC-MS: 757.3 (M + 1), 379.1 (M / 2 + 1)

[0094] 1H-NMR (300M, D2O): δ 1.68 - 1.73 (m, 4H), 2.08 - 2.13 (m, 4H), 2.28 (s, 6H), 2.95 - 3.33 (m, 8H), 4.28 - 4.32 (m, 16H), 4.37 - 4.45 (m, 4H), 7.23 (s, 4H)

[0095] Example 4

[0096] Referring to the preparation method in Example 1, only replace 2,5-bis(aminomethyl)furan with cis-2,5-bis(aminomethyl)thiophene to synthesize compound R3.

[0097]

[0098] LC-MS: 781.2 (M+1), 391.2 (M / 2+1)

[0099] H-NMR(300M, D2O): δ2.29(s, 6H), 3.97(s, 8H), 4.32 - 4.38(m, 16H), 6.93(s, 4H), 7.27(s, 4H).

[0100] Example 5

[0101] According to the method disclosed in Example 2, based on the compound R2 obtained in Example 3, couple compound X to prepare compounds F1 - F4;

[0102] The structures are as follows:

[0103]

[0104]

[0105] F1(1.9mg), LC-MS: 613.3 (M / 2+1);

[0106] F2(1.5mg), LC-MS: 847.4 (M / 2+1), 565.2 (M / 3+1);

[0107] F3(2.2mg), LC-MS: 720.6 (M / 3+1);

[0108] F4(1.1mg), LC-MS: 876.7 (M / 3+1), 658.5 (M / 4+1)

[0109] Example 6 Ga-68 radiolabeling of chelating ligand R1

[0110] Wash the Ge-Ga generator with a hydrochloric acid solution with a concentration of 0.1M to obtain an eluate containing the radionuclide 68 Ga 3+ Add a sodium acetate solution with a concentration of 1M to the eluate to adjust the pH value of the eluate to 4.0; add 20 nM chelating ligand R1 to the eluate, shake well and react at 60 °C for 10 min to obtain the radionuclide Ga-68 labeled compound 68 Ga-R1.

[0111] The radiochemical purity of the product was detected by instant thin-layer chromatography under the following conditions: iTLC-SG chromatographic plate; methanol / 1M ammonium acetate = 1 / 1 (v / v) developing agent. The results are as Figure 1 shown, in the reaction solution 68 the Ga-R1 product accounted for 95.1% of the total activity of the reaction solution, indicating that the chelating ligand R1 can be efficiently labeled at room temperature.

[0112] Example 7 Ga-68 radiolabeling of chelating ligand R2

[0113] The Ge-Ga generator was eluted with a 0.1M hydrochloric acid solution to obtain an eluate containing the radionuclide 68 Ga 3+ ; the pH value of the eluate was adjusted to 4.0 by adding a 1M sodium acetate solution to the eluate; 20 nM of chelating ligand R2 was added to the eluate, shaken well and reacted at room temperature for 10 min to obtain a radionuclide Ga-68-labeled compound 68 Ga-R1.

[0114] The radiochemical purity of the product was detected by instant thin-layer chromatography under the following conditions: iTLC-SG chromatographic plate; methanol / 1M ammonium acetate = 1 / 1 (v / v) developing agent. The results are as Figure 2 shown, in the reaction solution 68 the Ga-R2 product accounted for 96.8% of the total activity of the reaction solution, indicating that the chelating ligand R2 can be efficiently labeled at room temperature.

[0115] Example 8 Radiolabeling of chelating ligand R3

[0116] The radionuclide Ga-68-labeled compound 68 Ga-R3 was prepared according to the method disclosed in Example 6, and the radiochemical purity of the product was detected by instant thin-layer chromatography under the following conditions: iTLC-SG chromatographic plate; methanol / 1M ammonium acetate = 1 / 1 (v / v) developing agent. The results are as Figure 3 shown, it can be seen that the chelating ligand R3 can be efficiently labeled under room temperature conditions.

[0117] Example 9 Radiolabeling of the compound R1-1 with a macrocyclic conjugate targeting structure

[0118] The Ge-Ga generator was eluted with a 0.1M hydrochloric acid solution to obtain an eluate containing the radionuclide 68 Ga 3+The eluent; adding a sodium acetate solution with a concentration of 1 M to the eluent to adjust the pH value of the eluent to 4.2; adding 20 μM of compound R1-1 to the eluent, shaking well and reacting at 60 °C for 10 min, adding 5 mL of water to the reaction solution for dilution, then loading onto an Oasis HLB solid-phase extraction column and rinsing with 5 mL of water. The product is eluted with 1 mL of an ethanol solution with a concentration of 80%.

[0119] The product was analyzed by high performance liquid chromatography with a radioactive detector under the following conditions: Phenomenex Luna C18(2) chromatographic column (5 μm, 150×4.60 mm); flow rate 1 mL / min; gradient elution, from 0 to 3 minutes, acetonitrile was 10% and trifluoroacetic acid solution (0.1%) was 90%, from 3 to 10 minutes, acetonitrile increased from 10% to 70% and trifluoroacetic acid solution decreased from 90% to 30%, from 10 to 12 minutes, acetonitrile decreased from 70% to 10% and trifluoroacetic acid solution increased from 30% to 90%, from 12 to 15 minutes, acetonitrile remained 10% and trifluoroacetic acid solution remained 90%. The HPLC analysis results are as Figure 4 shown, 68 The retention time of Ga-R1-1 was 7.88 minutes, and the results showed that the radiochemical purity of the product was 97%.

[0120] Example 10

[0121] According to the method disclosed in Example 9, compounds R1-2, R1-3, and R1-4 were radiolabeled respectively, and the purity of the labeled products was analyzed by high performance liquid chromatography with a radioactive detector according to the method disclosed in Example 9. The results are as Figures 5 to 7 shown.

[0122] It can be seen that the radiochemical purity of the products after radiolabeling of compounds R1-2, R1-3, and R1-4 is very high.

[0123] Radiolabeling of Compound F1 with a Macrocyclic Coupling Targeting Structure in Example 11

[0124] The Ge-Ga generator was eluted with a hydrochloric acid solution with a concentration of 0.1 M to obtain an eluent containing the radionuclide 68 Ga 3+ The eluent; adding a sodium acetate solution with a concentration of 1 M to the eluent to adjust the pH value of the eluent to 4.2; adding 20 μM of compound R1-1 to the eluent, shaking well and reacting at room temperature for 10 min, adding 5 mL of water to the reaction solution for dilution, then loading onto an Oasis HLB solid-phase extraction column and rinsing with 5 mL of water. The product is eluted with 1 mL of an ethanol solution with a concentration of 80%.

[0125] The product was analyzed by high performance liquid chromatography with a radioactive detector under the following conditions: Phenomenex Luna C18(2) chromatographic column (5μm, 150×4.60mm); flow rate 1mL / min; gradient elution, from 0 to 3 minutes, acetonitrile was 10% and trifluoroacetic acid solution (0.1%) was 90%, from 3 to 10 minutes, acetonitrile increased from 10% to 70% and trifluoroacetic acid solution decreased from 90% to 30%, from 10 to 12 minutes, acetonitrile decreased from 70% to 10% and trifluoroacetic acid solution increased from 30% to 90%, from 12 to 15 minutes, acetonitrile remained 10% and trifluoroacetic acid solution remained 90%. The HPLC analysis results are as Figure 8 shown, 68 the retention time of Ga-R1-4 was 7.88 minutes, and the results showed that the radiochemical purity of the product was 97%.

[0126] Radioactive labeling of compounds F2, F3, and F4 in Example 12

[0127] According to the method disclosed in Example 11, compounds F2, F3, and F4 were respectively labeled with the radionuclide 68 Ga 3+ After labeling, each labeled product was analyzed by HPLC according to the chromatographic analysis conditions disclosed in Example 11, and the results are as Figures 9 to 11 shown.

[0128] According to the analysis result diagram, it can be seen that the radiochemical purity of the labeled product is high.

[0129] Example 12

[0130] 200μC of radiochemically labeled 68 Ga-R1-2 was injected into a nude mouse model bearing U87MG tumors via the tail vein, and PET image data was collected for 10 minutes 60 minutes after injection. The results are as Figure 12 shown, indicating that the compound 68 Ga-R1-2 had obvious uptake and retention in U87MG tumor tissues.

[0131] Example 13

[0132] According to the method disclosed in Example 12, the distribution of the labeled product 68 Ga-F2 in vivo was investigated. Similarly, 200μC of radiochemically labeled 68 Ga-F2 was injected into a nude mouse model bearing U87MG tumors via the tail vein, and PET image data was collected for 10 minutes 60 minutes after injection. The results are as Figure 13 shown, indicating that the compound 68 Ga-F2 had obvious uptake and retention in U87MG tumor tissues.

[0133] The above are the specific embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements are also regarded as the protection scope of the present invention.

Claims

1. A heterocyclic-containing chelating ligand compound, characterized in that, The chelating ligand compound includes a chelating group containing multiple nitrogen atoms and at least one linking arm connected to the nitrogen atom on the chelating group: Wherein: Z is a chelating group containing multiple nitrogen atoms and has the following structure: Wherein: K is a five-membered heterocyclic group; R1 and R2 are substituents on the benzene ring, and the substituent does not contain residues reactive with the target molecule; R1 and R2 can be the same or different; further preferably, R1 = R2; more preferably, both R1 and R2 are methyl; L is a linking arm part connected to the N atom in the chelating group Z, and the linking arm part L has a terminal group X connected to the target molecule or the targeting group.

2. The heterocyclic-containing chelating ligand compound according to claim 1, characterized in that: The heterocyclic-containing chelating ligand compound further includes a group Q, and the group Q is a heteroatom group with a lone pair of electrons; There are two ways for the group Q to be connected to the chelating group Z, One is that the group Q is connected between the chelating group Z and the linking arm part L, The other is that the group Q is directly connected to the N atoms in the chelating group Z that are not connected to the linking arm part L, 3. The heterocyclic-containing chelating ligand compound according to claim 1, characterized in that: The linking arm part L is selected from groups having the following formula: L m -X, Wherein: X is —COOH, —OH, —CO, —SH, —CO—N(CH3)OH, —NH2, —H2PO3, —H2PO4, —H2PO2 or a halogen; L m is a substituted or unsubstituted alkyl group, preferably, L m is a substituted or unsubstituted C0-C3 alkyl group.

4. The heterocyclic-containing chelating ligand compound according to claim 1, characterized in that: In the heterocyclic-containing chelating ligand compound: The group Q is selected from groups having the following formula, Q m -X Q ; Wherein: Q m is a substituted or unsubstituted alkyl group, preferably, Q m is a substituted or unsubstituted C0-C3 alkyl group; X Q is a heteroatom group with lone pair electrons, including but not limited to —COOH, —H2PO3, —H2PO4 or —H2PO2; And / or, the K is a substituted or unsubstituted furyl group, a substituted or unsubstituted thienyl group, a substituted or unsubstituted pyrrolyl group, a substituted or unsubstituted thiazolyl group, a substituted or unsubstituted oxazolyl group, a substituted or unsubstituted imidazolyl group, a substituted or unsubstituted tetrahydrofuryl group, a substituted or unsubstituted tetrahydrothienyl group.

5. The heterocyclic-containing chelating ligand compound according to claim 1, characterized in that: The heterocyclic-containing chelating ligand compound is selected from the following compounds:

6. The derivative of the heterocyclic-containing chelating ligand described in claim 1, characterized in that, The derivative is a compound having the structure shown by the following formula or a salt formed by it with an inorganic acid or an organic acid:

7. A conjugate formed by coupling the chelating ligand compound according to any one of claims 1 to 5 with a target molecule.

8. The preparation method of the heterocyclic chelating ligand compound according to claim 1, characterized in that, The method is prepared from substituted or unsubstituted 2,6-diformylphenol and as raw materials, wherein the definition of the K ring is as described in any one of claims 1-5.

9. A metal complex formed by the heterocyclic-containing chelating ligand compound according to any one of claims 1 to 5 or the conjugate according to claim 6.

10. Use of the heterocyclic-containing chelating ligand compound according to any one of claims 1 to 5, the derivative according to claim 6, the conjugate according to claim 7, and the metal complex according to claim 9 in the preparation of a radiopharmaceutical.

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