CN114853827B - Glucose derivative ligand compound and preparation method and application thereof - Google Patents

Glucose derivative ligand compound and preparation method and application thereof Download PDF

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CN114853827B
CN114853827B CN202210624052.0A CN202210624052A CN114853827B CN 114853827 B CN114853827 B CN 114853827B CN 202210624052 A CN202210624052 A CN 202210624052A CN 114853827 B CN114853827 B CN 114853827B
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dota
glucose
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CN114853827A (en
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杨大参
杨凌云
戴娟
罗志刚
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Nanjing Pet Tracer Co ltd
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    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
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    • C07—ORGANIC CHEMISTRY
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Abstract

The invention provides a glucose derivative ligand compound, a preparation method and application thereof, and relates to the technical field of radiopharmaceuticals chemistry. The compound has a structure shown as a formula (II), and the preparation method is simple. The longer linking agent introduced between the glucosamine and the DOTA makes the complex marked by the radionuclide more stable, and can improve the pharmacokinetic property. The radionuclide-labeled glucose derivative formula (I) provided by the invention has the advantages of high labeling rate, high in vivo and in vitro stability, good targeting property and the like, and can be further used for preparing nuclide diagnosis or treatment medicines for tumors.

Description

Glucose derivative ligand compound and preparation method and application thereof
Technical Field
The invention belongs to the technical field of radiopharmaceuticals chemistry, and particularly relates to a glucose derivative ligand compound, and a preparation method and application thereof.
Background
Glucose is an important substance required for energy metabolism, and after entering blood circulation, glucose transport bodies are relied on in vivo to enter cells, so that the energy metabolism of tumor cells is abnormal, and compared with normal cells, the glucose uptake is higher. Therefore, the glucose molecules can be modified by utilizing uptake of glucose and analogues thereof by tumor tissues and radionuclide labeling, so that the radioactive glucose metabolism molecular probe can be prepared, and the radioactive glucose metabolism molecular probe can be used for targeted diagnosis and treatment of tumors in vivo.
At present, the current time of the process, 18 F-FDG is the most commonly used glucose-based radiopharmaceutical, and is known as a century molecule in the field of molecular imaging. 18 F-FDG in combination with PET/CT has important value in diagnosis, staging, monitoring treatment response and assessing prognosis. 18 The powerful impact of F-FDG has prompted human intervention in other glucose-based imaging for Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT)Glucose radiopharmaceuticals have been studied intensively.
Wherein SPECT imaging research mainly comprises 99m Tc-marked glucose and its derivatives are the main ones, which are studied at present 99m Tc-labeled substances are 99m Tc-EC-DG、 99m Tc-DTPA-DG、 99m TcN-DGDTC 99m Tc-CN5DG, etc. Research by Yang et al in 2003 99m Tc-EC-DG tumor imaging findings, although 99m Tumor uptake ratio of Tc-EC-DG 18 F-FDG is low, but 99m The ratio of Tc-EC-DG tumor/brain tissue and tumor/muscle tissue is better than that of the same 18 F-FDG (radio, 2003,226 (2), 465-473). At present, the current time of the process, 99m Tc-EC-DG has entered phase II/III clinical trials. 2012, yang et al used 111 In radiolabels DOTA-DG, which is slowly taken up In the tumor, and the metabolic mechanism still needs to be further assessed (J Radioanal Nucl Ch,2013,295 (2), 1371-1375).
PET imaging also 68 Ga and 64 research on Cu-labeled glucose and its derivatives. In 2008, simon R et al pair 64 Cu-labeled glucose derivative 64 Cu-ATSE/A-G studies found that the marker had some tumor uptake, but no uptake was observed in the brain and heart, and was considered as a non-substituent of glucose metabolism (J nucleic Med,2008,49 (11), 1862-1868). In 2012, yang et al will 68 Ga-labeled DOTA-DG has been found to be significantly less ingested in tumors than in tumors 18 F-FDG(AJNucl Med Mol I,2012,2,499–507)。
Therefore, development of a radiolabeled glucose derivative with good stability, high tumor uptake and good imaging effect is the focus of current research.
In view of this, the present invention has been made.
Disclosure of Invention
The invention aims at providing a glucose derivative ligand compound, a preparation method and application thereof.
The second object of the present invention is to provide a radionuclide-labeled glucose derivative and application thereof.
The invention aims at realizing the following technical scheme:
a glucose-derived ligand compound having a structure as shown in formula II:
wherein m and n are integers of 0 to 10, respectively, but are not both 0 at the same time.
Preferably, m is an integer from 2 to 5 and n is from 0 to 5. More preferably, n is 3 and n is 0.
Specifically, the glucose-derived ligand compound has the structure:
the invention also provides a preparation method of the glucose derivative ligand compound II, and the synthetic route is as follows:
wherein R is 1 Is thatAny one of them; r is R 2 Any one selected from Boc, bn, cbz, fmoc, tos; m and n are as defined for compound I.
The specific reaction steps of the route are as follows:
in the first step, an amino group of the compound a is protected by an amino protecting agent to obtain a compound b.
In the first reaction step, the compound a is reacted with a protecting agent under alkaline conditions; the protecting reagent is selected from any one of Boc anhydride, bn-Br, cbz-Cl, fmoc-Cl and Tos-Cl. The pH of the alkaline condition is controlled between 8 and 9 by sodium hydroxide or sodium bicarbonate. The reaction temperature is-10-30 ℃.
Preferably, the amino protecting agent is Boc anhydride.
In a second step, the carboxyl group of the compound b uses an activated ester group R 1 Modification to give compound c.
In the second reaction step, the ester group R is activated 1 By R 1 The OH form participates in the reaction. R is R 1 -OH and compound b under DCC to form compound c; the R is 1 -OH is selected from any one of N-hydroxysuccinimide (NHS), tetrafluorophenol (TFP) or pentafluorophenol (PFP). The reaction temperature is-10-30 ℃.
Preferably, said R 1 -OH is tetrafluorophenol.
And thirdly, condensing the compound c with glucosamine under the condition of organic alkali to obtain a compound d.
In the third reaction step, the organic base is selected from triethylamine or DIPEA; preferably, the organic base is triethylamine. The reaction solvent is selected from CH 3 Cl、CH 2 Cl 2 One or more solvents selected from DMF, DMSO, THF and 1, 4-dioxane; preferably, the reaction solvent is CH 2 Cl 2 Or DMF. The reaction temperature is 0 to 30 ℃, preferably 25 ℃.
And fourthly, removing the amino protecting group on the compound d to obtain a compound e.
In the fourth step of reaction, removing the amino protecting group on the compound d under an acidic condition; the acid is hydrochloric acid or trifluoroacetic acid.
And fifthly, reacting and condensing the compound e with DOTA or a DOTA derivative to obtain a compound II.
In the fifth reaction step, DOTA or DOTA derivatives are reacted with compound e directly or in the form of an active ester. Preferably, the DOTA active ester form participates in the reaction; the DOTA active ester is selected from any one of DOTA-TFP, DOTA-PFP or DOTA-NHS; more preferably, the active ester is DOTA-TFP.
The invention also provides a radionuclide-labeled glucose derivative, which is prepared by labeling the glucose derivative ligand compound with a radionuclide M and has a structure shown as a formula I:
wherein M is a radionuclide, and M and n are the same as defined in compound II.
The M is selected from 64 Cu、 67 Cu、 67 Ga、 68 Ga、 90 Y、 111 In、 133 La、 135 La、 139 La、 140 La、 166 Ho、 177 Lu、 186 Re、 188 Re、 203 Pb、 212 Pb、 213 Bi、 225 Ac、 227 Any one of Th.
Preferably M is 68 Ga、 177 Lu or 133/135 La。
Specifically, the radionuclide-labeled glucose derivative structure is selected from:
the reaction of the radionuclide M-labeled glucose-derived ligand compound is performed under acidic and heated conditions.
The acidic condition is pH 4-7; preferably pH 4-5; the acidic reagent is selected from hydrochloric acid or nitric acid. The heating temperature is 50-100 ℃; the heating temperature is preferably 90 ℃.
The invention also provides an application of the radionuclide-labeled glucose derivative in preparing tumor diagnosis or treatment drugs.
Further, the tumor diagnosis medicine is PET or SPECT molecular diagnosis imaging agent.
Further, the therapeutic agent is a radionuclide therapeutic agent.
The PET or SPECT molecular diagnostic imaging agent refers to, for example, the use of 68 Ga、 133 La or La 177 A Lu-labeled compound of formula (II); the therapeutic medicine is prepared by precisely killing pathological cell nucleus tissue in short distance by utilizing alpha rays or beta rays and the like released by radionuclide in the decay process, thereby achieving the aim of treatmentA kind of electronic device 135 La or La 177 Lu-labeled compounds of formula (II).
In particular, the method comprises the steps of, 68 ga or 133 The La marked compound of formula (II) is PET molecular diagnostic imaging agent; 177 the Lu-labeled compound of formula (II) is a SPECT molecular diagnostic imaging agent, 135 la and La 177 The Lu-labeled compound of formula (II) is a nuclide therapeutic drug.
The invention designs and synthesizes a novel glucose derivative ligand compound, which connects glucose derivatives with a bifunctional chelating agent DOTA through a longer linking agent, and has the advantages of easily available raw materials and simple preparation. The introduction of the linking agent can reduce the steric hindrance of the chelating group directly coupled with the glucose group, the complex marked by the metal nuclide is more stable, and the pharmacokinetic property can be improved. The radionuclide-labeled glucose derivative provided by the invention has the advantages of high labeling rate, high in vivo and in vitro stability and good targeting property. Can be used for preparing nuclide diagnosis or therapeutic drugs for tumors.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are needed in the embodiments will be briefly described below, it being understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and other related drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 example 2 provides a compound 68 HPLC plot of Ga-I and compound Ga-I standard.
FIG. 2 example 4 provides a compound 133 HPLC diagram of La-I and compound La-I standard.
FIG. 3 example 6 provides a compound 68 Ga-I 18 F-FDG in microPET imaging contrast of tumor-bearing mice.
Detailed Description
The features and capabilities of the present invention are described in further detail below in connection with the examples. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The features and capabilities of the present invention are described in further detail below in connection with the examples.
Example 1
This example provides a glucose-derived ligand compound II-1 having the structural formula:
the embodiment also provides a preparation method of the compound II-1, and the synthetic route is as follows:
the specific operation is as follows:
step 1: in a 250ml round-bottomed flask, 10ml of NaOH (1N) and 20ml of 1, 4-dioxane were taken and cooled to 0 ℃. Di-tert-butyl dicarbonate (Boc anhydride) (1.1 mmol) was added to the reaction mixture. Stirred at room temperature for 8 hours. 1, 4-dioxane was removed under reduced pressure. Subsequently using saturated KHSO 4 The solution was acidified and the resulting solution extracted with ethyl acetate (3 x 40 ml). The organic layer was collected and distilled to give material b' in 85% yield.
Step 2: substance b' (1 mmol) and 2,3,5, 6-tetrafluorophenol (1.2 mmol) were mixed in 10mL of DMF and the mixture was reacted in an ice bath for 0.5h. DCC (1.5 mmol) was then added to the mixture and stirred at room temperature overnight. At the end of the reaction, the white precipitate in the reaction mixture was filtered and the filtrate was extracted twice with dichloromethane (50 mL) and water (50 mL). The organic layer was collected and distilled to give crude product. The crude product was purified by column chromatography on silica gel to give product c' in 65% yield.
Step 3: compound c' (1 mmol) and glucosamine (1.1 mmol) are dissolved in 50ml anhydrous CH 2 Cl 2 Triethylamine (4.8 mmol) was then added). Stirring for 3h at room temperature. Spin-drying the solvent and recrystallizing the crude product with acetone to give product d' in 58% yield.
Step 4: compound d' was prepared using CH 2 Cl 2 Dissolving, adding trifluoroacetic acid, and reacting for 2 hours at room temperature. At the end of the reaction, the solvent was removed by rotary evaporation and the solid was washed 3 times with ethyl acetate. The crude product obtained was purified by column chromatography on silica gel to give the product e' in 87% yield.
Step 3: the compound e' (1 mmol) and DOTA-TFP (1.1 mmol) were dissolved in anhydrous CH 2 Cl 2 Triethylamine (4.8 mmol) was then added. Stirring at room temperature for 3h, spin-drying the solvent, recrystallizing the crude product with diethyl ether, and purifying with silica gel column chromatography to obtain the product II-1 with a yield of 60%.
LC-MS：[M/2+H] + ＝378.18。
1 HNMR(500MHz,Chloroform-d)δ7.49–7.43(m,1H),6.48(t,J＝5.7Hz,1H),5.22(t,J＝5.9Hz,1H),5.10(d,J＝5.7Hz,1H),5.01(t,J＝7.3Hz,1H),4.95(dd,J＝8.0,0.9Hz,1H),4.49–4.39(m,2H),4.39–4.32(m,1H),3.90–3.81(m,2H),3.84–3.76(m,2H),3.79–3.65(m,6H),3.65–3.53(m,6H),3.47(d,J＝0.7Hz,6H),3.22(s,2H),2.56(d,J＝3.0Hz,16H),2.50(t,J＝7.7Hz,2H)。
Example 2
This example provides a radionuclide-labeled glucose derivative prepared by using the compound II-1 prepared in example 1 68 Ga is marked to obtain complex 68 Ga-I, the structure of which is shown below:
elution with 5mL of 0.1M HCl [ 68 Ga]GaCl 2 (300. Mu. Ci, 100. Mu.L) to a reaction flask, 350. Mu.L of 2M NaOAc buffer solution was added to adjust the pH to 4; added to an aqueous solution (20. Mu.L, 1 mg/mL) of the compound II-1 produced in example 1, and reacted at 90℃for 15 minutes. Diluting the crude reaction product by 10mL, adsorbing by a C18 column, and washing 10mL with sterilized injection water; eluting the C18 column with 0.5mL 80% ethanol to obtain the product 68 Ga-I, the conversion purity is 97%.
And (3) identification:
and (3) preparation of a standard substance: an aqueous solution (5 ml,10 mg/ml) of the compound II-1 obtained in example 1 was taken and mixed with GaCl 3 Is mixed with sodium acetate buffer solution (5 ml,20mg/ml, pH 4-4.5) and reacted at 90℃for 24 hours. Separating and purifying by preparative HPLC to obtain the stable metal Ga-marked metal complex standard Ga-I.
LC-MS：[M/2+H] + ＝411.13。
HPLC: standard UV peak rt= 6.128min, radioactivity peak rt= 6.308min, confirming that both show peak positions consistent. The HPLC profile is shown in FIG. 1.
Example 3
Will label the product 68 After Ga-I is placed for 4 hours at room temperature, the radiochemical purity is 97%; after being respectively placed in mouse serum and normal saline and incubated for 4 hours in a 37 ℃ water bath box, the radiochemical purity is respectively 95% and 97%, which shows that the kit has good in vitro stability.
Example 4
This example provides a radionuclide-labeled glucose derivative prepared by using the compound II-1 prepared in example 1 133 La is marked to obtain complex 133 La-I, the structure of which is shown below:
rinsing with 1mL of 0.05M HCl [ 133 La]LaCl 3 (200 μci,100 μl) into the reaction flask, the pH of the solution was adjusted to 4.5 with 50 μl NaOAc buffer (ph=9.0). Added to an aqueous solution (50. Mu.L, 0.4 mg/mL) of the compound II-1 produced in example 1, and reacted at 90℃for 30 minutes. The reaction solution is passed through a C18 column, and then the C18 column is washed by 10mL of water to obtain the product 133 La-I, 99% of the chemical.
And (3) identification:
and (3) preparation of a standard substance: an aqueous solution (2 ml,5 mg/ml) of the compound II-1 obtained in example 1 was taken and reacted with LaCl 3 Sodium acetate buffer solution (2 ml,10mg/ml, pH 4.5),heating to 90 ℃ for reaction for 15h, and separating and purifying by preparative HPLC to obtain a stable metal La marked metal complex standard La-I.
LC-MS：[M/2+H] + ＝446.12。
HPLC: the standard UV peak rt= 6.002min, the radioactive peak rt= 6.215min, confirming that the peak positions correspond. The HPLC profile is shown in FIG. 2.
Example 5
Will label the product 133 After La-I was left at room temperature for 24 hours, the radiochemical purity was 96%; after being respectively placed in mouse serum and physiological saline, and incubated for 24 hours in a 37 ℃ water bath box, the radiochemical purity is respectively 95% and 96%, which shows that the composition has good in vitro stability.
Example 6
For example 2 68 Ga-I (150. Mu.L, 200. Mu. Ci) was subjected to A549 tumor-bearing murine model microPET imaging studies at equivalent doses 18 F-FDG was used as a control and was dynamically scanned for 60min (5X 1 min-2X 2.5 min-2X 5 min-4X 10 min) while dosing. The impact data was reconstructed using a 3D MAP algorithm and the region of interest (ROI) was manually drawn over the major organ and tumor. The experimental results are shown in FIG. 3, which shows the tumor tissue pair 68 The Ga-I uptake is higher than that 18 F-FDG, and at 5-20min, 68 Ga-I has a significantly higher tumor/muscle ratio (TBR) than 18 F-FDG， 68 The TBR value of Ga-I is 1.89 + -0.2, 18 F-FDG was 1.34.+ -. 0.16 (n= 7,p)<0.002)， 68 Ga-I has a higher TBR value. In addition, with 18 Liver pair compared with F-FDG 68 The intake of Ga-I is low.
What has been described above is a specific embodiment of the present invention. It should be noted that modifications and adaptations to the invention may occur to one skilled in the art without departing from the principles of the present invention and are intended to be within the scope of the present invention.

Claims (8)

1. A glucose-derived ligand compound having a structure as shown in formula II:
wherein m is an integer of 2 to 5, and n is an integer of 0 to 5.
2. A process for the preparation of a glucose-derived ligand compound according to claim 1, characterized by the following synthetic route:
wherein R is 1 Is thatAny one of them; r is R 2 Any one selected from Boc, bn and Cbz, fmoc, tos; m and n are the same as in claim 1.
3. A process for the preparation of a glucose-derived ligand compound according to claim 2, comprising the reaction steps of:
the first step: using protecting groups R 2 Protecting the amino group of the compound a to obtain a compound b;
and a second step of: compounds b carboxyl groups Using activated ester groups R 1 Modifying to obtain a compound c;
and a third step of: condensing the compound c with glucosamine under the condition of organic base to obtain a compound d;
fourth step: removing the amino protecting group on the compound d to obtain a compound e;
fifth step: and (3) reacting and condensing the compound e with DOTA to obtain a compound II, wherein DOTA is a DOTA compound or DOTA active ester, and the DOTA active ester is selected from any one of DOTA-TFP, DOTA-PFP or DOTA-NHS.
4. A method of preparing a glucose-derived ligand compound according to claim 3, wherein the DOTA-active ester is DOTA-TFP.
5. A radionuclide-labeled glucose derivative prepared by labeling the glucose-derived ligand compound of claim 1 with a radionuclide M, having a structure as shown in formula I:
wherein M is 68 Ga, m and n are the same as in claim 1.
6. Use of a glucose-derived ligand compound according to claim 1 as a ligand for the preparation of a radionuclide-labeled glucose derivative according to claim 5 in the preparation of a tumor diagnostic drug.
7. Use of a radionuclide-labeled glucose derivative according to claim 5 in the preparation of a tumor diagnostic drug.
8. The use according to claim 6 or 7, wherein the diagnostic drug is a PET molecular diagnostic imaging agent.
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