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VISTA-targeted probe as well as preparation method and application thereof

A probe and targeting technology, applied in the field of medicine, can solve the problems of inability to distinguish immune targets and the impact of low expression levels, and achieve the effect of high target/non-target ratio and strong targeting.

Active Publication Date: 2022-04-22
XIAMEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Regrettably, 18 The high uptake of F-FDG in normal heart and brain tissue, the inability to distinguish immune targets, and the susceptibility to the patient's blood sugar and low expression levels of glucose transporters have become the obvious shortcomings of this imaging technique.

Method used

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  • VISTA-targeted probe as well as preparation method and application thereof
  • VISTA-targeted probe as well as preparation method and application thereof
  • VISTA-targeted probe as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] The synthesis of precursor compound DNCA or DNCA or HCA or DCA or NCA based on formula (I) structure comprises the following steps:

[0047] Dissolve p-SCN-Bn-NOTA or p-NCS-Bz-DOTA-GA or HYNIC-NHS or DOTA-NHS or NOTA-NHS and compound 1 in DMSO or DMF solution, add an appropriate amount of DIPEA, and react at room temperature for 4 to 12 hours . The product is separated and purified by HPLC, and the target fraction is collected and freeze-dried to obtain the corresponding compound NNCA, DNCA, HCA, DCA or NCA. The target product was confirmed by mass spectrometry. The mass spectrometry spectrum and HPLC spectrum of compound NNCA, DNCA or HCA are as follows Figure 1~6 shown.

[0048] The preparation methods of other VISTA targeting compounds based on the structure (I) can refer to the above synthesis process, the difference is that the corresponding compound structure can be obtained by replacing the corresponding nuclide labeling group.

[0049] The synthesis route o...

Embodiment 2

[0052] 68 The Ga nuclide labeling process is as follows:

[0053] Wet method: about 37 ~ 3700MBq 68 GaCl 3 Add the hydrochloric acid solution (washed from the germanium-gallium generator) into the centrifuge tube containing 0.5-2 mL of DNCA (20-200 μg) prepared in Example 2 in the acetic acid-acetate solution, and place it at room temperature to 100 ° C for 20 minutes. After cooling to room temperature, dilute with physiological saline or water for injection, and filter sterile to obtain the labeled compound injection.

[0054] Freeze-drying method: mix a certain amount of buffer solution and about 37-3700MBq 68 GaCl 3 Add the hydrochloric acid solution (leached from the germanium-gallium generator) into the freeze-dried kit containing DNCA (20-200μg), mix and dissolve, put it at room temperature to 100°C for 20 minutes, and then cool to room temperature. Diluted with water, and sterile filtered to obtain the labeled compound injection.

[0055] If the radiochemical puri...

Embodiment 3

[0058] 99m Tc nuclide labeling: using SnCl 2 As reducing agents, N-tris(hydroxymethyl)methylglycine (Tricine) and triphenylphosphine trisulphonic acid sodium salt (TPPTS) were used as synergistic ligands for 99m Marking of Tc.

[0059] Wet method: freshly prepared SnCl 2 Solution (SnCl 2 Hydrochloric acid solution) 20 μL was added to the solution containing 20-200 μg HCA compound, 1-50 mg Tricine and 1-10 mg TPPTS, and then immediately added 37-7400 MBq freshly rinsed Na 99m TCO 4 Eluate (washed from molybdenum-technetium generator), mix well, seal the cap, react at room temperature to 100°C for 30 minutes, cool to room temperature, dilute with normal saline or water for injection, and sterile filter to obtain the labeled compound Injection.

[0060] Freeze-drying method: about 37 ~ 3700MBq fresh Na 99m TCO 4 Add the eluent (leached from the molybdenum-technetium generator) into the freeze-dried kit containing 20-200 μg of HCA compound, 1-50 mg of Tricine and 1-10 mg o...

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Abstract

The invention discloses a VISTA targeted probe and a preparation method and application thereof, and relates to the field of medical chemistry, and a targeted compound is formed by connecting a VISTA inhibitor molecule and a nuclide labeling group in a specific chemical form. The invention also provides a radionuclide labeled diagnosis and treatment probe based on the targeting compound, and the diagnosis and treatment probe is prepared according to a wet method or a freeze-drying method. The invention also relates to application of the probe as a diagnosis and treatment reagent in human or animal tumors or immune diseases, and the probe has the advantages of simple preparation, good stability, high focus uptake and the like, and is suitable for clinical popularization.

Description

technical field [0001] The invention relates to the field of medical technology, in particular to a compound targeting T cell activation inhibitor of V-type immunoglobulin domain (VISTA) and a radionuclide-labeled disease diagnosis and treatment probe. Background technique [0002] The development of immunology has brought revolutionary changes to the treatment of major diseases such as tumors, and has become another effective treatment for cancer after surgery, radiotherapy, chemotherapy, and targeted therapy. Immunotherapy strategies represented by PD-1 / PD-L1 immunosuppressive pathway blockade and CAR-T cell therapy have brought good news to cancer patients. However, limited by the heterogeneity of the immune microenvironment, its therapeutic effect cannot be maximized. V-Domain Immunoglobulin-Containing Suppressor of T Cell Activation (VISTA, V-Domain Immunoglobulin-Containing Suppressor of T Cell Activation) is a very attractive target. VISTA, also known as PD-1H (Prog...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/12A61K51/04A61P1/16A61P9/00A61P11/06A61P17/00A61P17/06A61P19/02A61P25/00A61P29/00A61P35/00A61K103/10A61K103/00A61K103/30A61K101/02A61K103/32A61K103/40
CPCC07D413/12A61P35/00A61P19/02A61P29/00A61P1/16A61P25/00A61P17/00A61P17/06A61P9/00A61P11/06A61K51/0482Y02A50/30
Inventor 郭志德刘佳张现忠文雪君方建阳
Owner XIAMEN UNIV
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