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Granzyme B targeting complex, radiopharmaceutical and preparation method and application of granzyme B targeting complex and radiopharmaceutical

A technology for radiopharmaceuticals and complexes, applied in the field of nuclear medicine, can solve the problems of low tumor immunotherapy efficiency, lack of tumor specificity, and less than 30% effective rate, and achieve optimal pharmacokinetic properties and in vivo metabolic stability. , prepare a simple effect

Active Publication Date: 2022-02-11
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the current effective rate of tumor immunotherapy is low
Taking anti-PD-1 immune checkpoint inhibition as an example, its effective rate is often less than 30%
However, 18 F-FDG lacks tumor-specific, specific markers of active cells other than CTL or NK
It has obvious limitations in predicting and evaluating the efficacy of immunotherapy

Method used

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  • Granzyme B targeting complex, radiopharmaceutical and preparation method and application of granzyme B targeting complex and radiopharmaceutical
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  • Granzyme B targeting complex, radiopharmaceutical and preparation method and application of granzyme B targeting complex and radiopharmaceutical

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Experimental program
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Effect test

Embodiment 1

[0063] Synthesis of granzyme B targeting complexes.

[0064] The granzyme B targeting complex (compound 7) was synthesized according to the following solid-phase synthesis route. Wherein, R is any one of bifunctional chelating groups or derivatives thereof for radionuclide labeling. The bifunctional chelating group is a group formed by bifunctional chelating agents DOTA, NOTA, HYNIC, and MAG2.

[0065]

[0066] Concrete synthetic steps are as follows:

[0067] Reaction conditions: (a) DCM solution of Fmoc-NHS and DIPEA; (b) DMF / DCM solution of 2-chlorotriphenyl chloride resin and DIPEA; (c) DMF solution of 20% piperidine, Fmoc-(2S, 5S) DMF solution of -5-amino-1,2,4,5,6,7-hexahydroazepino[3,2,1-Hi]indole-4-one-2-carboxylic acid, HBTU, HOBt and DIPEA;( d) DMF solution of 20% piperidine, DMF solution of Fmoc-L-isoleucine, HBTU, HOBt and DIPEA; (e) DMF solution of 20% piperidine, Fmoc-(3-aminomethylphenyl) The DMF solution of acetic acid, HBTU, HOBt and EIPEA; (f) the DMF ...

Embodiment 2

[0075] Synthesis of DOTA coupling complex and its 68 Ga, 64 Cu, 111 In, 86 The labeling of any radionuclide in Y is prepared into corresponding radiopharmaceuticals. Specifically include the following steps:

[0076] Take 5 μmol of compound 6, dissolve it in 500 μL of DMSO, and then add 50 μmol of DOTA-NHS and 10 μmol of DIPEA. Mix well and react at room temperature for 2 hours. The crude product is purified by HPLC and freeze-dried to obtain the DOTA-coupled granzyme B targeting complex. For its mass spectrometric characterization, see figure 1 .

[0077] Dissolve 10nmol of DOTA coupling complex in 300μL of 0.1M sodium acetate buffer (pH=5.5); then add 185MBq of 68 GaCl 3 , 64 CuCl 2 , 111 InCl 3 or 86 YCl 3 , reacted at 37°C for 30min, then, the reaction solution was separated and purified by Sep-PakC18 chromatographic column, the purified product was diluted with normal saline and then sterile filtered to obtain the corresponding 68 Ga, 64 Cu, 111 In or 86...

Embodiment 3

[0079] Synthesis of NOTA coupling complex and its 68 Ga, 64 Cu or 18 F Labeling of any radionuclide to prepare corresponding radiopharmaceuticals. Specifically include the following steps:

[0080] Take 5 μmol of compound 6, dissolve it in 500 μL of DSMO, then add 50 μmol of NOTA-NHS, and 10 μmol of DIPEA. Mixed and reacted at room temperature for 2 hours, the crude product was purified by HPLC and freeze-dried to obtain the NOTA-coupled granzyme B targeting complex. For its mass spectrometric characterization, see image 3 .

[0081] 68 Ga or 64 Cu radiolabeling: Dissolve 10nmol of NOTA coupling complex in 300μL of 0.1M sodium acetate buffer (pH=5.5); then add 185MBq of 68 GaCl 3 or 64 CuCl 2 , reacted at 37°C for 15 minutes, and after cooling, the reaction solution was separated and purified by Sep-Pak C18 chromatographic column, and the purified product was diluted with normal saline and filtered aseptically to obtain the corresponding 68 Ga or 64 Cu-labeled co...

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Abstract

The invention belongs to the field of nuclear medicine, and relates to a granzyme B targeting complex, a radiopharmaceutical and a preparation method and application of the granzyme B targeting complex and the radiopharmaceutical. The structure of the granzyme B targeting complex is shown as a formula (I), wherein R is any one of a difunctional chelating group for radionuclide labeling or a derivative thereof. The granzyme B targeting complex provided by the invention can be labeled by radionuclide to prepare a granzyme B targeting radiopharmaceutical; wherein the granzyme B targeting radiopharmaceutical provided by the invention is simple to prepare, and has better pharmacokinetic characteristics and in-vivo metabolism stability compared with other granzyme B targeting drugs; and therefore, the expression level of granzyme B in body can be noninvasively monitored through nuclear medicine imaging.

Description

technical field [0001] The invention belongs to the field of nuclear medicine, and in particular relates to a granzyme B targeting complex and a preparation method thereof, a granzyme B targeting radiopharmaceutical and a preparation method thereof, and their application in nuclear medicine imaging diagnosis and treatment of related diseases such as tumors. Applications in therapeutic imaging monitoring. Background technique [0002] Granzyme is a kind of serine protease. Human granzyme includes five kinds of A, B, H, K, and M, which exist in cytotoxic T lymphocytes (cytotoxic T lymphocytes, CTL) and natural killer cells (natural killer cells, NK). released cell granules. As one of the most important effector molecules of granzyme, granzyme B can enter cells, mediate the activation of downstream caspase signaling pathway, induce cellular DNA fragmentation, and thus lead to cell apoptosis. At the same time, granzyme B can also cut nuclear proteins, including NuMA and P and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K51/04A61K47/54A61K38/48A61P35/00A61P37/02C07K5/083C07K1/04C07K1/107C07K1/13C07K1/20
CPCA61K51/0482A61K47/547A61K38/482A61P35/00A61P37/02C07K5/0808
Inventor 刘昭飞杨兴王琰璞徐红闯周昊毅
Owner PEKING UNIV
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