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Targeting PD-L1 polypeptide probe and application thereof in preparation of PET imaging agent

A PD-L1, targeting technology, applied in the field of application, preparation, and targeting of PD-L1 polypeptide probes in tumor positron emission tomography imaging agents, can solve the problem of no in vivo imaging research reports, labeling difficulties, in vivo Clearing slow and other issues

Pending Publication Date: 2022-08-05
NANFANG HOSPITAL OF SOUTHERN MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the antibodies used in radioimmunoimaging have defects such as large molecular weight, high price, difficult labeling, potential immunogenicity, and slow clearance in vivo[3]
In vitro studies have shown that RK-10 polypeptide (RK-10: GSGSGSTYLCGAISLAPKAQIKESL) is a small molecule peptide ligand targeting tumor PD-L1, but no in vivo imaging studies have been reported

Method used

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  • Targeting PD-L1 polypeptide probe and application thereof in preparation of PET imaging agent
  • Targeting PD-L1 polypeptide probe and application thereof in preparation of PET imaging agent
  • Targeting PD-L1 polypeptide probe and application thereof in preparation of PET imaging agent

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Example 1 Preparation of precursor NOTA-R-PDL1P

[0057]PDL1P was prepared by solid-phase peptide synthesis. After PDL1P was prepared by solid-phase peptide synthesis, it was reacted with L-lysine-BOC in basic dimethyl sulfoxide to generate PDL1P-Lys-BOC. PDL1P-Lys-BOC reacts with R-OH (R=4-methylphenylbutyryl or 4-iodophenylbutyryl) to form PDL1P-R-Lys-BOC, after removing the protecting group-BOC, it contains diisopropyl The primary product NOTA-R-PDL1P (R=4-methylphenylbutyryl or 4-iodophenylbutyryl) is obtained by reacting with p-SCN-Bn-NOTA in the slightly alkaline solution of ethylamine in dimethyl sulfoxide. . After removing the protecting group-BOC from PDL1P-Lys-BOC, it was then reacted with p-SCN-Bn-NOTA in a slightly alkaline solution containing diisopropylethylamine in dimethyl sulfoxide to obtain the primary product NOTA-R-PDL1P(R =-H). The initial product was separated and purified by preparative HPLC to collect the product peak, and after freeze-drying...

Embodiment 218

[0060] Example 2 [ 18 Radiosynthesis of F]AlF-NOTA-R-PDL1P

[0061] In the reaction flask filled with NOTA-R-PDL1P (R=H, 4-methylphenylbutyryl, or 4-iodophenylbutyryl) (50 μg / μL, 50 μL), 2 mM AlCl was added sequentially 3 Solution 6 μL, glacial acetic acid 4 μL and acetonitrile 300 μL, mix well. passed by the cyclotron 18 O(p,n) 18 F nuclear reaction produced 18 F - , in N 2 Under the carrier band, trapped in the Sep-Pak QMA anion cartridge, 18 O-water is collected in recycling bottles. Fill the QMA cartridge with 0.3-0.4 mL of normal saline. 18 F-eluted into a vial, and 50-100 μL of it was added to the above reaction vial. After stirring and mixing, the reaction was heated at 100°C for about 10 to 15 minutes. Cool, add 6-8 mL of water to the reaction flask, mix well, and transfer to HLB cartridge or SEP-PAK C18 cartridge. After all the solution in the reaction bottle was transferred, rinse the cartridge with 10 mL×3 water for injection, and blow dry the cartridge. ...

Embodiment 368

[0062] Example 3 [ 68 Ga]NOTA-R-PDL1P and [ 64 Radiosynthesis of Cu]NOTA-R-PDL1P

[0063] In a reaction tube containing 50 μL of the precursor NOTA-R-PDL1P (R=H, 4-methylphenylbutyryl, or 4-iodophenylbutyryl) (50 μg / μL), 200 μL of 1.25 M sodium acetate solution was added. from 68 Ge / 68 The Ga generator was eluted with 4 mL of 0.05M hydrochloric acid 68 GaCl 3 Put it into the above reaction tube, mix well, adjust the pH of the solution to 4.0, and heat at 100°C for about 10-15 minutes. Cool, add 4 mL of physiological saline to the reaction flask, mix well, and transfer to HLB cartridge or SEP-PAK C18 cartridge. After all the solution in the reaction bottle was transferred, rinse the small column with 10 mL×2 water for injection, and blow dry the small column. Then, the product was eluted with 1.5 mL of ethanol and collected into a receiving bottle after passing through a sterile filter. It was diluted with physiological saline into a product solution containing 5% ethan...

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Abstract

The invention relates to a positron nuclide labeled targeted programmed death receptor 1 ligand (PD-L1) polypeptide probe as well as a preparation method and application thereof. The structural formula of the targeted PD-L1 polypeptide probe [X] NOTA-R-PDL1P is as shown in the formula 1, and in the formula 1, R is-H, 4-methylphenylbutyryl or 4-iodobenzenebutyryl; x < n + > is 68Ga < 3 + >, [Al18F] < 2 + >, 64Cu < 2 + > or other radioactive metal ions. The targeted PD-L1 polypeptide probe prepared by the invention has excellent in-vivo pharmacokinetic characteristics, and the invention also relates to an application of the targeted PD-L1 polypeptide probe in preparation of a tumor PET (Polyethylene Terephthalate) imaging agent. Or Xn + = 68Ga < 3 + >, [Al18F] < 2 + >, 64Cu < 2 + > or other radioactive metal ions in formula 1.

Description

【Technical field】 [0001] The invention relates to a positron radionuclide-labeled targeting PD-L1 polypeptide probe and its application in the preparation of PET imaging agents, in particular to a targeting PD-L1 polypeptide probe, a preparation method and its application in tumor positron emission tomography (PET) imaging agents. 【Background technique】 [0002] The clinical translational application of immune checkpoint antibody inhibitors has opened up a new direction for tumor targeted therapy, which has attracted great attention of clinicians [1]. Cancer immunotherapy targeting immune checkpoint receptors cytotoxic T lymphocyte-associated protein 4 (CTLA-4) receptor, programmed death receptor 1 (PD1) and its ligand PD-L1 transform conventional anticancer immunotherapy [2]. In particular, immune checkpoint antibody inhibitors targeting PD-1 and PD-L1 have been used in cancers including melanoma (MM), non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), bladde...

Claims

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Application Information

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IPC IPC(8): C07K14/00C07K1/13C07K1/06A61K51/04A61K51/08A61K101/02A61K103/00
CPCC07K14/001A61K51/0482A61K51/08Y02P20/55
Inventor 唐刚华孙朋辉陈海波
Owner NANFANG HOSPITAL OF SOUTHERN MEDICAL UNIV
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