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Targeting fibroblast activation protein probe, preparation method and application thereof in the preparation of PET imaging agent

A PET imaging agent and fibroblast technology, applied in the field of target cell probes, can solve the problems of poor targeting and pharmacokinetic properties, cumbersome synthetic labeling process, and high physiological uptake, and achieve increased hydrophilicity. properties, excellent in vivo pharmacokinetic properties, and the effect of optimizing chemical structure

Active Publication Date: 2022-03-11
NANFANG HOSPITAL OF SOUTHERN MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In order to solve the poor targeting and pharmacokinetic properties of the existing FAPI imaging agents, and to overcome the defects of high physiological uptake of the existing FAPI imaging agents in the hepatobiliary system, biliary system, pancreas and intestinal system, The present invention provides a probe targeting fibroblast activation protein (FAP), specifically a class of novel FAPI probes (imaging agents) containing double ligands with excellent pharmacokinetic properties
[0005] In addition, in order to solve the problems of cumbersome, time-consuming and low radiochemical yields in the synthetic labeling process of the existing FAPI imaging agent, the present invention also provides a method for preparing the probe targeting fibroblast activation protein

Method used

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  • Targeting fibroblast activation protein probe, preparation method and application thereof in the preparation of PET imaging agent
  • Targeting fibroblast activation protein probe, preparation method and application thereof in the preparation of PET imaging agent
  • Targeting fibroblast activation protein probe, preparation method and application thereof in the preparation of PET imaging agent

Examples

Experimental program
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preparation example Construction

[0078] Preparation of the targeting FAP probe of the present invention.

[0079] First, the preparation of precursor raw materials is carried out. FAP pharmacophore modified ligand-PEG2 to form FAP pharmacophore ligand-PEG2, after FAP pharmacophore-PEG2 modified Asp2, Glu and glucopyranosamine-based ligand, finally modified chelating group- For NOTA or -DOTA, the product peaks are collected through preparative HPLC separation and purification, and freeze-dried to obtain the purified precursor material NOTA-FAPT or DOTA-FAPT.

[0080] The preparation of precursor raw materials NOTA-FAPT or DOTA-FAPT, in order to further solve the one-step automatic synthesis [X n+ ]NOTA-FAPT and its analog probes [X n+ ]DOTA-FAPT laid the foundation.

[0081] Secondly, the radiosynthesis of the probe is carried out, wherein, the radioactive metal nuclide X n+ = 68 Ga 3+ ,[Al 18 F] 2+ ,64Cu 2+ or other radioactive metal ions. Using NOTA-FAPT as the precursor raw material, respectively ...

Embodiment 1

[0090] The preparation of embodiment 1 precursor NOTA-FAPT

[0091] The precursor material NOTA-FAPT (R = 2-acetylamino-2-deoxy-β-D-glucopyranosamine) was prepared as follows:

[0092] FAP pharmacophore ligand-PEG2 is modified to form FAP pharmacophore ligand-PEG2, and then FAP pharmacophore ligand-PEG2 is used to modify ASP2, Glu and 2-acetylamino-2-deoxy-β-D After the -glucopyranosamine-based ligand is combined with -NOTA to generate NOTA-FAPT, the product peaks are collected by preparative HPLC separation and purification to obtain the purified precursor product NOTA-FAPT.

[0093]The chemical yield of NOTA-FAPT is high and the purity is greater than 95%. The HPLC and MS determination results of NOTA-FAPT are shown in Figure 1a and Figure 1b As shown, the molecular weight (Mr.) of NOTA-FAPT determined by mass spectrometry MS (m / z) is 1478.48.

[0094] Precursor materials DOTA-FAPT (R=2-acetylamino-2-deoxy-β-D-glucopyranosamine group, or glucosamine group) and NOTA-FAPT...

Embodiment 218

[0095] Example 2[ 18 Radiosynthesis of F]AlF-NOTA-FAPT

[0096] In a reaction flask filled with NOTA-FAPT (R=2-acetylamino-2-deoxy-β-D-glucopyranosyl) (50 μg / μL, 50 μL), sequentially add 2 mM AlCl 3 Mix 6 μL of solution, 5 μL of glacial acetic acid and 300 μL of acetonitrile. passed by cyclotron 18 O(p,n) 18 Produced by F nuclear reaction 18 f - , at N 2 Under the carrier band, trapped in the Sep-Pak QMA anion column, 18 O-water is collected in a recovery bottle. Use 0.3-0.4mL of physiological saline (or sodium acetate buffer) to anion (QMA) small column 18 f - Eluted into a vial, and 50 μL of it was added to the above reaction vial. After stirring and mixing, heat the reaction at 100°C for about 10-15 minutes. Cool, add 6-8mL of water to the reaction flask, mix well, and transfer to HLB small column or SEP-PAK C18 small column. After all the solutions in the reaction bottle have been transferred, wash the column with 10mL×3 water for injection, and dry the column....

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Abstract

The invention discloses a probe targeting fibroblast activation protein (FAP), a preparation method and its application in preparing a positron emission tomography (PET) imaging agent. The FAP probe of the present invention is a novel FAP probe containing double ligands with excellent pharmacokinetic properties [X n+ ]NOTA-FAPT, wherein, FAPT is composed of FAP pharmacophore ligand, glucopyranosesamine-based ligand and linking group, NOTA is 1,4,7-triazacyclononalkyl-N',N ”-diacetoxy-N-acetyl analogue, X n+ for 68 Ga 3+ 、[Al 18 F] 2+ , 64 Cu 2+ or other radioactive metal ions. By optimizing the chemical structure of the FAP probe of the present invention, the in vivo pharmacokinetic properties and targeting of the probe are improved, the hydrophilicity is increased, and the uptake of the liver system, biliary system and intestinal system is reduced, and automatic high-yield can be realized. High-rate radiosynthesis, which can be applied to the preparation of biological function imaging agents for tumors and various diseases.

Description

technical field [0001] The invention relates to the technical field of target cell probes, in particular to a fibroblast activation protein probe, a preparation method and its application in the preparation of a PET imaging agent. Background technique [0002] In the traditional diagnosis and treatment methods, it is mainly aimed at the target of tumor parenchymal cells. Recently, the tumor microenvironment and tumor stroma have come into increasing focus, enabling new diagnostic and therapeutic modalities. Cancer-associated fibroblasts (CAFs) are a major component of tumors, accounting for up to 90% of total tumor mass. CAFs differ from normal fibroblasts by their relatively specific expression of fibroblast activation protein (FAP), which is often associated with poor prognosis and outcome in the respective cancers. FAP has dipeptidyl peptidase and collagenase activity, can cleave substrates of many dipeptidyl peptidase activities including gelatin and denatured type I c...

Claims

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Application Information

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IPC IPC(8): C07K5/117C07K1/107C07K1/14
CPCC07K5/1024
Inventor 唐刚华黄佳文胡孔珍韩彦江傅丽兰
Owner NANFANG HOSPITAL OF SOUTHERN MEDICAL UNIV
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