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A sort of 18 f-labeled compounds and pod protease-targeted pet imaging probes

A technology for compounds and precursor compounds, applied in the fields of radiopharmaceuticals and nuclear medicine, can solve the problem that positron emission tomography has not been applied, and achieve the effects of reducing non-specific uptake, promoting application and simple operation

Active Publication Date: 2021-05-18
JIANGSU INST OF NUCLEAR MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Current research on the detection of legumain activity mainly focuses on strategies for fluorescence imaging, while positron emission tomography (PET) imaging has not yet been applied

Method used

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  • A sort of <sup>18</sup> f-labeled compounds and pod protease-targeted pet imaging probes
  • A sort of <sup>18</sup> f-labeled compounds and pod protease-targeted pet imaging probes
  • A sort of <sup>18</sup> f-labeled compounds and pod protease-targeted pet imaging probes

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] 18 The F-labeled compound has a precursor compound of the structure shown in the following formula 1, and its synthetic route is,

[0074]

[0075] Intermediate compound 1-2 was synthesized according to the method reported in the literature [Lin, J. et al. Chem Commun (Camb) 2017, 53, (48), 6476-6479.],

[0076]

[0077] Weigh compound 1-2 (38mg, 0.08mmol), compound 1-1 (50mg, 0.09mmol) and HBTU (62mg, 0.16mmol), add it to the reaction bottle, and dissolve it with ultra-dry DMF ultrasonically for 1min (model: KQ2200E, power : 100W), then add DIPEA (88μL, 0.53mmol), N 2 Reaction at room temperature under protection for 2h. After separation and purification by column chromatography (eluent: DCM:MeOH (volume ratio) = 35:1 to 15:1, the solvent was collected and rotary evaporated, and dried in vacuum for 2 hours to obtain compound 1-3 (60 mg, yield 72%) .

[0078] The obtained compound 1-3 was dissolved in 4 mL of DCM:MeCN:TFA=1:1:2 (volume ratio), the solution tur...

Embodiment 2

[0083] 18 The F-labeled compound has a precursor compound of the structure shown in the following formula 2, and its synthetic route is,

[0084]

[0085] Polypeptide Ac-HEHEHEAAN-OH, compound 2-1, was synthesized by solid-phase peptide synthesis, and the synthetic route was as follows:

[0086] By sequentially linking Fmoc-N-trityl-L-asparagine (298 mg, 0.5 mmol), N-fluorenylmethoxycarbonyl-L-alanine (156 mg, 0.5 mmol), N-fluorenylmethoxycarbonyl- L-alanine (156mg, 0.5mmol), Fmoc-L-glutamic acid-5-tert-butyl ester hydrate (213mg, 0.5mmol), Fmoc-trityl-L-histidine (310mg, 0.5 mmol), Fmoc-L-glutamic acid-5-tert-butyl hydrate (213mg, 0.5mmol), Fmoc-trityl-L-histidine (310mg, 0.5mmol), Fmoc-L-glutamine Acid-5-tert-butyl hydrate (213mg, 0.5mmol), Fmoc-trityl-L-histidine (310mg, 0.5mmol), acetic anhydride (1mL, 10mmol), de-resin, rotary evaporation solvent, Ether was precipitated, and compound 2-1 was obtained after vacuum drying (634 mg, yield 56%).

[0087]

[0088] Com...

Embodiment 3

[0094] Radiosynthesis:

[0095] probe 18 The radiosynthetic route of F-1 compound is as follows,

[0096]

[0097] Produced on demand by a medical cyclotron 18 F fluoride ion. After production is complete, the 18 The F fluoride ion is passed to the anion exchange column (QMA), and the pyridazine buffer solution (300 μL, pH=2.5) is used to 18 F anion (150-300mCi) is eluted into polypropylene reaction tube (1mL) from QMA column, the AmBF synthesized in embodiment 1 3 -CBT-Cys(StBu)-AAN (precursor compound of the structure shown in formula 1, that is, probe precursor 1) (25mM, 30μL) was added to the reaction tube and incubated at 80°C for 30min (80°C is the radiosynthesized Optimal conditions).

[0098] Radioactive purification:

[0099] After the radiosynthesis is complete, transfer the reaction solution to a centrifuge tube containing 20 mL of ultrapure water, and then the resulting radiolabeled probe 18 F-1 was successively loaded on a C18 purification column (colum...

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Abstract

The invention discloses a method in the technical field of radiopharmaceuticals and nuclear medicine 18 F-labeled compound and leguminase-targeted PET imaging probe. The present invention provides a compound represented by formula (I), which undergoes cleavage of asparagine sites and reduction of disulfide bonds in the tumor microenvironment with high expression of pod protease, and utilizes biocompatible CBT-Cys click condensation reaction, form radioactive dimers 18 F‑1‑dimer, which increases tumor imaging. The present invention adopts "one-step ion exchange" 18 The compound with the structure shown in formula (I) is synthesized by the F labeling method, and the method is simple to operate and does not require further purification by preparative HPLC. The present invention also provides a PET imaging probe targeting pod protease, which is the compound shown in (I). The PET imaging probe has the advantages of stability, high sensitivity, strong specificity, good safety and the like.

Description

technical field [0001] The invention relates to the technical field of radiopharmaceuticals and nuclear medicine, in particular to a 18 F-labeled compound, bean protease-targeted PET imaging probe, preparation method and application. Background technique [0002] Legumain, also known as asparagine endopeptidase, is a lysosomal cysteine ​​protease. Legumain has high selectivity and is the only enzyme known to humans that can recognize asparagine (Asn) at the P1 site of a peptide substrate. Recent studies have shown that legumain enzymes can participate in a variety of biological events, such as inhibiting osteoclast formation, affecting the efficiency and kinetics of major histocompatibility complex (MHC) class II antigen presentation, and regulating M2 macrophages in obstructive cells. The role of reducing renal interstitial fibrosis in renal disease is of great significance to maintaining normal renal physiology and homeostasis. In addition, studies have shown that the u...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/06C07K1/13C12Q1/37
CPCC07K7/06C12Q1/37
Inventor 邱玲林建国吕高超刘清竹李珂黄洪波彭莹谢敏浩
Owner JIANGSU INST OF NUCLEAR MEDICINE
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