18F labeled compound and pod protease targeted PET imaging probe

A compound, 18F technology, applied in the field 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, increasing specificity, and increasing water solubility

Active Publication Date: 2019-12-31
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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  • 18F labeled compound and pod protease targeted PET imaging probe
  • 18F labeled compound and pod protease targeted PET imaging probe
  • 18F labeled compound and pod protease targeted PET imaging probe

Examples

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 The F anion (150-300mCi) is eluted from the QMA column into a polypropylene reaction tube (1mL), and the AmBF synthesized in Example 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 co...

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Abstract

The invention discloses an 18F-labeled compound and a pod protease targeted PET imaging probe, which relates to the technical fields of radiopharmaceuticals and nuclear medicine. The invention provides a compound shown as a formula (I), asparagine site shearing and disulfide bond reduction are carried out in a tumor microenvironment with high expression of pod protease, and a radioactive dimer 18F-1-dimer is formed by virtue of a biocompatible CBT-Cys click condensation reaction, so that the tumor imaging effect is improved. The compound with a structure shown in the formula (I) is synthesizedby adopting a one-step ion exchange 18F labeling method, the method is simple to operate, and preparative HPLC for further purification is not needed. The invention further provides the pod proteasetargeted PET imaging probe which is a compound shown in (I). The PET imaging probe has the advantages of high 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 Applications(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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