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Somatostatin precursor compound and somatostatin ligand compound of octreotide and preparation and application thereof

A technology of ligand compounds and precursor compounds, which is applied in the field of radiopharmaceuticals and nuclear medicine, can solve the problems of unfavorable reaction temperature for biomolecules, more Ga decay during labeling time, general thermodynamic stability, etc., and achieve easy automatic synthesis and stable labeling products , Conducive to the effect of commercial application and clinical promotion

Inactive Publication Date: 2019-05-31
THE AFFILIATED HOSPITAL OF SOUTHWEST MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

DOTA is 68 Ga 3+ ions are most commonly used as coordination chelators, but the formation of 68 The Ga-DOTA chelate is not very stable because the ring radius of DOTA is 68 too large for Ga ions ( 68 Ga 3+ Ionic radius compared to 64 Cu 2+ Smaller), general thermodynamic stability
At the same time, the coordination kinetics of ring-structured chelating agents are relatively inert, leading to 68 The reaction conditions for Ga-labeled DOTA are relatively harsh, the labeling reaction time is long, and the reaction temperature is high. 68 Ga is very unfavorable, because 68 Ga is a nuclide with a short half-life, and the labeling time is too long to cause 68 Ga decays more, and too high reaction temperature is not conducive to temperature-sensitive biomolecules

Method used

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  • Somatostatin precursor compound and somatostatin ligand compound of octreotide and preparation and application thereof
  • Somatostatin precursor compound and somatostatin ligand compound of octreotide and preparation and application thereof
  • Somatostatin precursor compound and somatostatin ligand compound of octreotide and preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 168

[0044] Example 1 68 Preparation of Ga-NOTA-TATE

[0045] 1. Synthesis of NOTA-TATE

[0046] NOTA-TATE was synthesized by standard FMOC solid-phase peptide synthesis method, the specific steps are as follows:

[0047] 1) Dissolve Throl-resin and Fmoc-amino acid in N,N-dimethylformamide, add HATU, and condense at room temperature for 4 hours.

[0048] 2) Wash the condensation reaction product 3 times with N,N-dimethylformamide, add N,N-dimethylformamide (DMF) / piperidine / piperidine at a volume ratio of 96:2:2 The mixed solution of diazabicyclo (DBU) was deprotected, and after incubating in a 37° C. incubator for 5 minutes, the solvent was removed, and the coupling steps were repeated sequentially according to the desired peptide sequence.

[0049] 3) Add a mixed solution of dichloromethane / acetic acid / trifluoroethanol with a volume ratio of 3:1:1, stir gently for 2 hours, cleave the polypeptide from the resin, and incubate overnight at room temperature with dimethyl sulfoxide ...

Embodiment 268

[0061] Example 2 68 Micro-PET / CT imaging of Ga-NOTA-TATE in normal mice

[0062] To the tail vein of normal adult mice, inject the compound prepared in Example 1 68 Ga-NOTA-TATE 100uCi / mouse, observe the distribution of ligand compounds in normal mice at different time points after injection.

[0063] attached Figure 4 for injection 68 Micro-PET / CT images of normal mice 10min, 30min, 1h, 2h after Ga-NOTA-TATE. From attached Figure 4 It can be seen that in 68Imaging of mice 10 minutes after Ga-NOTA-TATE injection showed increased radioactive distribution in the heart blood pool, liver, and kidneys, increased radioactive discharge into the bladder, mildly increased radioactive distribution in the brain, lungs, small intestine, and muscles, and extremities and bones There was no increase in the distribution of radioactivity in the spine and spine; at 30 minutes of injection, the distribution of radioactivity in the blood pool of the liver and heart decreased, and the dist...

Embodiment 368

[0064] Example 3 68 Distribution of Ga-NOTA-TATE in normal adult rats

[0065] Six normal adult rats, half male and half male, were pre-anesthetized with 3% isoflurane-oxygen mixed gas, placed on the PET / CT scanning bed, and treated with 1.5% isoflurane Anesthesia was maintained with isoflurane-oxygen mixture and respiration was monitored. Inject 400uCi / cat by tail vein 68 Immediately after Ga-NOTA-TATE, Micro-PET / CT dynamic imaging was performed for 4 hours. After acquisition and image reconstruction, use the software provided by the supplier to delineate the myocardium, blood pool, liver, kidney, brain, muscle, bone, stomach, and small intestine on the whole-body attenuation-corrected coronal image as regions of interest (ROI). Get it 68 Ga-NOTA-TATE in 30s, 5min, 10min, 30min, 1h, 2h, 4h per gram of tissue injection dose percentage (%ID / g), the results are shown in Table 1 and Figure 5 shown.

[0066] Table 1 68 Biodistribution of Ga-NOTA-TATE in normal rats viscer...

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Abstract

The invention provides a somatostatin precursor compound of octreotide, and belongs to the technical field of radioactive drugs and nuclear medicine.The precursor compound is NOTA-TATE, and the structure is shown in the following formula I (the formula is shown in the description). The invention also provides a somatostatin ligand compound of the octreotide, wherein the precursor compound NOTA-TATE is labeled by using radionuclide A to obtain A-NOTA-TATE.The invention also provides a method for preparing the somatostatin precursor compound and the somatostatin ligand compound of the octreotide.The ligand compound obtained by nuclide labeled NOTA-TATE is a colorless transparent liquid injection, has the advantages of simple preparation process, short time-consuming, high labeling rate, stable labeling, good affinity with somatostatin receptors, good targeting for tumor and good imaging effect,can be used for differential diagnosis, staging, accurate localization of focus, treatment andcurative effect monitoring of neuroendocrine tumors, and has good application prospects.

Description

technical field [0001] The invention belongs to the technical field of radiopharmaceuticals and nuclear medicine, and specifically relates to an octreotide-type somatostatin precursor compound, a ligand compound, and its preparation and application. Background technique [0002] Neuroendocrine tumors (NETs), originating from neuroendocrine cell tumors, can occur anywhere in the body, the most common sites are the stomach, intestines, pancreas and other digestive systems (about 72%), followed by the lungs (about 25%), etc. . The annual incidence rate in European and American countries is 2-5 / 100,000. Analysis shows that in the past 30 years, the global incidence rate has increased significantly, which may be closely related to the development of imaging technology and the improvement of diagnostic methods. [0003] Overexpression of specific subtypes of somatostatin receptors (Somatostatin Receptors, SSTRs) was found in NETs. SSTRs is a kind of glycoprotein, which has been ...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/06C07K1/04C07K1/13A61K51/08A61K51/04A61P35/00A61K103/34
Inventor 陈跃夏雨霄曾成润赵艳红李子博廖斌杜一华王瑛陈正君刘洋陈琳
Owner THE AFFILIATED HOSPITAL OF SOUTHWEST MEDICAL UNIV
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