Somatostatin analogue and application thereof

A technology of somatostatin and analogs, applied in the field of biomedicine, can solve the problems of low tumor specificity and missed diagnosis, and achieve the effect of good targeting, short labeling time and mild conditions

Pending Publication Date: 2021-12-10
HTA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

A series of somatostatin analogues are currently designed to modify the structure of natural somatostatin, such as the classic somatostatin analogues Octreotide and Lanreotide, which have been widely used in neuroendocrine tumors, Diagnosis and treatment of SSTR-positive tumors such as gastrointestinal tumors and thyroid cancer, but it only has a high affinity for SSTR2-positive tumors, and has low specificity for other subtypes of positive tumors, which is likely to cause missed diagnosis

Method used

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  • Somatostatin analogue and application thereof
  • Somatostatin analogue and application thereof
  • Somatostatin analogue and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention. Unless otherwise specified, the technical means used in the examples are conventional means well known to those skilled in the art, and the raw materials used are all commercially available products. Example 1 Preparation of somatostatin analogue NODA-MPAA-KE108 and its labeled compound

[0037] The structure of the somatostatin analog provided in this embodiment is shown in formula I):

[0038]

[0039] Wherein, R is a bifunctional chelating group, and R1 is a radionuclide.

[0040] The bifunctional chelating group is -DTPA, -NOTA, -p-SCN-Bn-NOTA, -DOTA or -MPAA-NODA and the like.

[0041] R1 can be selected from 18 F. 64 Cu, 68 At least one of radionuclides such as Ga.

[0042] 1, the preparation method of somatostatin analog is as follows:

[0043] (1) Synthesis of NODA-MPAA-KE108 polypeptide (see figure 1 )

[0044] ① Res...

Embodiment 2

[0066] Example 2 Affinity test with SSTR

[0067] Affinity studies of somatostatin analogs with each subtype of SSTR were tested using surface plasmon resonance (SPR). Ultrafiltration centrifugation was used to detris the five subtype receptors of SSTR1-5, and a dextran chip was used. Each chip was set with a reference channel, and the other channels were used to couple SSTR proteins. The SSTR protein was formulated in pH 4.5 sodium acetate buffer (10 mM) at a concentration of 200 μg / mL for coupling to the chip. The somatostatin analog (1mM) was sequentially diluted with phosphonate Tween solution (PBST) into 10 gradients (0.1-100μM), and a blank PBST was added every 5 gradients, starting from the low concentration. machine test. The test results are shown in Table 1.

[0068] Table 1 Affinity constants K of somatostatin and its analogs with five protein isoforms d Value (M)

[0069]

[0070] Note: For SST14 and SST28, see Gao J, Tong H, Huang Z, et al. Affinity analys...

Embodiment 3

[0072] Example 3 In vitro stability studies

[0073] Take 100 μL of [Al 18 F]NODA-MPAA-KE108 was added to physiological saline solution (pH7.4), incubated at room temperature for 0.5h, 1h, and 2h, and then detected by HPLC. Similarly, 100 μL of [Al 18 F]NODA-MPAA-KE108 was added to 1.9 mL of 10% fetal bovine serum, incubated at 37°C for 0.5 h, 1 h, and 2 h, 400 μL of the above serum was added to 100 μL of acetonitrile, mixed, vortexed, centrifuged through the membrane, and then tested by HPLC. For test results see Image 6 (a and b), the results show that [Al 18 F]NODA-MPAA-KE108 maintained good stability in normal saline (a) and 10% fetal bovine serum (b), and the radiochemical purity was >95%.

[0074] Example 4 PET imaging of tumor-bearing mice

[0075] AR42J tumor-bearing mice (BALB / c nude mice, male, about 20 g) with a tumor diameter of about 0.5-1 cm were injected through the tail vein [Al 18 F]NODA-MPAA-KE108 (3.7MBq / 100μL·mice), PET imaging was performed at 0.5h a...

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Abstract

The invention provides a somatostatin analogue and application thereof. The structure of the somatostatin analogue is as shown in formula I), a Phe-D-Trp-Lys-Thr motif with high affinity to a somatostatin receptor is reserved in the structure of the somatostatin analogue, the probe structure is modified through different chelating agents and different nuclides, and a broad-spectrum radiolabeled somatostatin molecular probe targeting a somatostatin receptor is designed. All subtypes of somatostatin receptors are targeted, and the probe is used as an early diagnosis probe for broad-spectrum neuroendocrine tumors. Therefore, precise medical treatment of early diagnosis, early discovery and early treatment of neuroendocrine tumors is realized.

Description

technical field [0001] The invention belongs to the field of biomedicine, and in particular relates to a somatostatin analogue and its application. Background technique [0002] Neuroendocrine tumors (NETs) are a heterogeneous group of tumors originating from different neuroendocrine organs, including a broad lineage ranging from classical carcinoids with good prognosis to highly malignant undifferentiated neuroendocrine carcinomas, 85% of which arise from the digestive tract , 10% originate from the lung, and can still be found in the larynx, thymus, adrenal gland, ovary, skin, prostate and other parts. Studies have shown that up to 94% of NETs cells have high expression of somatostatin receptor (SSTR), and even some poorly differentiated tumor cells also have SSTR expression on the surface. Due to the heterogeneity of tumors, different SSTR subtypes (ie, SSTR1-5) are expressed on the surface of different tumor cells, and different SSTR subtypes are expressed in the same t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K1/16C07K1/13A61K51/08A61P35/00A61K101/02A61K103/00
CPCC07K7/06A61K51/083A61P35/00
Inventor 成伟华高菲董瑞林宋志浩张蕴瀚陈孟毅邱珊珊
Owner HTA CO LTD
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