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CN-121990969-A - Tumor targeted imaging compound, and preparation method, composition and application thereof

CN121990969ACN 121990969 ACN121990969 ACN 121990969ACN-121990969-A

Abstract

The invention discloses a compound for tumor targeted imaging, a preparation method, a composition and application thereof, wherein the structural general formula of the compound is shown as the following formula I, X-Y-Z formula (I), wherein X is a target head, Y is a linker, and Z is a dye. The tumor targeted imaging compound can perform fluorescence imaging through targeted tumor, so that the distribution condition of tumor tissues is determined according to the condition of fluorescence imaging, and the disease state is further diagnosed or determined or the operation is performed; the compound is obtained through specific design, has the advantages of good targeting property, high affinity with tumor tissues, high signal response speed, high resolution ratio and the like, and can effectively reduce the positive cutting edge rate and the false positive rate.

Inventors

  • ZHAO JING
  • YANG DAWEI
  • LI JIUPENG

Assignees

  • 新斗生物科技(苏州)有限公司

Dates

Publication Date
20260508
Application Date
20250918
Priority Date
20241107

Claims (10)

  1. 1. A tumor targeted imaging compound has a structural general formula shown in the following formula I: X-Y-Z formula (I), Wherein X is a target head which is of the following structure or an alkali metal salt thereof (preferably Na salt), , Y is a linker selected from one of the following structures: 、 、 、 Or an alkali metal salt thereof, wherein n=2 to 12, Or an alkali metal salt thereof, 、 ; Z is a dye selected from the following structures, , 。
  2. 2. The compound for tumor-targeted imaging according to claim 1, The linker is Or an alkali metal salt thereof, wherein n=2 to 12.
  3. 3. The compound for tumor-targeted imaging according to claim 2, wherein n=5 to 10, preferably 5 to 7.
  4. 4. The compound for tumor-targeted imaging according to claim 3, wherein the compound is compound A, compound B, compound C, compound D, compound E, compound F and compound G, Wherein, the structural formula of the compound A is shown as the following formula: (Compound A); the structure of the compound B is shown as the following formula: (Compound B); the structure of the compound C is shown as the following formula: (Compound C); the structure of the compound D is shown as the following formula: (Compound D); the structure of the compound E is shown as the following formula: (Compound E); The structure of the compound F is shown as the following formula: (Compound F); the structure of the compound G is shown as the following formula: (Compound G).
  5. 5. A method of preparing a compound for tumor targeted imaging according to any one of claims 1 to 4, comprising the steps of: 1) Firstly, forming a compound 1 comprising a target head X and a connector Y through reaction; Preferably, the compound 1 is obtained by a method comprising the steps of synthesizing the linker Y and then reacting the linker with the target X, or The compound 1 is obtained by a method comprising the following steps of firstly reacting a Y1 substructure material of a linker Y with a target X to obtain a compound 11 with the Y1 substructure material connected with the target, and then reacting the compound 11 with a Y2 substructure material of the linker Y to obtain the compound 1 of the target X and the linker Y; 2) Then reacting the compound 1 with a dye Y to form a compound for tumor targeted imaging, thus obtaining the tumor targeted imaging compound; Preferably, the compound 1 is any one of the following compounds: 、 、 、 、 、 、 。
  6. 6. The method of preparing a compound for tumor-targeted imaging according to claim 5, wherein in step 2), the dye is S0456, IRDye800, and analogues thereof; Preferably, when the dye is IRDye800 and its analogues, the compound 1 and dye are reacted in buffer solution at pH 7.2-9.0, room temperature for 1.5-3 h, preferably at pH 8.4, room temperature for 2h, or When the dye is S0456 or the like, the compound 1 and the dye react in a sodium carbonate solution at 70-75 ℃ for 0.5-1.5h, preferably for 1h.
  7. 7. A composition for tumor-targeted imaging comprising a compound according to any one of claims 1 to 4 or a compound obtainable by a method according to claim 5 or 6, and an adjuvant, preferably a pharmaceutically acceptable carrier, excipient or diluent.
  8. 8. A kit for tumor targeting comprising a compound of tumor targeted imaging according to any one of claims 1 to 4 or a compound obtained by the method of claim 5 or 6.
  9. 9. Use of a compound according to any one of claims 1 to 4, a compound obtainable by a method according to claim 5 or 6, a composition according to claim 7 or a kit according to claim 8 for the preparation of a fluorescence imaging agent.
  10. 10. Use of a compound according to any one of claims 1 to 4, a compound obtained by a method according to claim 5 or 6, a composition according to claim 7 or a kit according to claim 8 for the manufacture of a medicament for detection in oncology, in particular for performing fluorescence imaging, thereby diagnosing, determining or performing surgery, preferably the tumor is a PSMA-expressing related disease, such as prostate cancer.

Description

Tumor targeted imaging compound, and preparation method, composition and application thereof Technical Field The invention belongs to the technical field of biological detection, and relates to a compound, a preparation method, a composition and application thereof, in particular to a compound for tumor targeted imaging, and a preparation method, a composition and application thereof. Background Prostate cancer is a tumor caused by malignant hyperplasia of prostate epithelial cells, is the most common malignant tumor of male genitourinary system, and can cause abnormal urination, pelvic discomfort, erectile dysfunction and the like of patients. Prostate cancer is also a worldwide health disease, and reports of the world health organization international cancer research center (International Agency for Research on Cancer, IARC) and the Global cancer epidemiology database (Global CANCER STATISTICS, GLOBOCAN) show that new cancer cases worldwide rise year by year, and the incidence and mortality of cancer in China are still the first Global threat affecting the health of people in China. Prostate Specific Membrane Antigen (PSMA) is a type II transmembrane glycoprotein consisting of 750 amino acids, which has a molecular weight of more than 100 kD after glycosylation, and is expressed in non-prostate tissues such as the duodenum, the kidney, the salivary gland, the neuroendocrine system, and the proximal tubular, except in the prostate, but the expression of PSMA in prostate cancer tissues can be raised 100 to 1000 fold as compared to normal tissues, and is also overexpressed in cancerous lymph nodes and bone metastases, and the proportion of PSMA expressed in prostate cancer tumors is very high, almost all stages of the disease. In one Immunohistochemical (IHC) analysis, PSMA expression was detected in 94% of prostate cancer samples. In addition, increased PSMA expression is associated with tumor classification, pathological stage, and biochemical recurrence. And the transmembrane conformational structure of PSMA enables internalization of the binding agent by the endosomal complex, which is highly advantageous for successful targeting of the ligand. Surgical operation is a main means of prostate cancer treatment, and can be performed in an open, laparoscopic, robotic-assisted laparoscopic mode, and the like. The purpose of radical prostatectomy is to completely eliminate the tumor while retaining the function of controlling urine and as much as possible of erectile function. Although the prior art can help to identify larger lesions before and after operation, the tumor cannot be positioned in real time in operation due to technical limitation, and the operation incisional margin cannot be accurately judged. According to clinical statistics, when 20% to 48% of prostate cancer patients leave the operating room, tumor margins are positive, which is directly related to biochemical recurrence (BCR) and cancer management, with BCR occurring within 5 years in about 32% to 38% of patients. Furthermore, in prostate cancer, the most common sites of BCR and positive tumor margin are the outside of the back and the apex of the prostate, which are areas closely related to nerves responsible for erectile function and urinary control. The purpose of radical prostatectomy is to completely eliminate the tumor while retaining the function of controlling urine and as much as possible of erectile function. Since erectile dysfunction and urinary incontinence are the primary possible side effects of prostatectomy, surgeons may prefer to preserve tissue and nerves outside the back of the prostate and surrounding the tip of the prostate to maintain the quality of life of the patient. Thus, careful preservation of these regions may lead to tumor tissue being left behind, increasing the risk of BCR. Fluorescence guided intra-operative imaging techniques can help reduce tumor positive cut-offs and identify hidden metastatic lymph nodes, thereby improving prognosis in prostate cancer patients. For imaging in the prostate cancer operation, the Prostate Specific Membrane Antigen (PSMA) is a type II transmembrane glycoprotein with extracellular binding sites, the extracellular region accounts for 95% of the PSMA and is a specific molecular target point of small molecules and antibodies, the expression level of the PSMA is obviously up-regulated in almost all prostate cancer (PCa) cell membranes, only 5% -10% of PCa focus PSMA expression is negative, and the PSMA expression level of PCa is 100-1000 times that of non-pathological prostate tissues. With the widespread popularity of endoscopic surgery and the rapid development of surgical robots, there is an increasing demand for precise intraoperative positioning and identification of surgery. Compared with the conventional open surgery, the intraoperative fluorescence visualization technology is vigorously developed under the wide application of fluorescent endoscopes, indocyanine green (IC