Search

CN-121974976-A - Targeting alpha v beta 3 polypeptide nuclide probe and preparation method and application thereof

CN121974976ACN 121974976 ACN121974976 ACN 121974976ACN-121974976-A

Abstract

The invention relates to the technical field of nuclide probes, and discloses a targeting alpha v beta 3 polypeptide nuclide probe, a preparation method and application thereof, wherein the targeting alpha v beta 3 polypeptide nuclide probe comprises a radionuclide-labeled compound shown in formula I. The targeting alpha v beta 3 polypeptide nuclide probe provided by the invention can be used as a diagnosis and treatment reagent for tumors with high expression of alpha v beta 3 protein in human or animal bodies, is especially suitable for tumor imaging and radionuclide therapy, and has higher tumor/muscle uptake ratio and good application potential as shown by animal experiments. Formula I.

Inventors

  • LI YUNLONG

Assignees

  • 南京诺源医疗器械有限公司

Dates

Publication Date
20260505
Application Date
20260211

Claims (10)

  1. 1. The targeting alpha v beta 3 polypeptide nuclide probe is characterized by comprising a radionuclide-labeled compound shown in formula I: Formula I; wherein, the Y group is any one of a group I or a group II: group I and group II; The radionuclide includes any of 55 Co、 68 Ga、 64 Cu、 86 Y、 89 Zr、 90 Y、 111 In、 177 Lu、 225 Ac.
  2. 2. The target αvβ3 polypeptide nuclide probe of claim 1, wherein the compound of formula i marked by the radionuclide is any one of NY- αvβ3-R1 or NY- αvβ3-R2; Wherein, the structural formula of NY-alpha v beta 3-R1 is as follows: the structural formula of NY-alpha v beta 3-R2 is as follows: 。
  3. 3. a method for preparing a target αvβ3 polypeptide nuclide probe for realizing the preparation of the target αvβ3 polypeptide nuclide probe according to any one of claims 1 to 2, comprising the steps of: S1, starting synthesis from the rightmost end of polypeptide DOTA-Glu-Glu-Glu-Cys-Arg-Gly-Asp-Lys-Gly-Pro-Asp-Cys-OH, coupling FMOC-Cys-OH with resin by taking a condensation reagent DIEA and DCM as solvents, adding methanol and DCM solution after reaction at room temperature, and then adding DIEA for reaction to seal unreacted sites on the resin, wherein the reaction formula is as follows: ; s2, removing FMOC by adopting a DMF solution containing 20% of piperidine, reacting at room temperature, and washing resin by adopting DMF after removal to obtain resin peptide NH2-Cys-resin, wherein the reaction formula is shown as follows: ; s3, FMOC-Asp-OH condensation, namely dehydrating and condensing FMOC-Asp-OH and resin peptide by taking a condensation reagent DIC+HOBT and DMF as solvents, and reacting at room temperature to obtain FMOC-Asp-Cys-resin, wherein the reaction formula is shown as follows: ; S4, repeating the steps S2-S3, and sequentially condensing residual amino acids to complete the synthesis of DOTA-Glu-Glu-Glu-Cys-Arg-Gly-Asp-Lys-Gly-Pro-Asp-Cys-resin peptide, wherein the reaction formula is as follows: ; s5, polypeptide cleavage, namely, cleaving DOTA-Glu-Glu-Glu-Cys-Arg-Gly-Asp-Lys-Gly-Pro-Asp-Cys-resin peptide by using a cleavage solution, filtering the cleavage solution into glacial ethyl ether after cleavage is finished, freeze-drying to obtain polypeptide PFFC, and dissolving the polypeptide PFFC and then freeze-drying, wherein the reaction formula is as follows: ; S6, polypeptide disulfide bond polycyclization, namely dissolving freeze-dried polypeptide PFFC by using acetonitrile and water, regulating pH by using ammonium bicarbonate to be slightly alkaline, stirring to form disulfide bonds, and monitoring whether complete disulfide bond formation is formed by mass spectrum, wherein the reaction formula is shown as follows: ; s7, radiolabeling, namely mixing a sodium acetate solution, a compound solution shown in formula I and a radionuclide solution, and reacting to obtain the targeting alpha v beta 3 polypeptide nuclide probe, wherein the reaction formula is shown as follows: 。
  4. 4. The method of claim 3, wherein in step S1, the reaction time at room temperature is 1.5h, and the reaction time for adding DIEA is 20min.
  5. 5. The method of claim 3, wherein in the step S2, the reaction time at room temperature is 20min, the resin is washed 4 times, and the washing time is 1min.
  6. 6. The method of claim 3, wherein in step S3, the reaction time at room temperature is 1h.
  7. 7. The method of claim 3, wherein in step S5, the ratio of the lysate is 95% TFA, 1%H 2 O, 2% EDT and 2% TIS, and the lysis time is 2h.
  8. 8. The method for preparing a target αvβ3 polypeptide nuclide probe according to claim 3, wherein in step S7: And/or the volume ratio of the sodium acetate solution to the radionuclide solution is 1:1; and/or the concentration of the sodium acetate solution is 1-3M, and the pH is 4; and/or the concentration of the compound solution shown in the formula I is 5 multiplied by 10 -6 M; and/or the radionuclide solution has a radioactivity of 1-10 mCi; and/or the temperature of the radiolabelling is 85-95 ℃, and the time of the radiolabelling is 5-20 min.
  9. 9. Use of a targeted αvβ3 polypeptide nuclide probe according to any one of claims 1 to 2 or a racemate, stereoisomer or pharmaceutically acceptable salt thereof in the preparation of a reagent for tumor development; Wherein the tumor comprises any one of triple negative breast cancer, ovarian cancer, non-small cell lung cancer, pancreatic cancer and glioblastoma.
  10. 10. Use of a targeted αvβ3 polypeptide nuclide probe according to any one of claims 1 to 2 or a racemate, stereoisomer or pharmaceutically acceptable salt thereof in the preparation of a reagent for identifying an αvβ3 overexpressed tumor.

Description

Targeting alpha v beta 3 polypeptide nuclide probe and preparation method and application thereof Technical Field The invention relates to the technical field of nuclide probes, in particular to a targeting alpha v beta 3 polypeptide nuclide probe, a preparation method and application thereof. Background Integrins are heterodimeric transmembrane glycoproteins consisting of different alpha and beta subunits that play an important role in cell-cell and cell-matrix interactions. Among them, integrin αvβ3 and its role in angiogenesis and tumor metastasis are of particular interest, and it acts by promoting migration of endothelial cells and tumor cells. The increasing popularity of targeted therapies has prompted urgent need for imaging monitoring of tumor targeted therapeutic response—for this reason, only a fraction of patients will respond positively to such highly specific drugs. However, since the mechanism of action of anti-angiogenic drugs is to prevent tumor progression rather than shrink tumor volume, methods of assessing tumor response by tumor size reduction are not applicable and the assessment process can be very time consuming. There is an urgent need for imaging biomarkers that can predict early response of tumors to non-cytotoxic drugs to predict subsequent clinical efficacy. Such biomarkers not only facilitate clinical trials of new drugs, but also assist in the selection of optimal treatment regimens for individual patients ("personalized medicine"). Positron Emission Tomography (PET) uses the tracer [ 18 F ] FDG to assess glucose metabolism, [ 18 F ] FLT to assess proliferation, or [ 68 Ga ] dottatoc to qualitatively assess somatostatin receptor (SST receptor) expression, and has shown good application prospects in clinical studies assessing the efficacy of cytotoxic chemotherapy and peptide receptor radiotherapy. Similarly, targeting angiogenesis specific molecular markers (e.g., integrin αvβ3) using PET imaging techniques can be used to assess the efficacy of anti-angiogenic therapies. Since published studies have mostly focused on the imaging of integrin αvβ3, and to date αvβ3 is the only integrin successfully visualized in PET imaging, a completely new nuclear probe was developed for this target. A variety of extracellular matrix (ECM) proteins, such as vitronectin, fibrinogen and fibronectin, can interact with integrins through arginine-glycine-aspartic acid (RGD) amino acid sequences in single letter codes. Based on these findings, monomeric, multimeric linear and cyclic peptides comprising the RGD sequence have been developed. It has evolved as one of the most prominent lead compounds in the development of molecular imaging compounds for assessing αvβ3 expression. To evaluate this approach for the first time, researchers synthesized radioiodinated RGD peptides that have comparable affinity and selectivity to lead compounds. In vivo experiments show that these peptides have receptor-specific tumor uptake, but are cleared mainly by the hepatobiliary route, resulting in higher concentrations of radioactivity in the liver and intestinal tract, which is unfavorable for patient studies. Therefore, there is a need to develop nuclide probes with the advantages of high active targeting, strong specificity, good water solubility, and the like. In view of this, the present invention has been made. Disclosure of Invention Aiming at the problems in the related art, the invention provides a targeting alpha v beta 3 polypeptide nuclide probe and a preparation method and application thereof, so as to overcome the technical problems in the prior related art. According to the invention, a novel alpha v beta 3 targeting radioligand is obtained through a strategy of enhancing tumor uptake by trimeric glutamic acid and enhancing tumor penetrability by CRGDKGPDC amino acid sequences, and is used for PET imaging, and the nuclide probe can specifically target alpha v beta 3 over-expressed tumor from the design, synthesis and in-vitro and in-vivo evaluation of the ligand, so that noninvasive tumor diagnosis and monitoring are realized. For this purpose, the invention adopts the following specific technical scheme: According to a first aspect of the present invention, there is provided a targeting αvβ3 polypeptide nuclide probe, the targeting αvβ3 polypeptide nuclide probe comprising a radionuclide-labeled compound of formula i: Formula I; wherein, the Y group is any one of the group I or the group II, The attachment site representing a group: group I and group II. Further, the radionuclide includes any one of 55Co、68Ga、64Cu、86Y、89Zr、90Y、111In、177Lu、225Ac, preferably 68 Ga. Further, the radionuclide-labeled compound shown in the formula I is any one of NY-alpha v beta 3-R1 or NY-alpha v beta 3-R2; Wherein, the structural formula of NY-alpha v beta 3-R1 is as follows: the structural formula of NY-alpha v beta 3-R2 is as follows: 。 According to a second aspect of the present invention, there is provided a method