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WO-2025252221-A9 - GLYCOPEPTIDE TARGETING TUMOR-RELATED FIBROBLAST ACTIVATION PROTEIN, RADIONUCLIDE MARKER AND USE THEREOF

WO2025252221A9WO 2025252221 A9WO2025252221 A9WO 2025252221A9WO-2025252221-A9

Abstract

A FAP glycopeptide as represented by Formula (I), and a radionuclide marker thereof and the use thereof. The FAP glycopeptide is obtained by modifying a linker portion that forms a cyclic peptide on the basis of a polypeptide FAP-2286 structure, and further introducing mono- or di-saccharide molecules. After being marked with radionuclides, the glycopeptide shows superior tumor uptake and lower liver uptake compared to FAP-2286, resulting in better imaging outcomes, facilitating the development of candidate radionuclide pharmaceuticals with further research value, and contributing to the ultimate goal of developing FAP-targeted cyclic peptide radiopharmaceuticals with independent intellectual property rights. Drawing_references_to_be_translated

Inventors

  • CHENG, ZHEN
  • QU, CHUNRONG
  • Song, Miaomiao
  • CAO, Rui
  • WU, TAO
  • GAN, Xin
  • LI, Xuefei
  • XU, SHAOHUA

Assignees

  • 中国科学院上海药物研究所

Dates

Publication Date
20260507
Application Date
20250606
Priority Date
20240607

Claims (20)

  1. The following compound or salt thereof is represented by formula (I): G can independently represent a monosaccharide, disaccharide, or trisaccharide group, or a phenyl group substituted with a monosaccharide, disaccharide, or trisaccharide group; L represents a dipeptide or tripeptide linker; M represents a metal chelating group that can bind to radioactive nuclides; n is an integer from 1 to 3.
  2. The compound of claim 1 or a salt thereof, wherein, G independently represents a monosaccharide group or a phenyl group substituted with a monosaccharide group; Preferably, each of G is independently selected from the following groups: Preferably, each of G is independently selected from the following groups: Preferably, each of G is independently selected from the following groups: Preferably, each of G is independently selected from the following groups: Preferably, G is a group consisting of the following:
  3. The compound or salt thereof according to claim 1 or 2, wherein, L is selected from the following groups: Preferably, L is selected from the following groups: Preferably, L is selected from the following groups:
  4. The compound or salt thereof according to any one of claims 1-3, wherein, M is a group selected from the following structures: Preferably, M is Preferably, M is Preferably, M is
  5. The compound or salt thereof according to any one of claims 1-4, wherein n is an integer of 1 or 2; preferably, n is an integer of 1.
  6. The compound of claim 1 or a salt thereof, wherein, G is independently selected from the following groups: L is selected from the following groups: M and L are linked by an amide bond and are groups selected from the following structures:
  7. The compound of claim 1 or a salt thereof, wherein, G is independently selected from the following groups: M is
  8. The compound of claim 1 or a salt thereof, wherein, G is independently selected from the following groups: L is selected from the following groups: M is a group selected from the following structures: n is an integer that is either 1 or 2.
  9. The compound of claim 1 or a salt thereof, wherein, G is independently selected from the following groups: L is selected from the following groups: M is n is an integer that is either 1 or 2.
  10. The compound of claim 1 or a salt thereof, wherein, G is independently selected from the following groups: L is selected from the following groups: M is n is an integer that is either 1 or 2.
  11. The compound of claim 1 or a salt thereof, wherein, G is selected from the following groups: L is selected from the following groups: M is n is an integer where n is 1.
  12. The compound of claim 1 or a salt thereof, wherein, G represents the following groups: L represents the following groups: M is n is an integer where n is 1.
  13. The compound of claim 1 or a salt thereof, wherein the compound is preferably selected from:
  14. Radionuclide markers, comprising the compound or salt thereof as described in any one of claims 1-13, and the radionuclide; Preferably, the radionuclide is selected from radiodiagnostic radionuclides and radiotherapy radionuclides; Preferably, The radioactive diagnostic nuclide is selected from any one or more of 86Y , 18F , 51Mn , 52mMn , 52gMn , Al[ 18F ], 64Cu , 67Ga , 68Ga , 89Zr, 99mTc , 111In , 123I , 124I , 125I , 44Sc , 47Sc , and 203Pb ; preferably any one or more of 86Y , 18F , 51Mn , 52mMn , 52gMn , Al[ 18F ] , 64Cu , 67Ga , 68Ga , 89Zr , 99mTc , 111In , 123I , 124I , 125I , 44Sc , and 47Sc ; preferably 86Y , Al[ 18F ], 64Cu , 68Ga , and 203Pb. Any one or more of 89 Zr, 99 mTc, 124 I, and 203 Pb; preferably any one or more of 86 Y, Al[ 18F ], 64 Cu, 68 Ga, 89 Zr, 99 mTc, and 124 I; more preferably 68 Ga, 203 Pb, or 64 Cu; more preferably 68 Ga or 64 Cu; more preferably 68 Ga; more preferably 203 Pb; more preferably 64 Cu; Preferably, The radioactive therapeutic nuclide is selected from any one or more of 67Cu , 90Y , 125I , 131I , 153Sm , 166Ho , 177Lu , 186Re , 188Re , 211At , 212Pb , 212Bi , 213Bi , 223Ra , 225Ac , 227Th , 161Tb, and 149Tb ; preferably any one or more of 67Cu , 90Y , 125I , 131I , 153Sm , 166Ho , 177Lu , 227Th , 186Re , 188Re , 211At , 212Pb , 212Bi , 213Bi , 223Ra, 225Ac , and 227Th ; preferably 67Cu , 90Y , 125I , ... The preferred elements are any one or more of 131 I, 177 Lu, 227 Th, 223 Ra, 225 Ac, 211 At, 161 Tb, and 149 Tb; preferably any one or more of 67 Cu, 90 Y, 125 I, 131 I, 177 Lu, 227 Th, 223 Ra, 225 Ac, and 211 At; more preferably 227 Th, 177 Lu, 225 Ac, or 212 Pb; more preferably 177 Lu, 225 Ac, or 212 Pb; more preferably 177 Lu or 212 Pb; more preferably 177 Lu; more preferably 212 Pb.
  15. The radionuclide marker of claim 14, wherein the radionuclide marker is selected from:
  16. The radionuclide marker of claim 14, wherein the radionuclide marker is selected from:
  17. The radionuclide marker of claim 14, wherein the radionuclide marker is selected from:
  18. The radionuclide marker of claim 14, wherein the radionuclide marker is selected from:
  19. Use of the compound or salt thereof of any one of claims 1-13 or the radionuclide label of any one of claims 14-18 in the preparation of tumor imaging agents or antitumor drugs.
  20. The use as described in claim 19, wherein the tumor is a tumor that highly expresses FAP, such as a solid tumor (especially a solid tumor that highly expresses FAP); particularly, the tumor is an epithelial tumor, sarcoma, or mesothelioma; particularly, the tumor is selected from sarcoma, mesothelioma, esophageal tumor, glioblastoma, melanoma, colorectal cancer, pancreatic cancer, lung cancer, breast cancer, gastric cancer, kidney cancer, cervical cancer, liver cancer, prostate cancer, or glottic cancer.

Description

A class of glycopeptides and radionuclide markers targeting tumor-associated fibroblast activation proteins and their applications Technical Field This invention relates to the field of peptide technology that targets tumor-associated fibroblast activation protein (FAP), specifically to a class of FAP glycopeptides and their radionuclide labels and applications. Background Technology The development of radiopharmaceuticals has become an important direction in new drug research and development both internationally and domestically, attracting the attention of numerous research institutions, enterprises, and the market. In particular, therapeutic radiopharmaceuticals targeting tumors, which can effectively diagnose and treat tumors with radionuclide therapy, represent a cutting-edge direction in drug research. Lutathera (lutetium oxide octreotide), a radiolabeled peptide targeting the somatostatin receptor, and Pluvicto (formerly 177 Lu-PSMA-617), a small radiomolecule targeting prostate-specific membrane antigen (PSMA), were approved for marketing by the US FDA in 2018 and 2022, respectively. Malignant tumors comprise both tumor cells and their surrounding microenvironment. The tumor microenvironment, also known as the tumor stroma, includes various non-malignant cells that collectively shape an environment conducive to tumor growth. Non-cancer stromal cells, through the production of various growth factors, chemokines, and cytokines, promote extracellular matrix remodeling, induce angiogenesis, induce cell migration, develop drug resistance, and evade immune surveillance, thereby promoting tumor invasion and metastasis. Studies have confirmed that cancer-associated fibroblasts (CAFs) are a major component of non-cancer stromal cells in the tumor microenvironment, and fibroblast activation protein (FAP) is widely expressed on the surface of CAFs, making it a highly promising tumor biomarker. FAP is a membrane-bound glycoprotein belonging to the dipeptidyl peptidase 4 (DPP4) family. It possesses both dipeptidyl peptidase and endopeptidase activities and shares 52% protein homology with DPP4. This protein consists of 760 amino acids, including a short intracellular region (6 amino acids), a transmembrane region (20 amino acids), and a large extracellular region (734 amino acids). In normal tissues, FAP is generally not expressed or expressed at very low levels, but it is overexpressed in fibroblasts (CAFs) and is also highly expressed in over 90% of epithelial tumors. It can directly promote the proliferation, migration, and invasion of mesenchymal fibroblasts and other cell types, leading to tumor angiogenesis, extracellular matrix degradation, and evasion of immune surveillance. Recent studies have shown that FAP is a very promising target for radiotherapy-therapeutic drugs. The University of Heidelberg in Germany has successfully developed a series of small molecule probes targeting FAP, such as FAPI-02 and FAPI-04, and labeled them with 68 Ga and 177 Lu to become radiotherapy-therapeutic drugs. Clemens Kratochwil et al. evaluated 68 Ga-FAPI PET/CT scans of 80 patients who could not be accurately diagnosed using 18 F-FDG imaging or other traditional imaging methods. However, after administration of 68 Ga-FAPI-04, 54 primary tumors and 229 metastatic lesions were detected in 28 cancer types included in the analysis [Kratochwil C., et al. (68)Ga-FAPI PET/CT: Tracer Uptake in 28 Different Kinds of Cancer. J Nucl Med, 2019, 60(6), 801-805.]. Compared to 18F -FDG, 68Ga -FAPI-04 can detect more primary and metastatic tumor lesions. This probe can accurately diagnose and stage metastatic lesions of various tumors, showing great promise for application and potentially becoming a widely used screening and radionuclide therapy tool in clinical oncology. Furthermore, the imaging procedure of this probe is simplified, requiring no fasting or blood sugar control, making it more acceptable to patients. FAP-2286, a cyclic peptide probe targeting FAP, consists of a 7-amino acid cyclic peptide and a metal ligand moiety, with an affinity ranging from 0.4 to 1.4 nM. Compared to the 177 Lu-FAPI series of small molecule FAP inhibitor probes, 177 Lu-FAP-2286 still exhibits high tumor uptake signal 72 hours after administration, while FAPI-46 shows only a weak signal in tumors. Therefore, radiotherapy drugs based on the cyclic peptide FAP-2286 have greater research and development potential in tumor treatment. Currently, research on 68Ga -FAP-2286 and 177Lu -FAP-2286 is in Phase I/II clinical trials (NCT04939610). Although 68Ga -FAP-2286 and 177Lu -FAP-2286 show high uptake of FAP-highly expressed tumors, their retention time in the kidneys is relatively long, at 2.2% ID/g, 1.1% ID/g, and 0.6% ID/g at 3h, 24h, and 72h respectively, all higher than the small molecule probe FAPI-46, which can easily cause radiotoxic nephropathy or increase the renal burden [Zboralski D., et al. Preclinical evaluation of FAP-2286 for fibroblast acti