WO2022002022A1 - Marqueur à radionucléide et son utilisation - Google Patents

Marqueur à radionucléide et son utilisation Download PDF

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Publication number
WO2022002022A1
WO2022002022A1 PCT/CN2021/103005 CN2021103005W WO2022002022A1 WO 2022002022 A1 WO2022002022 A1 WO 2022002022A1 CN 2021103005 W CN2021103005 W CN 2021103005W WO 2022002022 A1 WO2022002022 A1 WO 2022002022A1
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Prior art keywords
pharmaceutically acceptable
radionuclide
diastereomer
enantiomer
compound
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PCT/CN2021/103005
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English (en)
Chinese (zh)
Inventor
王倩倩
王宇
吴方舟
吴然
王雷
宋紫辉
李振虎
王梦哲
郭飞虎
韩贝贝
Original Assignee
北京拓界生物医药科技有限公司
天津恒瑞医药有限公司
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Priority to CN202180004915.8A priority Critical patent/CN114401749B/zh
Publication of WO2022002022A1 publication Critical patent/WO2022002022A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/31—Somatostatins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/61—Growth hormone [GH], i.e. somatotropin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids

Definitions

  • the present disclosure belongs to the field of radiopharmaceutical labeling and nuclear medicine, and particularly relates to a targeted nuclide-labeled polypeptide radiopharmaceutical.
  • Somatostatin SST
  • SST-14 and SST-28 which contain 14 28 amino acid residues, respectively, and play important biological functions, including inhibition of growth hormone, inhibition of pancreatic hormone secretion, and inhibition of gastrin The production of hormones and the differentiation and proliferation of tumor cells, etc.
  • Somatostatin acts through five somatostatin receptors (SSTRs) (ie SSTR1-5). They belong to the G protein-coupled receptor family and are glycoproteins with seven transmembrane segments.
  • the natural SST has a short half-life, only 2-3 min, and has strong affinity for all five receptors, and its practical application value is low. Therefore, a variety of SST analogs have been designed and synthesized. Among them, the representative ones are Octreotide, Lanreotide, Vapreotide and Pasireotide, etc.
  • the half-life can reach 1.5-2 hours.
  • Certain selectivity, for example, the affinity of octreotide for SSTR2, SSTR3 and SSTR5 is significantly better than that of SSTR1 and SSTR4, and the affinity for SSTR2 is the strongest.
  • SSTR SSTR2
  • SST SSTR2 protein kinase inhibitor
  • Most neuroendocrine tumors have been shown to express high SSTR2 and can be targeted for somatostatin analog therapy.
  • Neuroendocrine tumors are a group of rare tumors with a high degree of heterogeneity. Neuroendocrine cells are located throughout the body, so neuroendocrine tumors can occur anywhere in the body, but the most common are the stomach, intestine, and pancreas. Digestive system neuroendocrine tumors account for about 2/3 of all neuroendocrine tumors. Neuroendocrine tumors are divided into two categories: non-functional (about 80%) and functional (about 20%). Functional gastroenteropancreatic neuroendocrine tumors are mainly characterized by related clinical symptoms caused by the secretion of biologically active hormones by the tumor, such as skin flushing, sweating, asthma, diarrhea, hypoglycemia, refractory peptic ulcer, diabetes, etc. Functional gastroenteropancreatic neuroendocrine tumors are mainly pancreatic neuroendocrine tumors, including insulinoma, somatostatinoma, glucagonoma, gastrinoma, etc.
  • somatostatin analogues such as long-acting octreotide and lanreotide, play a role in controlling symptomatic tumor proliferation
  • molecular targeted drugs Everolimus (mTOR inhibitor) and sunitinib (multi-target angiogenesis inhibitor), etc.
  • SSA somatostatin analogues
  • Everolimus mTOR inhibitor
  • sunitinib multi-target angiogenesis inhibitor
  • PRRT Peptide receptor radionuclide therapy
  • Lutathera has extremely high tumor targeting for the treatment of neuroendocrine tumors, limiting radiation damage to normal tissues.
  • the kidney typically filters out molecules below 60kDa, and the most direct way to reduce clearance is to increase the size of the molecule, either by glycosylation, polyethylene glycol (PEG), or with the Fc structure of immunoglobulin G (IgG). domain fusion.
  • a more common approach to prolonging their half-life in vivo utilizes a ligand to anchor the polypeptide to a serum protein with a longer lifespan, especially albumin.
  • Albumin is the most abundant protein in plasma, with a molecular weight of 66.5kDa, accounting for 40%-60% of total plasma proteins, and its half-life in plasma is about 15-19 days.
  • the present disclosure provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, a diastereomer, or a deuterium substitute or a radionuclide label thereof,
  • X 1 , X 2 and X 3 are independently selected from natural amino acids or unnatural amino acids or peptides consisting of them;
  • -CH 2 - in the R 1 is optionally replaced by a cycloalkyl group selected from -O-, -NH-, -NH(CO)- or 3-12 members;
  • a is selected from an integer between 0-4;
  • b is selected from an integer between 0-15;
  • c is selected from an integer between 0-5;
  • d is selected from an integer between 0-5;
  • e is selected from an integer between 0-3;
  • f is selected from an integer between 0-3;
  • g is selected from an integer between 1-8;
  • h is selected from an integer between 0-3;
  • R 2 is a ⁇ Y - [( ⁇ Glu) k -CO- (CH 2) m CH 3] ⁇ ; or ⁇ Y - [( ⁇ Glu) k -CO- (CH 2) n COOH] ⁇ ;
  • Y is selected from Lys, D-Lys, Orn, Dap, Dab or Cys residues;
  • k is selected from 0, 1, 2 or 3;
  • y is selected from 0, 1, 2 or 3;
  • n is selected from an integer between 6-30;
  • n is selected from an integer between 6-30;
  • R 3 is a chelating group, optionally complexed with a radionuclide.
  • the present disclosure provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, a diastereomer, or a deuterium substitute or a radionuclide label thereof,
  • X 1 , X 2 and X 3 are independently selected from natural amino acids or unnatural amino acids or peptides consisting of them;
  • -CH 2 - in the R 1 is optionally replaced by a cycloalkyl group selected from -O-, -NH-, -NH(CO)- or 3-12 members;
  • a is selected from an integer between 0-4;
  • b is selected from an integer between 0-15;
  • c is selected from an integer between 0-5;
  • d is selected from an integer between 0-5;
  • e is selected from an integer between 0-3;
  • f is selected from an integer between 0-3;
  • g is selected from an integer between 1-8;
  • h is selected from an integer between 0-3;
  • R 2 is a ⁇ Y - [( ⁇ Glu) k -CO- (CH 2) m CH 3] ⁇ ; or ⁇ Y - [( ⁇ Glu) k -CO- (CH 2) n COOH] ⁇ ;
  • Y is selected from Lys, D-Lys, Orn, Dap, Dab or Cys residues;
  • k is selected from 0, 1, 2 or 3;
  • n is selected from an integer between 6-30;
  • n is selected from an integer between 6-30;
  • R 3 is a chelating group, optionally complexed with a radionuclide.
  • the R 2 is ⁇ Y-[( ⁇ Glu) k -CO-(CH 2 ) m CH 3 ] ⁇ , the m is selected from an integer between 8 and 20, and k is selected from 0 or 1.
  • the R 2 is ⁇ Y-[( ⁇ Glu) k -CO-(CH 2 ) m CH 3 ] ⁇ , the m is selected from an integer between 9-16, and k is selected from 0 or 1.
  • the R 2 is ⁇ Y-[( ⁇ Glu) k -CO-(CH 2 ) n COOH] ⁇ , the n is selected from an integer between 8 and 20, and k is selected from 0 or 1.
  • the R 2 is ⁇ Y-[( ⁇ Glu) k -CO-(CH 2 ) n COOH] ⁇ , the n is selected from an integer between 9 and 16, and k is selected from 0 or 1.
  • the R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • a is selected from 0, 1 or 2;
  • b is selected from 0, 1, 2, 3, 4, 5, 6 or 8;
  • c is selected from 1, 2 or 3;
  • d is selected from 0 or 1;
  • e is selected from 0, 1, 2 or 3;
  • f is selected from 0, 1 or 2;
  • g is selected from 1, 2, 3 or 4;
  • h is selected from 0 or 1.
  • -CH 2 - in said R 1 is optionally replaced by a cycloalkyl group selected from 5-8 members, preferably a cyclohexyl group.
  • the R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the h is selected from zero.
  • the X 1 is selected from the amino acid residue of Tyr or Phe;
  • X 2 is selected from the amino acid residue of Trp or D-Trp;
  • X 3 is selected from Thr-ol, Thr-OH or Thr-NH 2 .
  • X 1 is selected from amino acid residues of Tyr or Phe;
  • X 2 is selected from amino acid residues of Trp or D-Trp;
  • X 3 is selected from Thr-OH.
  • the Y is selected from Lys or D-Lys.
  • the R 2 is ⁇ Lys-[( ⁇ Glu) k -CO-(CH 2 ) m CH 3 ] ⁇ or
  • m is selected from an integer between 8 and 20, and k is selected from 0 or 1.
  • the R 2 is ⁇ Lys-[( ⁇ Glu) k -CO-(CH 2 ) m CH 3 ] ⁇ or
  • m is selected from an integer between 9 and 16, and k is selected from 0 or 1.
  • the X 1 is selected from the amino acid residue of Tyr;
  • X 2 is selected from the amino acid residue of D-Trp;
  • X 3 is selected from the Thr-OH;
  • R 1 is ⁇ NH- (CH 2) a CH 2 O- (CH 2 CH 2 O) b - (CH 2) c - [NH (CO)] d - (CH 2) e - (CO) ⁇ f;
  • a is selected from 0, 1 or 2;
  • b is selected from 0, 1, 2, 3, 4, 5, 6 or 8;
  • c is selected from 1, 2 or 3;
  • d is selected from 0 or 1;
  • e is selected from 0, 1, 2 or 3;
  • f is selected from 0, 1 or 2;
  • the R 2 is ⁇ Lys-[( ⁇ Glu) k -CO-(CH 2 ) m CH 3 ] ⁇ or ⁇ D-Lys-[( ⁇ Glu) k -CO-(CH 2 ) m CH 3 ] ⁇ , m is selected from an integer between 8 and 20, and k is selected from 0 or 1.
  • the X 1 is selected from the amino acid residue of Tyr;
  • X 2 is selected from the amino acid residue of D-Trp;
  • X 3 is selected from the Thr-OH;
  • R 1 is ⁇ NH- (CH 2) a CH 2 O- (CH 2 CH 2 O) b - (CH 2) c - [NH (CO)] d - (CH 2) e - (CO) ⁇ f;
  • a is selected from 0, 1 or 2;
  • b is selected from 0, 1, 2, 3, 4, 5, 6 or 8;
  • c is selected from 1, 2 or 3;
  • d is selected from 0 or 1;
  • e is selected from 0, 1, 2 or 3;
  • f is selected from 0, 1 or 2;
  • the R 2 is ⁇ Lys-[( ⁇ Glu) k -CO-(CH 2 ) m CH 3 ] ⁇ or ⁇ D-Lys-[( ⁇ Glu) k -CO-(CH 2 ) m CH 3 ] ⁇ , m is selected from an integer between 9-16, and k is selected from 0 or 1.
  • the X 1 is selected from the amino acid residue of Tyr;
  • X 2 is selected from the amino acid residue of D-Trp;
  • X 3 is selected from the Thr-OH;
  • R 1 is ⁇ NH- (CH 2) a CH 2 O- (CH 2 CH 2 O) b - (CH 2) c - [NH (CO)] d - (CH 2) e - (CO) ⁇ f;
  • a is selected from 1;
  • b is selected from 0, 1 or 2;
  • c is selected from 1 or 2;
  • d is selected from 0;
  • e is selected from 0;
  • f is selected from 0, 1 or 2;
  • the R 2 is ⁇ Lys-[( ⁇ Glu) k -CO-(CH 2 ) m CH 3 ] ⁇ or ⁇ D-Lys-[( ⁇ Glu) k -CO-(CH 2 ) m CH 3 ] ⁇ , m is selected from an integer between 8 and 20, and k is selected from 0 or 1.
  • the X 1 is selected from the amino acid residue of Tyr;
  • X 2 is selected from the amino acid residue of D-Trp;
  • X 3 is selected from the Thr-OH;
  • R 1 is ⁇ NH- (CH 2) a CH 2 O- (CH 2 CH 2 O) b - (CH 2) c - [NH (CO)] d - (CH 2) e - (CO) ⁇ f;
  • a is selected from 1;
  • b is selected from 0, 1 or 2;
  • c is selected from 1 or 2;
  • d is selected from 0;
  • e is selected from 0;
  • f is selected from 0, 1 or 2;
  • the R 2 is ⁇ Lys-[( ⁇ Glu) k -CO-(CH 2 ) m CH 3 ] ⁇ or ⁇ D-Lys-[( ⁇ Glu) k -CO-(CH 2 ) m CH 3 ] ⁇ , m is selected from an integer between 9-16, and k is selected from 0 or 1.
  • the X 1 is selected from the amino acid residue of Tyr;
  • X 2 is selected from the amino acid residue of D-Trp;
  • X 3 is selected from the Thr-OH;
  • R 1 is ⁇ NH- (CH 2) a CH 2 O- (CH 2 CH 2 O) b - (CH 2) c - [NH (CO)] d - (CH 2) e - (CO) ⁇ f;
  • a is selected from 1;
  • b is selected from 1;
  • c is selected from 1;
  • d is selected from 0;
  • e is selected from 0;
  • f is selected from 1 or 2;
  • the R 2 is ⁇ Lys-[( ⁇ Glu) k -CO-(CH 2 ) m CH 3 ] ⁇ or ⁇ D-Lys-[( ⁇ Glu) k -CO-(CH 2 ) m CH 3 ] ⁇ , m is selected from an integer between 8 and 20, and k is selected from 0 or 1.
  • the X 1 is selected from the amino acid residue of Tyr;
  • X 2 is selected from the amino acid residue of D-Trp;
  • X 3 is selected from the Thr-OH;
  • R 1 is ⁇ NH- (CH 2) a CH 2 O- (CH 2 CH 2 O) b - (CH 2) c - [NH (CO)] d - (CH 2) e - (CO) ⁇ f;
  • a is selected from 1;
  • b is selected from 1;
  • c is selected from 1;
  • d is selected from 0;
  • e is selected from 0;
  • f is selected from 1 or 2;
  • the R 2 is ⁇ Lys-[( ⁇ Glu) k -CO-(CH 2 ) m CH 3 ] ⁇ or ⁇ D-Lys-[( ⁇ Glu) k -CO-(CH 2 ) m CH 3 ] ⁇ , m is selected from an integer between 9-16, and k is selected from 0 or 1.
  • the R 2 is ⁇ Lys-[( ⁇ Glu) k -CO-(CH 2 ) n COOH] ⁇ or ⁇ D-Lys-[( ⁇ Glu) k -CO-(CH 2 ) n COOH] ⁇ , the n is selected from an integer between 8 and 20, and k is selected from 0 or 1.
  • the R 2 is ⁇ Lys-[( ⁇ Glu) k -CO-(CH 2 ) n COOH] ⁇ or ⁇ D-Lys-[( ⁇ Glu) k -CO-(CH 2 ) n COOH] ⁇ , the n is selected from an integer between 9-16, and k is selected from 0 or 1.
  • the X 1 is selected from the amino acid residue of Tyr;
  • X 2 is selected from the amino acid residue of D-Trp;
  • X 3 is selected from the Thr-OH;
  • R 1 is ⁇ NH- (CH 2) a CH 2 O- (CH 2 CH 2 O) b - (CH 2) c - [NH (CO)] d - (CH 2) e - (CO) ⁇ f;
  • a is selected from 0, 1 or 2;
  • b is selected from 0, 1, 2, 3, 4, 5, 6 or 8;
  • c is selected from 1, 2 or 3;
  • d is selected from 0 or 1;
  • e is selected from 0, 1, 2 or 3;
  • f is selected from 0, 1 or 2;
  • R 2 is the ⁇ Lys - [( ⁇ Glu) k -CO- (CH 2) n COOH] ⁇ or ⁇ D-Lys - [( ⁇ Glu ) k -CO- (CH 2) n COOH] ⁇ , the n is selected from an integer between 8 and 20, and k is selected from 0 or 1.
  • the X 1 is selected from the amino acid residue of Tyr;
  • X 2 is selected from the amino acid residue of D-Trp;
  • X 3 is selected from the Thr-OH;
  • R 1 is ⁇ NH- (CH 2) a CH 2 O- (CH 2 CH 2 O) b - (CH 2) c - [NH (CO)] d - (CH 2) e - (CO) ⁇ f;
  • a is selected from 0, 1 or 2;
  • b is selected from 0, 1, 2, 3, 4, 5, 6 or 8;
  • c is selected from 1, 2 or 3;
  • d is selected from 0 or 1;
  • e is selected from 0, 1, 2 or 3;
  • f is selected from 0, 1 or 2;
  • R 2 is the ⁇ Lys - [( ⁇ Glu) k -CO- (CH 2) n COOH] ⁇ or ⁇ D-Lys - [( ⁇ Glu ) k -CO- (CH 2) n COOH] ⁇ , the n is selected from an integer between 9-16, and k is selected from 0 or 1.
  • the X 1 is selected from the amino acid residue of Tyr;
  • X 2 is selected from the amino acid residue of D-Trp;
  • X 3 is selected from the Thr-OH;
  • R 1 is ⁇ NH- (CH 2) a CH 2 O- (CH 2 CH 2 O) b - (CH 2) c - [NH (CO)] d - (CH 2) e - (CO) ⁇ f;
  • a is selected from 1;
  • b is selected from 0, 1 or 2;
  • c is selected from 1 or 2;
  • d is selected from 0;
  • e is selected from 0;
  • f is selected from 0, 1 or 2;
  • R 2 is ⁇ Lys - [( ⁇ Glu) k -CO- (CH 2) n COOH] ⁇ or ⁇ D-Lys - [( ⁇ Glu ) k -CO- (CH 2) n COOH] ⁇ , n is selected from the Integer between 8-20, k is selected from 0 or 1.
  • the X 1 is selected from the amino acid residue of Tyr;
  • X 2 is selected from the amino acid residue of D-Trp;
  • X 3 is selected from the Thr-OH;
  • R 1 is ⁇ NH- (CH 2) a CH 2 O- (CH 2 CH 2 O) b - (CH 2) c - [NH (CO)] d - (CH 2) e - (CO) ⁇ f;
  • a is selected from 1;
  • b is selected from 0, 1 or 2;
  • c is selected from 1 or 2;
  • d is selected from 0;
  • e is selected from 0;
  • f is selected from 0, 1 or 2;
  • R 2 is the ⁇ Lys - [( ⁇ Glu) k -CO- (CH 2) n COOH] ⁇ or ⁇ D-Lys - [( ⁇ Glu ) k -CO- (CH 2) n COOH] ⁇ , the n is selected from an integer between 9-16, and k is selected from 0 or 1.
  • the X 1 is selected from the amino acid residue of Tyr;
  • X 2 is selected from the amino acid residue of D-Trp;
  • X 3 is selected from the Thr-OH;
  • R 1 is ⁇ NH- (CH 2) a CH 2 O- (CH 2 CH 2 O) b - (CH 2) c - [NH (CO)] d - (CH 2) e - (CO) ⁇ f;
  • a is selected from 1;
  • b is selected from 1;
  • c is selected from 1;
  • d is selected from 0;
  • e is selected from 0;
  • f is selected from 1 or 2;
  • R 2 is ⁇ Lys - [( ⁇ Glu) k -CO- (CH 2) n COOH] ⁇ or ⁇ D-Lys - [( ⁇ Glu ) k -CO- (CH 2) n COOH] ⁇ , n is selected from the Integer between 8-20, k is selected from 0 or 1.
  • the R 2 is ⁇ Y-[(Glu) y -( ⁇ Glu) k -CO-(CH 2 ) m CH 3 ] ⁇ or ⁇ Y-[Glu) y -( ⁇ Glu) k -CO-(CH 2 ) n COOH] ⁇ ,
  • Said m and n are each independently selected from integers between 8-20, and y or k are the same or different, and each is independently selected from 0 or 1.
  • the R 2 is ⁇ Y-[(Glu) y -( ⁇ Glu) k -CO-(CH 2 ) m CH 3 ] ⁇ or ⁇ Y-[Glu) y -( ⁇ Glu) k -CO-(CH 2 ) n COOH] ⁇ ,
  • m and n are each independently selected from an integer between 9 and 16, and y or k are the same or different, and are each independently selected from 0 or 1.
  • the X 1 is selected from the amino acid residue of Tyr;
  • X 2 is selected from the amino acid residue of D-Trp;
  • X 3 is selected from the Thr-OH;
  • R 1 is ⁇ NH- (CH 2) a CH 2 O- (CH 2 CH 2 O) b - (CH 2) c - [NH (CO)] d - (CH 2) e - (CO) ⁇ f;
  • a is selected from 1;
  • b is selected from 1;
  • c is selected from 1;
  • d is selected from 0;
  • e is selected from 0;
  • f is selected from 1 or 2;
  • R 2 is the ⁇ Lys - [( ⁇ Glu) k -CO- (CH 2) n COOH] ⁇ or ⁇ D-Lys - [( ⁇ Glu ) k -CO- (CH 2) n COOH] ⁇ , the n is selected from an integer between 9-16, and k is selected from 0 or 1.
  • the X 1 is selected from the amino acid residue of Tyr;
  • X 2 is selected from the amino acid residue of D-Trp;
  • X 3 is selected from the Thr-OH;
  • R 1 is ⁇ NH- (CH 2) a CH 2 O- (CH 2 CH 2 O) b - (CH 2) c - [NH (CO)] d - (CH 2) e - (CO) ⁇ f;
  • a is selected from 1;
  • b is selected from 1;
  • c is selected from 1;
  • d is selected from 0;
  • e is selected from 0;
  • f is selected from 1 or 2.
  • R 2 is a ⁇ Y - [( ⁇ Glu) k -CO- (CH 2) m CH 3] ⁇ ; or ⁇ Y - [( ⁇ Glu) k -CO- (CH 2) n COOH] ⁇ ;
  • Y is selected from Lys, D-Lys, Orn, Dap, Dab or Cys residues;
  • k is selected from 0, 1, 2 or 3;
  • n is selected from an integer between 6-30, m is preferably an integer between 8-20;
  • n is selected from integers between 6-30, n is preferably selected from integers between 8-20
  • R 3 is selected from a cyclodextrin, a crown ether or a molecular structure as follows:
  • the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or its enantiomer, diastereomer or its deuterium element substitution or its radionuclide label is selected from
  • the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or its enantiomer, diastereomer or its deuterium substitution or its radionuclide label is selected from
  • the compound of formula (I) provided by the present disclosure, or a pharmaceutically acceptable salt thereof, or its enantiomer, diastereomer, or its deuterium element substitution or its radionuclide FITC was the R 3 complexed with a radionuclide, the radionuclide is selected from 18 F, 76 Br, 124 I , 125 I, 64Cu, 67 Cu, 86 Y, 90 Y, 67 Ga, 68 Ga , 89 Zr, 44 Sc, 99m Tc, 111 In, 177 Lu, 186 Re, 188 Re, 169 Er, 121 Sn, 127 Te, 142 Pr, 143 Pr, 198 Au, 153 Sm, 109 Pd, 165 Dy, 212 Pb, 213 Bi, 169 Yb, or 225 Ac.
  • the radionuclide is selected from 18 F, 76 Br, 124 I , 125 I, 64Cu, 67 Cu, 86 Y, 90 Y, 67 Ga,
  • the compound of formula (I) provided by the present disclosure or a pharmaceutically acceptable salt thereof, or its enantiomer, diastereomer, or its deuterium element substitution or its radionuclide
  • a radionuclide label, the radionuclide complexed with R 3 , and the radionuclide is selected from 177 Lu.
  • the present disclosure provides a pharmaceutical composition, comprising the compound represented by the above formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, or a deuterium element substitution thereof or a radionuclide thereof A marker and one or more pharmaceutically acceptable excipients or pharmaceutical carriers.
  • the pharmaceutically acceptable excipients or pharmaceutical carriers described in the present disclosure include fillers, disintegrants, binders, stabilizers, osmotic pressure regulators, pH regulators, and the like.
  • compositions provided by the present disclosure are suitable for intravenous administration.
  • the present disclosure provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or its enantiomer, diastereomer, or its deuterium element substitution, or its radionuclide label, or a compound comprising the formula
  • the compound shown in (I), or a pharmaceutically acceptable salt thereof, or its enantiomer, diastereomer, or its deuterium substitution or a pharmaceutical composition of its radionuclide label is used in the preparation of The use of tumor diagnostic reagents in medicine.
  • the present disclosure provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or its enantiomer, diastereomer, or its deuterium element substitution, or its radionuclide label, or a compound comprising the formula
  • the compound shown in (I), or a pharmaceutically acceptable salt thereof, or its enantiomer, diastereomer, or its deuterium substitution or a pharmaceutical composition of its radionuclide label is used in the preparation of Use in medicaments for the treatment of tumors.
  • the tumors described in this disclosure are selected from neuroendocrine tumors selected from the group consisting of gastroenteropancreatic neuroendocrine tumors, carcinoids, pheochromocytomas, paraganglioma, medullary thyroid carcinoma, pulmonary nerve Endocrine tumor, thymic neuroendocrine tumor, carcinoid or pancreatic neuroendocrine tumor, pituitary adenoma, vasoactive intestinal peptide tumor, adrenal tumor, Merkel cell carcinoma, breast cancer, non-Hodgkin lymphoma, Hodgkin lymphoma , head and neck tumors, urothelial carcinoma (bladder), renal cell carcinoma, small cell lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor, neuroblastoma, bile duct tumor, cervical tumor, Ewing's sarcoma, bone flesh tumor, small cell lung cancer, prostate cancer, melanoma, meningioma, glioma, medulloblastoma, gas
  • the tumor is a somatostatin receptor positive tumor.
  • Another aspect of the present disclosure provides a method for preparing the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or its enantiomer, diastereomer, or its deuterium element substitution or its radionuclide label
  • the method for the compound comprising the step of generating a disulfide bond with the compound represented by the formula (II),
  • the method further comprises the step of complexing a radionuclide with R 3 , the radionuclide is selected from 18 F, 76 Br, 124 I, 125 I, 64Cu, 67 Cu, 86 Y, 90 Y, 67 Ga, 68 Ga, 89 Zr, 44 Sc, 99m Tc, 111 In, 177 Lu, 186 Re, 188 Re, 169 Er, 121 Sn, 127 Te, 142 Pr, 143 Pr, 198 Au, 153 Sm , 109 Pd, 165 Dy, 212 Pb, 213 Bi, 169 Yb, or 225 Ac.
  • the radionuclide is selected from 18 F, 76 Br, 124 I, 125 I, 64Cu, 67 Cu, 86 Y, 90 Y, 67 Ga, 68 Ga, 89 Zr, 44 Sc, 99m Tc, 111 In, 177 Lu, 186 Re, 188 Re, 169 Er, 121 Sn, 127 Te, 142 Pr,
  • the method further comprises the step of radionuclide complexed with R 3, the radionuclide is 177 Lu.
  • the present disclosure provides another aspect of formula (I), the radionuclide marker compound, the R 3 complexed with a radionuclide, the radionuclide is selected from 177 Lu, formula (I ) and the precursor 17 LuCl 3 at a temperature selected from the step of 60-120 °C reaction.
  • the reaction temperature is selected from 70-100°C.
  • the reaction temperature is selected from 85-95°C.
  • the pH of the reaction system is selected from 3.5-7.
  • the pH of the reaction system is selected from 4-6.5.
  • the pH of the reaction system is selected from 5-6.
  • the methods provided by the present disclosure for preparing radionuclide labels of compounds of formula (I) occur in an ammonium acetate or sodium acetate buffer solution.
  • the radionuclide label of the present disclosure has a longer half-life, can reduce the dose and the number of times of administration, improve the response rate, reduce toxicity, and improve patient compliance, and is expected to become a new generation of PRRT therapeutic drugs.
  • the polypeptide compound and its derivatives provided by the present disclosure adopt the method of solid-phase synthesis
  • the synthesis carrier is Fmoc-Thr(tBu)-Wang resin
  • the ⁇ -amino group of the amino acid derivative used in the synthesis process is composed of Fmoc group (fluorenyl formyl) Carbonyl) protection
  • the side chain of amino acid selects the following protecting groups according to the different functional groups: Cysteine side chain sulfhydryl is protected by Trt (trityl), D-tryptophan side chain indolyl, lysine side
  • the chain amino group is protected by Boc (tert-butoxycarbonyl), the tyrosine side chain phenol group, the glutamic acid side chain carboxyl group or main chain carboxyl group, and the threonine side chain hydroxyl group are protected by t-Bu (tert-butyl).
  • the lysine side chain amino group was protected by Mtt (4-methyl-trityl).
  • Mtt (4-methyl-trityl).
  • the Fmoc-Thr(tBu)-Wang resin was fully swollen in dichloromethane (DCM) at first, and a solution containing 20% 4-methylpiperidine in N,N-dimethylformamide (DMF) was used.
  • DCM dichloromethane
  • DMF N,N-dimethylformamide
  • the Fmoc protecting group on the ⁇ -amino group is removed, and then the carboxyl group of the C-terminal amino acid residue is condensed onto the polymer insoluble resin in the form of an amide bond.
  • the solid phase carrier is condensed with the next amino acid derivative in the sequence in excess to form an amide bond to extend the peptide chain.
  • the obtained reduced crude product was lyophilized, oxidized with 30% DMSO (dimethyl sulfoxide) aqueous solution, and purified and separated directly by C-18 reverse-phase preparative chromatography column with 0.1% trifluoroacetic acid in acetonitrile/water system to obtain polypeptide and pure products of its derivatives.
  • the obtained pure naked peptide is labeled with radionuclide to obtain the target nuclide peptide molecule.
  • amino acid sequences of the present disclosure contain standard one-letter or three-letter codes for the twenty amino acids, and all amino acid residues in the present disclosure are preferably configured in the L-form unless explicitly stated.
  • D-Phe and D-Trp are D-type amino acids.
  • somatostatin receptor positivity is defined as high expression of the receptor:
  • Natural amino acid refers to the 20 conventional amino acids (ie, alanine (A), cysteine (C), aspartic acid (D), glutamic acid (E), phenylalanine (F) , Glycine (G), Histidine (H), Isoleucine (I), Lysine (K), Leucine (L), Methionine (M), Asparagine (N), Proline (P), Glutamine (Q), Arginine (R), Serine (S), Threonine (T), Valine (V), Tryptophan (W) and Tyrosine (Y).
  • Unnatural amino acid refers to an amino acid that is not naturally encoded or found in the genetic code of any organism. They can be, for example, pure synthetic compounds. Examples of unnatural amino acids include, but are not limited to, hydroxyproline, gamma-carboxyglutamic acid, O-phosphoserine, azetidine carboxylic acid, 2-aminoadipic acid, 3-aminoadipic acid, beta -Alanine, aminopropionic acid, 2-aminobutyric acid, 4-aminobutyric acid, 6-aminocaproic acid, 2-aminoheptanoic acid, 2-aminoisobutyric acid, 3-aminoisobutyric acid, 2-amino Pimelic acid, tert-butylglycine, 2,4-diaminoisobutyric acid (Dap), desmosine, 2,2'-diaminopimelic acid, 2,3-diaminopropionic acid (Dab) , N-ethyl
  • X is selected from A, B, or C
  • X is selected from A, B and C
  • X is A, B or C
  • X is A, B and C
  • X is A, B and C
  • substitution in this patent refers to the replacement of one amino acid residue by a different amino acid residue.
  • Optional or “optionally” means that the subsequently described event or circumstance can, but need not, occur, and that the description includes instances where the event or circumstance occurs or instances where it does not.
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • “Pharmaceutically acceptable salts” refers to salts of the compounds of the present disclosure that are safe and effective when used in mammals, and that possess the desired biological activity.
  • a linkage refers to the connection between two cysteines within a molecule by a disulfide bond.
  • FIG. 3-1 SPECT imaging of 177 Lu-DOTA-TATE in AR42J tumor-bearing mice (1-1h);
  • FIG 3-2 SPECT imaging of 177 Lu-DOTA-TATE in AR42J tumor-bearing mice (1-4h);
  • FIG. 3-3 SPECT imaging of 177 Lu-DOTA-TATE in AR42J tumor-bearing mice (1-8h);
  • FIG. 3-4 SPECT imaging of 177 Lu-DOTA-TATE in AR42J tumor-bearing mice (1-24h);
  • FIG. 3-5 SPECT imaging of 177 Lu-DOTA-TATE in AR42J tumor-bearing mice (1-48h);
  • FIG. 4-1 SPECT imaging of 177 Lu-DOTA-TATE in AR42J tumor-bearing mice (2-1h);
  • FIG. 4-3 SPECT imaging of 177 Lu-DOTA-TATE in AR42J tumor-bearing mice (2-8h);
  • FIG. 4-4 SPECT imaging of 177 Lu-DOTA-TATE in AR42J tumor-bearing mice (2-24h);
  • FIG 4-5 SPECT imaging of 177 Lu-DOTA-TATE in AR42J tumor-bearing mice (2-48h);
  • FIG. 5-1 SPECT imaging of 177 Lu-18 labeled compounds in AR42J tumor-bearing mice (1-1h);
  • FIG 5-2 SPECT imaging of 177 Lu-18 labeled compounds in AR42J tumor-bearing mice (1-4h);
  • FIG. 5-3 SPECT imaging of 177 Lu-18 labeled compounds in AR42J tumor-bearing mice (1-4h-block);
  • FIG. 5-4 SPECT images of 177 Lu-18 labeled compounds in AR42J tumor-bearing mice (1-8h);
  • FIG. 5-5 SPECT imaging of 177 Lu-18 labeled compounds in AR42J tumor-bearing mice (1-24h);
  • FIG. 5-6 SPECT imaging of 177 Lu-18 labeled compounds in AR42J tumor-bearing mice (1-48h);
  • FIG. 6-1 SPECT imaging of 177 Lu-18 labeled compounds in AR42J tumor-bearing mice (2-1h);
  • FIG 6-2 SPECT imaging of 177 Lu-18 labeled compounds in AR42J tumor-bearing mice (2-4h);
  • FIG 6-3 SPECT imaging of 177 Lu-18 labeled compounds in AR42J tumor-bearing mice (2-8h);
  • FIG 6-4 SPECT imaging of 177 Lu-18 labeled compounds in AR42J tumor-bearing mice (2-24h);
  • FIG. 6-5 SPECT imaging of 177 Lu-18 labeled compounds in AR42J tumor-bearing mice (2-48h);
  • FIG. 7-1 SPECT imaging of 177 Lu-20 labeled compounds in AR42J tumor-bearing mice (1-1h);
  • FIG. 7-2 SPECT imaging of 177 Lu-20 labeled compounds in AR42J tumor-bearing mice (1-4h);
  • FIG. 7-3 SPECT imaging of 177 Lu-20 labeled compounds in AR42J tumor-bearing mice (1-4h-block);
  • FIG. 7-4 SPECT imaging of 177 Lu-20 labeled compounds in AR42J tumor-bearing mice (1-8h);
  • FIG. 7-5 SPECT imaging of 177 Lu-20 labeled compounds in AR42J tumor-bearing mice (1-24h);
  • FIG. 7-6 SPECT images of 177 Lu-20 labeled compounds in AR42J tumor-bearing mice (1-48h);
  • FIG 8-1 SPECT imaging of 177 Lu-20 labeled compounds in AR42J tumor-bearing mice (2-1h);
  • FIG 8-2 SPECT imaging of 177 Lu-20 labeled compounds in AR42J tumor-bearing mice (2-4h);
  • FIG. 8-3 SPECT imaging of 177 Lu-20 labeled compounds in AR42J tumor-bearing mice (2-8h);
  • FIG 8-4 SPECT imaging of 177 Lu-20 labeled compounds in AR42J tumor-bearing mice (2-24h);
  • FIG 8-5 SPECT imaging of 177 Lu-20 labeled compounds in AR42J tumor-bearing mice (2-48h);
  • FIG 9-1 SPECT imaging of 177 Lu-21 labeled compound in AR42J tumor-bearing mice (1-1h);
  • FIG 9-2 SPECT images of 177 Lu-21 labeled compounds in AR42J tumor-bearing mice (1-4h);
  • FIG 9-3 SPECT imaging of 177 Lu-21-labeled compound in AR42J tumor-bearing mice (1-4h-block);
  • FIG. 9-4 SPECT imaging of 177 Lu-21 labeled compounds in AR42J tumor-bearing mice (1-8h);
  • FIG. 9-6 SPECT imaging of 177 Lu-21 labeled compound in AR42J tumor-bearing mice (1-48h);
  • FIG 10-1 SPECT imaging of 177 Lu-21-labeled compound in AR42J tumor-bearing mice (2-1h);
  • FIG 10-3 SPECT imaging of 177 Lu-21-labeled compound in AR42J tumor-bearing mice (2-8h);
  • FIG 10-4 SPECT imaging of 177 Lu-21 labeled compounds in AR42J tumor-bearing mice (2-24h);
  • FIG 10-5 SPECT imaging of 177 Lu-21-labeled compound in AR42J tumor-bearing mice (2-48h);
  • the peptide chain sequence according to compound 1 was synthesized in order from the carboxyl terminus to the amino terminus. First weigh Fmoc-Cys(Trt)-OH (1mmol), 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate (HCTU) (1mmol) and N,N -Diisopropylethylamine (DIEA, 2mmol), dissolved in DMF (6mL), the above solution was added to the resin obtained in step 1, and the reaction was shaken at room temperature for 2 hours. After the reaction was completed, use DMF, dichloromethane (DCM) The resin was washed alternately 2 times and finally washed 3 times with DMF.
  • HCTU 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate
  • DIEA N,N -Diisopropylethylamine
  • step 1 deprotection and condensation process of the above amino acid derivatives, and condense in sequence: Fmoc-Thr(tBu)-OH, Fmoc-Lys(Boc)-OH, Fmoc-D-Trp(Boc)-OH, Fmoc-Tyr (tBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-D-Phe-OH, Fmoc-Lys(Mtt)-OH and DOTA-tris(tBu)ester gave fully protected polypeptide molecules.
  • hexafluoroisopropanol/dichloromethane mixed solution (30% v/v, 10 mL) to the resin connected with polypeptide molecules in step 2, shake and react at room temperature for 45 minutes, then remove, and then add hexafluoroisopropanol /dichloromethane mixed solution (30% v/v, 10 mL), shake and react at room temperature for 45 minutes, then extract and remove, and wash the resin 6 times with DMF after the reaction.
  • Step 5 Disulfide bond generation and purification by reversed-phase liquid chromatography
  • step 4 The reduced crude product obtained in step 4 was lyophilized, dissolved in DMSO/water (30% v/v, concentration: 1.5 mg/mL), stirred at room temperature for 24 h, added with a few drops of trifluoroacetic acid, and passed through a 0.22 um membrane. After filtration, it was separated by a WATERS Prep150 preparative high performance liquid chromatography system, and the mobile phases were A (0.1% trifluoroacetic acid, 10% acetonitrile/water solution) and B (0.1% trifluoroacetic acid, 90% acetonitrile/water solution).
  • the chromatographic column is an X-SELECT OBD C-18 (WATERS, 19*250mm) reversed-phase chromatographic column, and the detection wavelength of the chromatograph during the purification process is set to 220 nm, and the flow rate is 15 mL/min.
  • the product-related fractions were collected and lyophilized to obtain the pure polypeptide of compound No. 1 with a yield of 20%.
  • the purity of the polypeptide was detected by the WATERS H-CLASS analytical ultra-high performance liquid chromatography system (chromatographic column: ACQUITY UPLC CSH C18 2.1*150mm), and its purity was 94.54%.
  • the molecular weight of the compound was confirmed by an Agilent Q-TOF 6530 system (chromatographic column: ACQUITY UPLC CSH C18 2.1*150 mm), and the mass spectrum shown in the mass spectrum was: 1801.75 [M+H] + .
  • the purity of the polypeptide was detected by the WATERS H-CLASS analytical ultra-high performance liquid chromatography system (chromatographic column: ACQUITY UPLC CSH C18 2.1*150mm), and the purity was 93.06%.
  • the molecular weight of the compound was confirmed by an Agilent Q-TOF 6530 system (chromatographic column: ACQUITY UPLC CSH C18 2.1*150 mm), and the mass spectrum shown in the mass spectrum was: 1946.84 [M+H] + .
  • the peptide chain sequence according to compound 3 was synthesized in order from the carboxyl terminus to the amino terminus. First weigh Fmoc-Cys(Trt)-OH (1mmol), 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate (HCTU) (1mmol) and N,N -Diisopropylethylamine (DIEA, 2mmol), dissolved in DMF (6mL), the above solution was added to the resin obtained in step 1, and the reaction was shaken at room temperature for 2 hours. After the reaction was completed, use DMF, dichloromethane (DCM) The resin was washed alternately 2 times and finally washed 3 times with DMF.
  • HCTU 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate
  • DIEA N,N -Diisopropylethylamine
  • step 1 deprotection and condensation process of the above amino acid derivatives, and condense in sequence: Fmoc-Thr(tBu)-OH, Fmoc-Lys(Boc)-OH, Fmoc-D-Trp(Boc)-OH, Fmoc-Tyr (tBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-D-Phe-OH, Fmoc-miniPEG, Fmoc-miniPEG, Fmoc-Lys(Mtt)-OH and DOTA-tris(tBu)ester fully protected of polypeptide molecules.
  • hexafluoroisopropanol/dichloromethane mixed solution (30% v/v, 10 mL) to the resin connected with polypeptide molecules in step 2, shake and react at room temperature for 45 minutes, then remove, and then add hexafluoroisopropanol /dichloromethane mixed solution (30% v/v, 10 mL), shake and react at room temperature for 45 minutes, then extract and remove, and wash the resin 6 times with DMF after the reaction.
  • Step 5 Disulfide bond generation and purification by reversed-phase liquid chromatography
  • step 4 The reduced crude product obtained in step 4 was lyophilized, dissolved in DMSO/water (30% v/v, concentration: 1.5 mg/mL), stirred at room temperature for 24 h, added with a few drops of trifluoroacetic acid, and passed through a 0.22 um membrane. After filtration, it was separated by a WATERS Prep150 preparative high performance liquid chromatography system, and the mobile phases were A (0.1% trifluoroacetic acid, 10% acetonitrile/water solution) and B (0.1% trifluoroacetic acid, 90% acetonitrile/water solution).
  • the chromatographic column is an X-SELECT OBD C-18 (WATERS, 19*250mm) reversed-phase chromatographic column, and the detection wavelength of the chromatograph during the purification process is set to 220 nm, and the flow rate is 15 mL/min.
  • the product-related fractions were collected and lyophilized to obtain the pure polypeptide of compound No. 3 with a yield of 17%.
  • the purity of the polypeptide was detected by the WATERS H-CLASS analytical ultra-high performance liquid chromatography system (chromatographic column: ACQUITY UPLC CSH C18 2.1*150mm), and its purity was 91.88%.
  • the molecular weight of the compound was confirmed by an Agilent Q-TOF 6530 system (chromatographic column: ACQUITY UPLC CSH C18 2.1*150 mm), and the mass spectrum shown in the mass spectrum was: 2092.09 [M+H] + .
  • the peptide chain sequence according to compound 5 was synthesized in order from the carboxyl terminus to the amino terminus. First weigh Fmoc-Cys(Trt)-OH (1mmol), 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate (HCTU) (1mmol) and N,N -Diisopropylethylamine (DIEA, 2mmol), dissolved in DMF (6mL), the above solution was added to the resin obtained in step 1, and the reaction was shaken at room temperature for 2 hours. After the reaction was completed, use DMF, dichloromethane (DCM) The resin was washed alternately 2 times and finally washed 3 times with DMF.
  • HCTU 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate
  • DIEA N,N -Diisopropylethylamine
  • step 1 deprotection and condensation process of the above amino acid derivatives, and condense in sequence: Fmoc-Thr(tBu)-OH, Fmoc-Lys(Boc)-OH, Fmoc-D-Trp(Boc)-OH, Fmoc-Tyr (tBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-D-Phe-OH, Fmoc-miniPEG, Fmoc-miniPEG, Fmoc-D-Lys(Mtt)-OH and DOTA-tris(tBu)ester were obtained Fully protected polypeptide molecule.
  • hexafluoroisopropanol/dichloromethane mixed solution (30% v/v, 10 mL) to the resin connected with polypeptide molecules in step 2, shake and react at room temperature for 45 minutes, then extract and remove, and then add hexafluoroisopropanol/
  • the mixed solution of dichloromethane (30% v/v, 10 mL) was shaken and reacted at room temperature for 45 minutes and then extracted, and after the reaction was completed, the resin was washed with DMF for 6 times.
  • Step 5 Disulfide bond generation and purification by reversed-phase liquid chromatography
  • step 4 The reduced crude product obtained in step 4 was lyophilized, dissolved in DMSO/water (30% v/v, concentration: 1.5 mg/mL), stirred at room temperature for 24 h, added with a few drops of trifluoroacetic acid, and passed through a 0.22 um membrane. After filtration, it was separated by a WATERS Prep150 preparative high performance liquid chromatography system, and the mobile phases were A (0.1% trifluoroacetic acid, 10% acetonitrile/water solution) and B (0.1% trifluoroacetic acid, 90% acetonitrile/water solution).
  • the chromatographic column is an X-SELECT OBD C-18 (WATERS, 19*250mm) reversed-phase chromatographic column, and the detection wavelength of the chromatograph during the purification process is set to 220 nm, and the flow rate is 15 mL/min.
  • the product-related fractions were collected and lyophilized to obtain the pure polypeptide of compound No. 5 with a yield of 19%.
  • the purity of the polypeptide was detected by the WATERS H-CLASS analytical ultra-high performance liquid chromatography system (chromatographic column: ACQUITY UPLC CSH C18 2.1*150mm), and its purity was 92.84%.
  • the molecular weight of the compound was confirmed by an Agilent Q-TOF 6530 system (chromatographic column: ACQUITY UPLC CSH C18 2.1*150 mm), and the mass spectrum shown in the mass spectrum was: 2092.08 [M+H] + .
  • the peptide chain sequence according to compound 8 was synthesized in order from the carboxyl terminus to the amino terminus. First weigh Fmoc-Cys(Trt)-OH (1mmol), 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate (HCTU) (1mmol) and N,N -Diisopropylethylamine (DIEA, 2mmol), dissolved in DMF (6mL), the above solution was added to the resin obtained in step 1, and the reaction was shaken at room temperature for 2 hours. After the reaction was completed, use DMF, dichloromethane (DCM) The resin was washed alternately 2 times and finally washed 3 times with DMF.
  • HCTU 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate
  • DIEA N,N -Diisopropylethylamine
  • step 1 deprotection and condensation process of the above amino acid derivatives, and condense in sequence: Fmoc-Thr(tBu)-OH, Fmoc-Lys(Boc)-OH, Fmoc-D-Trp(Boc)-OH, Fmoc-Tyr (tBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-D-Phe-OH, Fmoc-miniPEG, Fmoc-miniPEG, Fmoc-Lys(Mtt)-OH and DOTA-tris(tBu)ester fully protected of polypeptide molecules.
  • hexafluoroisopropanol/dichloromethane mixed solution (30% v/v, 10 mL) to the resin connected with polypeptide molecules in step 2, shake and react at room temperature for 45 minutes, then extract and remove, and then add hexafluoroisopropanol/
  • the mixed solution of dichloromethane (30% v/v, 10 mL) was shaken and reacted at room temperature for 45 minutes and then extracted, and after the reaction was completed, the resin was washed with DMF for 6 times.
  • tert-butyl hydrogen dodecanedioate (1mmol), 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate (HCTU) (1mmol) and N,N -Diisopropylethylamine (DIEA, 2mmol), dissolved in DMF (6mL), added to the resin, shaken at room temperature for 2 hours, and washed with DMF and dichloromethane (DCM) alternately for 3 times after the reaction .
  • DMF dichloromethane
  • Step 5 Disulfide bond generation and purification by reversed-phase liquid chromatography
  • step 4 The reduced crude product obtained in step 4 was lyophilized, dissolved in DMSO/water (30% v/v, concentration: 1.5 mg/mL), stirred at room temperature for 24 h, added with a few drops of trifluoroacetic acid, and passed through a 0.22 um membrane. After filtration, it was separated by a WATERS Prep150 preparative high performance liquid chromatography system, and the mobile phases were A (0.1% trifluoroacetic acid, 10% acetonitrile/water solution) and B (0.1% trifluoroacetic acid, 90% acetonitrile/water solution).
  • the chromatographic column is an X-SELECT OBD C-18 (WATERS, 19*250mm) reversed-phase chromatographic column, and the detection wavelength of the chromatograph during the purification process is set to 220 nm, and the flow rate is 15 mL/min.
  • the product-related fractions were collected and lyophilized to obtain the pure polypeptide of compound No. 8 with a yield of 21%.
  • the purity of the polypeptide was detected by the WATERS H-CLASS analytical ultra-high performance liquid chromatography system (chromatographic column: ACQUITY UPLC CSH C18 2.1*150mm), and the purity was 90.88%.
  • the molecular weight of the compound was confirmed by an Agilent Q-TOF 6530 system (chromatographic column: ACQUITY UPLC CSH C18 2.1*150 mm), and the mass spectrum shown in the mass spectrum was: 2065.99 [M+H] + .
  • the peptide chain sequence according to compound 14 was synthesized in order from the carboxy terminus to the amino terminus. First weigh Fmoc-Cys(Trt)-OH (1mmol), 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate (HCTU) (1mmol) and N,N -Diisopropylethylamine (DIEA, 2mmol), dissolved in DMF (6mL), the above solution was added to the resin obtained in step 1, and the reaction was shaken at room temperature for 2 hours. After the reaction was completed, use DMF, dichloromethane (DCM) The resin was washed alternately 2 times and finally washed 3 times with DMF.
  • HCTU 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate
  • DIEA N,N -Diisopropylethylamine
  • step 1 deprotection and condensation process of the above amino acid derivatives, and condense in sequence: Fmoc-Thr(tBu)-OH, Fmoc-Lys(Boc)-OH, Fmoc-D-Trp(Boc)-OH, Fmoc-Tyr (tBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-D-Phe-OH, Fmoc-miniPEG, Fmoc-miniPEG, Fmoc-Lys(Mtt)-OH and DOTA-tris(tBu)ester are fully protected of polypeptide molecules.
  • Step 3 Mtt deprotection, glutamic acid coupling of lysine side chain and fatty acid modification
  • hexafluoroisopropanol/dichloromethane mixed solution (30% v/v, 10 mL) to the resin connected with polypeptide molecules in step 2, shake and react at room temperature for 45 minutes, then extract and remove, and then add hexafluoroisopropanol/
  • the mixed solution of dichloromethane (30% v/v, 10 mL) was shaken and reacted at room temperature for 45 minutes and then extracted, and after the reaction was completed, the resin was washed with DMF for 6 times.
  • Step 5 Disulfide bond generation and purification by reversed-phase liquid chromatography
  • step 4 The reduced crude product obtained in step 4 was lyophilized, dissolved in DMSO/water (30% v/v, concentration: 1.5 mg/mL), stirred at room temperature for 24 h, added with a few drops of trifluoroacetic acid, and passed through a 0.22 um membrane. After filtration, it was separated by a WATERS Prep150 preparative high performance liquid chromatography system, and the mobile phases were A (0.1% trifluoroacetic acid, 10% acetonitrile/water solution) and B (0.1% trifluoroacetic acid, 90% acetonitrile/water solution).
  • the chromatographic column is an X-SELECT OBD C-18 (WATERS, 19*250mm) reversed-phase chromatographic column, and the detection wavelength of the chromatograph during the purification process is set to 220 nm, and the flow rate is 15 mL/min.
  • the product-related fractions were collected and lyophilized to obtain the pure polypeptide of compound No. 14.
  • the purity of the polypeptide was detected by the WATERS H-CLASS analytical ultra-high performance liquid chromatography system (chromatographic column: ACQUITY UPLC CSH C18 2.1*150mm).
  • the peptide chain sequence according to compound 18 was synthesized in order from the carboxy terminus to the amino terminus. First weigh Fmoc-Cys(Trt)-OH (1mmol), 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate (HCTU) (1mmol) and N,N -Diisopropylethylamine (DIEA, 2mmol), dissolved in DMF (6mL), the above solution was added to the resin obtained in step 1, and the reaction was shaken at room temperature for 2 hours. After the reaction was completed, use DMF, dichloromethane (DCM) The resin was washed alternately 2 times and finally washed 3 times with DMF.
  • HCTU 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate
  • DIEA N,N -Diisopropylethylamine
  • step 1 deprotection and condensation process of the above amino acid derivatives, and condense in sequence: Fmoc-Thr(tBu)-OH, Fmoc-Lys(Boc)-OH, Fmoc-D-Trp(Boc)-OH, Fmoc-Tyr (tBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-D-Phe-OH, Fmoc-miniPEG, Fmoc-miniPEG, Fmoc-Lys(Mtt)-OH and DOTA-tris(tBu)ester fully protected of polypeptide molecules.
  • Step 3 Mtt deprotection, glutamic acid coupling of lysine side chain and fatty acid modification
  • hexafluoroisopropanol/dichloromethane mixed solution (30% v/v, 10 mL) to the resin connected with polypeptide molecules in step 2, shake and react at room temperature for 45 minutes, then extract and remove, and then add hexafluoroisopropanol/
  • the mixed solution of dichloromethane (30% v/v, 10 mL) was shaken and reacted at room temperature for 45 minutes and then extracted, and after the reaction was completed, the resin was washed with DMF for 6 times.
  • tert-butyl tetradecanedioate (1mmol), 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate (HCTU) (1mmol) and N,N -Diisopropylethylamine (DIEA, 2mmol), dissolved in DMF (6mL), added to the resin, shaken at room temperature for 2 hours, and washed with DMF and dichloromethane (DCM) alternately for 3 times after the reaction .
  • DMF dichloromethane
  • Step 5 Disulfide bond generation and purification by reversed-phase liquid chromatography
  • step 4 The reduced crude product obtained in step 4 was lyophilized, dissolved in DMSO/water (30% v/v, concentration: 1.5 mg/mL), stirred at room temperature for 24 h, added with a few drops of trifluoroacetic acid, and passed through a 0.22 um membrane. After filtration, it was separated by a WATERS Prep150 preparative high performance liquid chromatography system, and the mobile phases were A (0.1% trifluoroacetic acid, 10% acetonitrile/water solution) and B (0.1% trifluoroacetic acid, 90% acetonitrile/water solution).
  • the chromatographic column is an X-SELECT OBD C-18 (WATERS, 19*250mm) reversed-phase chromatographic column, and the detection wavelength of the chromatograph during the purification process is set to 220 nm, and the flow rate is 15 mL/min.
  • the product-related fractions were collected and lyophilized to obtain the pure polypeptide of compound No. 18.
  • the purity of the polypeptide was detected by the WATERS H-CLASS analytical ultra-high performance liquid chromatography system (chromatographic column: ACQUITY UPLC CSH C18 2.1*150mm), and its purity was 98.81%.
  • the molecular weight of the compound was confirmed by an Agilent Q-TOF 6530 system (chromatographic column: ACQUITY UPLC CSH C18 2.1*150 mm), and the mass spectrum shown in the mass spectrum was: 2223.07 [M+H] + .
  • step 3 the side chain of lysine was sequentially combined with Fmoc-Glu(OtBu)-OH, Fmoc-Glu-OtBu and tetradecanedioic acid hydrogen tertiary Butyl ester coupling.
  • the purity of the polypeptide was detected by the WATERS H-CLASS analytical ultra-high performance liquid chromatography system (chromatographic column: ACQUITY UPLC CSH C18 2.1*150mm), and its purity was 98.05%.
  • the molecular weight of the compound was confirmed by an Agilent Q-TOF 6530 system (chromatographic column: ACQUITY UPLC CSH C18 2.1*150 mm), and the mass spectrum shown in the mass spectrum was: 1176.56 ⁇ [M+2H] 2+ /2 ⁇ .
  • the peptide chain sequence according to compound 21 was synthesized in order from the carboxy terminus to the amino terminus. First weigh Fmoc-Cys(Trt)-OH (1mmol), 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate (HCTU) (1mmol) and N,N -Diisopropylethylamine (DIEA, 2mmol), dissolved in DMF (6mL), the above solution was added to the resin obtained in step 1, and the reaction was shaken at room temperature for 2 hours. After the reaction was completed, use DMF, dichloromethane (DCM) The resin was washed alternately 2 times and finally washed 3 times with DMF.
  • HCTU 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate
  • DIEA N,N -Diisopropylethylamine
  • step 1 deprotection and condensation process of the above amino acid derivatives, and condense in sequence: Fmoc-Thr(tBu)-OH, Fmoc-Lys(Boc)-OH, Fmoc-D-Trp(Boc)-OH, Fmoc-Tyr (tBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-D-Phe-OH, Fmoc-miniPEG, Fmoc-miniPEG, Fmoc-Lys(Mtt)-OH and DOTA-tris(tBu)ester fully protected of polypeptide molecules.
  • Step 3 Mtt deprotection, glutamic acid coupling of lysine side chain and fatty acid modification
  • hexafluoroisopropanol/dichloromethane mixed solution (30% v/v, 10 mL) to the resin connected with polypeptide molecules in step 2, shake and react at room temperature for 45 minutes, then extract and remove, and then add hexafluoroisopropanol/
  • the mixed solution of dichloromethane (30% v/v, 10 mL) was shaken and reacted at room temperature for 45 minutes and then extracted, and after the reaction was completed, the resin was washed with DMF for 6 times.
  • Step 5 Disulfide bond generation and purification by reversed-phase liquid chromatography
  • step 4 The reduced crude product obtained in step 4 was lyophilized, dissolved in DMSO/water (30% v/v, concentration: 1.5 mg/mL), stirred at room temperature for 24 h, added with a few drops of trifluoroacetic acid, and passed through a 0.22 um membrane. After filtration, it was separated by a WATERS Prep150 preparative high performance liquid chromatography system, and the mobile phases were A (0.1% trifluoroacetic acid, 10% acetonitrile/water solution) and B (0.1% trifluoroacetic acid, 90% acetonitrile/water solution).
  • the chromatographic column is an X-SELECT OBD C-18 (WATERS, 19*250mm) reversed-phase chromatographic column, and the detection wavelength of the chromatograph during the purification process is set to 220 nm, and the flow rate is 15 mL/min.
  • the product-related fractions were collected and lyophilized to obtain the pure polypeptide of compound No. 21.
  • the purity of the polypeptide was detected by the WATERS H-CLASS analytical ultra-high performance liquid chromatography system (chromatographic column: ACQUITY UPLC CSH C18 2.1*150mm), and its purity was 99.64%.
  • the molecular weight of the compound was confirmed by an Agilent Q-TOF 6530 system (chromatographic column: ACQUITY UPLC CSH C18 2.1*150 mm), and the mass spectrum shown in the mass spectrum was: 2380.15 [M+H] + .
  • the affinity of polypeptide backbone compounds for SSTR2 receptors was tested by the method of radioligand-receptor competition binding (Eurofins Panlabs).
  • the CHO-K1 cells stably expressing the SSTR2 receptor were collected to prepare cell membranes, which were mixed with 0.3 nM radioactive 125 I-Somatostatin 14 ligand and 3-fold serial dilution of the somatostatin analog polypeptide to be tested, and the initial test concentration was 10 ⁇ M. After incubation at 25°C for 4 hours, the cell membrane mixture was filtered and washed three times, and the level of radioactive 125 I-specific labeling on the cell membrane was determined.
  • Competitive binding curve fitting and IC50 calculations were performed using MathIQTM. Among them, Somatostatin 14 was used as a test control, and Lutathera polypeptide backbone (DOTA-TATE) was used as a positive control.
  • DOTA-TATE Lutathera polypeptide backbone
  • the hemolytic effect of the somatostatin analog compound 3 in acetate buffer was tested in BALB/c mouse and human whole blood samples.
  • the red blood cells were resuspended in 900 ⁇ L of PBS, centrifuged at 2,000 g for 10 min at 4°C, the supernatant was gently discarded, and the washing was repeated twice.
  • test results are shown in Figures 1 and 2.
  • the results show that in the BALB/c mouse and human whole blood samples, the peptide solution with a concentration of 300ug/mL and below has no hemolytic effect.
  • the Activated GPCR Internalization Assays method tests the level of internalization of somatostatin analog polypeptides to the SSTR2 receptor (Eurofins DiscoverX). This method is based on the ⁇ -galactosidase fragment complementation mechanism established by Eurofins DiscoverX, which divides ⁇ -galactosidase into fusion receptor EA and fusion ligand ED. EA and ED approach and combine to form active ⁇ -galactosidase. Lactosidase. The specific test steps are as follows: the day before the test, the stable cell line was inoculated into a 384-well plate, 20uL per well, and cultured at 37°C overnight.
  • the compounds to be tested were at 500 nM as the initial test concentration, 3-fold serial dilution, 5 uL per well was added to the cells, and the cells were mixed and cultured at 37°C for 3 hours. Add 12uL of detection substrate to each well, incubate for 1 hour at room temperature, and then place it in PerkinElmer Envision TM to read the chemiluminescence value.
  • Somatostatin 28 was used as a test control
  • Lutathera polypeptide backbone (DOTA-TATE) was used as a positive control.
  • the plasma stability of Compound 3 was investigated in rat and human plasma samples, respectively.
  • the thawed plasma samples in a 37°C water bath were centrifuged at 10,000g for 5 minutes, and the supernatant was taken and checked for pH in the range of 7.2-8.0.
  • 2uL of 1mM polypeptide solution was added to 398uL of plasma samples (double wells), and incubated with shaking at 60rpm in a 37°C water bath.
  • 50uL samples were taken at 0, 15, 30, 60, and 120 minutes, respectively, and 400uL of methanol containing internal standard was added to stop the reaction, vortexed for 10 minutes, and centrifuged at 3,220g for 30 minutes at room temperature.
  • the supernatant was diluted with ultrapure water and detected by LC/MS/MS.
  • Lutathera polypeptide backbone (DOTA-TATE) was used as a positive control
  • propylamine was used as a human plasma test control
  • lovastatin was used as a rat plasma test control.
  • the plasma pharmacokinetics of the polypeptides were studied in a rat model.
  • the Lutathera polypeptide backbone (DOTA-TATE) served as a positive control.
  • DOTA-TATE Compound 3 Cmax(ng/ml) 3947 2177 Tmax(min) 2 5 C0(ng/ml) 4367.015 6606.516 T1/2(h) 0.477 2.232 AUC0-t(h*ng/ml) 1951.765 5918.786 AUC0-inf(h*ng/ml) 2057.516 5922.123 Vd(ml/kg) 228.989 151.366 CL(ml/h/kg) 486.023 168.858 MRT0-inf(h) 0.6506 3.1304
  • the affinity of polypeptide backbone compounds for SSTR2 receptors was tested by the method of radioligand-receptor competition binding (Eurofins Panlabs).
  • the CHO-K1 cells stably expressing the SSTR2 receptor were collected to prepare cell membranes, which were mixed with 0.3 nM radioactive 125 I-Somatostatin 14 ligand and 3-fold serial dilution of the somatostatin analog polypeptide to be tested, and the initial test concentration was 10 ⁇ M. After incubation at 25°C for 4 hours, the cell membrane mixture was filtered and washed three times, and the level of radioactive 125 I-specific labeling on the cell membrane was determined.
  • Competitive binding curve fitting and IC50 calculations were performed using MathIQTM.
  • Somatostatin 14 was used as a test control
  • Lutathera polypeptide backbone (DOTA-TATE) and DOTA-EB-TATE were used as positive controls.
  • EB molecules have been reported to prolong the half-life of polypeptide molecules by binding to albumin in plasma.
  • the plasma pharmacokinetics of the polypeptides were studied in a rat model.
  • Lutathera polypeptide backbone (DOTA-TATE) and DOTA-EB-TATE served as positive controls.
  • the experimental results are shown in Table 13.
  • the tested 5 compounds were all clear and transparent after being labeled with 177 Lu, and the pH measurement results ranged from 5.4 to 5.8.
  • the radiochemical purity of the prepared 177 Lu-labeled compounds was detected by HPLC and iTLC. The results were all greater than 99%.
  • Example 22 About 9.25 MBq (250 ⁇ Ci) of the 177 Lu-labeled compound in Example 22 was added to physiological saline, and stored in a 10 mL glass vial with a halogenated butyl rubber stopper. Store in an airtight, lead-proof jar at room temperature. After 24 hours, 10 ⁇ L samples were taken, and the samples were taken separately, and the radiochemical purity of the label was detected by HPLC/iTLC.
  • Example 24 Determination of the lipid-water distribution coefficient of the labeled compound
  • the experimental results are shown in Table 15.
  • the tested labeled compounds are all water-soluble, and the order of water-solubility is 177 Lu-20> 177 Lu-18> 177 Lu-19> 177 Lu-21> 177 Lu-15.
  • mice were allocated per compound, 3 per time point. Each mouse was administered 20 ⁇ Ci/100 ⁇ L, and blood was collected from the orbital and tail veins at 2 min, 10 min, 1 h, 4 h, 24 h, and 48 h after administration, collected in a pre-weighed sample tube, weighed and recorded the weight of the blood sample. The radioactivity was counted using a ⁇ -counter.
  • the test sample was accurately diluted 100 times, and 0.1 mL was taken into the counting tube as the standard 1% ID (that is, one percent of the administered dose), and the 1% ID standard and biological Radioactivity counts of the samples.
  • Data for blood are expressed as radioactive counts per gram of blood as a percentage of total administered dose (radioactive counts) (%ID/g).
  • the pharmacokinetic parameters were calculated according to the blood concentration data, and the uptake results of each labeled compound in the blood of normal mice are shown in Table 16. .
  • Example 26 SPECT scan imaging of AR42J xenogeneic tumor model
  • Lutathera 177-Lu-DOTA-TATE, No. 01
  • Another marketed drug Lutathera was used as a positive drug for comparison, and the specificity of the candidate probe was verified by blocking inhibition experiments (100 ⁇ g Lutathera compound was injected 10 minutes before administration).
  • the imaging results of each labeled compound in tumor-bearing mice are shown in 3-1 to 10-5. Select and delineate the ROI value of each organ, and then calculate the target to non-target (T/NT) ratio. The results are shown in the table. 17. The results showed that the labeled compounds 18, 20, and 21 had high uptake in AR42J tumors, and a good target/non-target ratio could be achieved 1 h after injection. In particular, the tumor uptake of compound 18 was significantly higher than that of the positive drug Lutathera ( 01).
  • Example 27 Preliminary evaluation of single-dose pharmacodynamic therapy in AR42J tumor model
  • 29 AR42J tumor-bearing mice were divided into 5 groups, namely compound No. 18 low-dose and high-dose groups, Control negative control group, Lutathera (DOTA-TATE) positive drug group, and DOTA-EB-TATE marker positive drug group. , 5-7 animals per group.
  • the radionuclide treatment was started by a single tail vein injection. Except for the No. 18 low-dose group, which was given 0.5mCi, the other groups were given a dose of 1mCi.
  • the body weight and tumor size of tumor-bearing nude mice were monitored every 2 days after the start of treatment. The tumor size was measured by an electronic vernier caliper, and the calculation formula of the tumor volume was 1/2 ⁇ long diameter ⁇ short diameter 2 .
  • the growth curve of the tumor volume is shown in FIG. 11 .

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Abstract

L'invention concerne un composé représenté par la formule (I), ou un sel pharmaceutiquement acceptable associé, ou un énantiomère ou un diastéréoisomère associé, ou un substituant associé contenant l'élément deutérium. Au moyen d'une complexation avec un radionucléide, le composé peut se lier à un récepteur de la somatostatine (SSTR) qui est hautement exprimé dans les tumeurs et qui peut être situé dans un tissu tumoral positif aux SSTR avec une sélectivité élevée, ce qui permet d'atteindre le but d'un diagnostic et d'un traitement ciblant une maladie.
PCT/CN2021/103005 2020-06-29 2021-06-29 Marqueur à radionucléide et son utilisation WO2022002022A1 (fr)

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CN114984255B (zh) * 2022-05-31 2023-09-26 苏州大学 一种放射性核素标记的PSMA-αvβ3双靶点偶联体及其应用

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