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CN-121971661-A - Radiopharmaceutical and application thereof

CN121971661ACN 121971661 ACN121971661 ACN 121971661ACN-121971661-A

Abstract

The invention provides a radioactive drug and application thereof, which relate to the technical field of nuclear medicine, the radioactive drug provided by the invention can be used as an integrin alpha 4 β 7 imaging agent, by using a nuclear medicine PET imaging technique, it is possible to diagnose and image the focus of a disease (for example, inflammatory bowel disease or tumor disease) in which the expression of integrin alpha 4 β 7 is positive. The chelating part in the integrin alpha 4 β 7 radiopharmaceuticals can be replaced by NOTA chelating agents, NODAGA chelating agents, DOTAGA chelating agents, THP chelating agents and TRAP chelating agents, and the chelating agents are used for labeling 68 Ga、 61 Cu、 64 Cu、 177 Lu metal nuclides, so that PET imaging and nuclide treatment of multiple nuclides are further realized.

Inventors

  • YANG GUANGJIE
  • HUO LI
  • ZHANG HAIQIONG

Assignees

  • 中国医学科学院北京协和医院

Dates

Publication Date
20260505
Application Date
20251212

Claims (10)

  1. 1. A radiopharmaceutical, wherein the radiopharmaceutical is formed by labelling a precursor compound with a radionuclide, the precursor compound having a structure according to formula (I): (I) Wherein, the N is an integer of 0 to 12, and n is preferably an integer of 2 to 8; BFC is a chelating moiety, representing A group formed after formation of a peptide bond with the bifunctional chelating agent.
  2. 2. The radiopharmaceutical of claim 1, wherein in said radiopharmaceutical, said radionuclide is chelated with a chelating moiety of said precursor compound to form said radiopharmaceutical.
  3. 3. The radiopharmaceutical according to claim 1 or 2, wherein the bifunctional chelating agent is selected from at least one of DOTA-tri (tert-butyl ester) (CAS number: 137076-54-1), DOTA-NHS (CAS number: 1823122-52-6), p-SCN-Bn-DOTA (CAS number: 1020407-41-3), dotga (CAS number: 656242-49-8), p-SCN-Bn-NOTA (CAS number: 1206475-68-4), NOTA-NHS (CAS number: 1338231-09-6), nodga-NHS (CAS number: 1407166-70-4), THP-NCS (CAS number: 1807847-98-8), TRAP (CAS number: 1242003-07-1), p-SCN-Bn-deferoxamine (CAS number: 1222468-90-7).
  4. 4. A radiopharmaceutical according to claim 1 or 3, wherein the radionuclide is selected from at least one of 111 In、 61 Cu、 64 Cu、 67 Cu、 68 Ga、 18 F、 90 Y、 177 Lu、 124 I、 89 Zr、 44 Sc.
  5. 5. The radiopharmaceutical of claim 1 or 4, wherein the bifunctional chelating agent forming the chelating moiety is selected from DOTA class chelating agents or NOTA class chelating agents when the radionuclide is selected from at least one of 68 Ga、 64 Cu、 177 Lu.
  6. 6. A composition comprising a radiopharmaceutical of any one of claims 1 to 5.
  7. 7. The composition of claim 6, further comprising a pharmaceutically acceptable adjuvant or carrier.
  8. 8. Use of a radiopharmaceutical according to any one of claims 1 to 5 or a composition according to any one of claims 6 to 7 for the preparation of a medicament for the diagnosis and/or treatment of a disease associated with positive expression of integrin alpha 4 β 7 .
  9. 9. The use according to claim 8, wherein the medicament comprises an imaging diagnostic or a radioactive targeting therapeutic for diseases associated with positive expression of integrin alpha 4 β 7 .
  10. 10. The use according to claim 8 or 9, wherein the disease is selected from inflammatory bowel disease or a neoplastic disease; preferably, the inflammatory bowel disease is selected from at least one of crohn's disease, ulcerative colitis, and/or the neoplastic disease is selected from at least one of colorectal cancer, gastrointestinal lymphoma.

Description

Radiopharmaceutical and application thereof Technical Field The invention relates to the technical field of nuclear medicine, in particular to a radioactive drug and application thereof. Background Inflammatory bowel diseases (Inflammatory bowel disease, IBD), including Ulcerative Colitis (UC) and Crohn's Disease (CD), are chronic immune-mediated gastrointestinal disorders that can lead to impaired quality of life. These diseases present challenges to clinical patient management due to their complex pathophysiology, chronic nature and propensity for recurrence. Taking ulcerative colitis as an example, the Chinese guidelines for diagnosis and treatment of ulcerative colitis suggest that colonoscopy and mucosal biopsy are the main basis for diagnosis of ulcerative colitis, and are conventionally used for UC diagnosis, efficacy evaluation and disease monitoring, and the diagnosis should be performed by entering the terminal ileum as far as possible and taking multiple sections and points of materials in affected and unaffected areas for mucosal biopsy. However, this diagnostic method is invasive, and generally does not show the ability to detect all lesions and changes in lesion cell and molecular levels in the body. Compared with the traditional endoscopy and biopsy, the nuclear medicine imaging has the advantages that the patient does not need to prepare the intestinal canal in advance before examination, the focus of inflammatory bowel disease can be detected noninvasively and noninvasively, a plurality of focuses of the whole intestinal section can be detected simultaneously, missed diagnosis is avoided, functional information of the focus of the intestinal canal can be reflected from the molecular level, and comprehensive information of the structure and the function can be obtained when fusion imaging is carried out by combining with CT or MR. The current limitation of limiting the application of nuclear medicine imaging in inflammatory bowel disease is the lack of excellent nuclear medicine imaging probes. In the development of inflammatory bowel disease, T cells and their surface expressed integrin alpha 4β7 play a key role. At the inflammatory site, after the integrin alpha 4β7 on the surface of the T cells is combined with the mucosa addressee cell adhesion molecule-1 (MAdCAM-1) expressed by the endothelial cells of the intestinal tract, the T cells can penetrate through blood vessels to enter the intestinal mucosa, so that local immunity is disordered, and chronic inflammation is caused. Vedelizumab (Vedolizumab) is a humanized IgG1 monoclonal antibody which specifically antagonizes integrin alpha 4β7, and can block T cells from migrating from blood vessels to intestinal mucosa and alleviate local inflammatory response of intestinal tracts. Vedelizumab has been approved by the FDA and EMA for induction and maintenance therapy in patients with moderate to severe ulcerative colitis and crohn's disease. In current treatment regimens, vedolizumab is administered by intravenous infusion 1 time at weeks 0, 2 and 6 and every 8 weeks thereafter, if no therapeutic benefit is observed at week 14, indicating that vedolizumab is not effective for the patient and should not continue to be used, and patients with reduced response may be helped to re-respond and remit clinically by increasing the frequency of administration or boosting the dose. In summary, in the current patient flow of the vedelizumab for treating inflammatory bowel disease, the following problems exist that 1) patients cannot be screened, whether the patients respond to the vedelizumab treatment or not can be confirmed after at least 14 weeks, and the treatment of the patients is delayed to a certain extent. At present, a better method for screening patient groups with better treatment response to the vedelizumab is not available. 2) The vallizumab needs to closely monitor the curative effect and timely evaluate and adjust the scheme during the treatment period, and the current evaluation methods comprise fecal calprotectin examination, enteroscope examination or small intestine CT/magnetic resonance examination, which are difficult to evaluate the number and the function of the lesions of the whole intestine section and are difficult to realize for long-term follow-up monitoring. There is no better method for monitoring the disease development change and treatment response of patients in the treatment process. Therefore, if a nuclear medicine imaging probe capable of specifically binding to integrin alpha 4β7 is developed, it can reflect the local T cell infiltration of inflammatory lesions to some extent, and patients responding to the integrin-resistant treatment can be selected. Dearling et al, using 64 Cu-labeled antibody FIB504.64 to visualize integrin beta 7, showed some uptake in the model, but the antibody probe had relatively high uptake in the liver and low uptake in intestinal lesions, affecting lesion detection to some extent (Infl