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CN-121991166-A - Radioligand compounds and uses thereof

CN121991166ACN 121991166 ACN121991166 ACN 121991166ACN-121991166-A

Abstract

Provided herein are compounds for delivering one or more radiotherapeutic or radiodiagnostic agents. In some embodiments, the compounds have a radioactive agent binding portion (RBM) that is linked to a GRPR binding portion (GBM) by a linker (RBM-L-GBM), wherein at least one of L and GBM is optionally substituted with an albumin binding portion (ABM). In some embodiments, the one or more therapeutic or diagnostic agents are delivered to the cancer cell.

Inventors

  • CAO XIAODONG
  • HUANG WEI
  • CHEN QIUXIA
  • DING FENG

Assignees

  • 成都纽瑞特医疗科技股份有限公司

Dates

Publication Date
20260508
Application Date
20251105
Priority Date
20241105

Claims (20)

  1. 1. A compound of formula I, or a stereoisomer or pharmaceutically acceptable salt thereof: C-L-OLP (formula I), Wherein, the C is a chelator of or chelated with a radionuclide or natural metal ion, L is absent or a linker, and OLP is an oligopeptide that binds to a target protein expressed in cancer cells or tissues, and Wherein L or OLP is optionally substituted with an albumin binding moiety Z1.
  2. 2. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein OLP is-Pa 1-Pa2-Pa3-Pa4-Pa5-Pa6-Pa7-Y1, or -Pa1-Pa2-Pa3-Pa4-Pa5-Pa6-Pa7-Pa8-Y2; And wherein Pa1 is selected from the group consisting of: D-Phe、D-Tyr、 pa2 is selected from the group consisting of: L-Gln、L-Hse、 L-Lys, or Pa3 is: L-Trp, or Pa4 is selected from the group consisting of: L-Ala, L-Val, or L-Leu; pa5 is L-Val; Pa6 is selected from the group consisting of: Gly、 Pa7 is: L-His, or Pa8 is selected from the group consisting of: L-Leu, L-Phe, or Y1 is selected from the group consisting of: And, a step of, in the first embodiment, Y2 is Wherein R1 is selected from the group consisting of C1-C5 alkynyl, C1-C5 alkylene, C1-C3 alkyl substituted with cyano, or Y2 is Wherein R2 is C1-C5 alkyl.
  3. 3. A compound according to claim 2, or a stereoisomer or pharmaceutically acceptable salt thereof, Selected from the group consisting of: And/or Is that
  4. 4. The compound of claim 4, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a linker.
  5. 5. The compound of claim 4, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the linker is selected from the group consisting of:
  6. 6. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the chelator is selected from the group consisting of DOTA, DOTAGA, DOTAM monoacid 、NOTA、DTPA、NODAGA、DOTP、TCMC、3P-C-DEPA、TETA、CB-TE2A、Sar、Me-Sar、DiAmSar、NETA、MACROPA、PCTA、PCTAGA、4-CB-PCTAGA、3-CB-PCTA、4-CB-PCTA、PSC, and H2dedpa.
  7. 7. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein L or OLP is not substituted with an albumin binding moiety Z1.
  8. 8. The compound of any one of claims 1 to 7, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the linker is selected from the group consisting of:
  9. 9. A compound according to any one of claim 1 to 7, or a stereoisomer or pharmaceutically acceptable salt thereof, OLP is-Pal-Pa 2-Pa3-Pa4-Pa5-Pa6-Pa7-Y1, or -Pal-Pa2-Pa3-Pa4-Pa5-Pa6-Pa7-Pa8-Y2; Wherein, the Pal, pa2, pa3, pa4, pa5, pa6, pa7, and Pa8 are as defined in claim 2, and Y1 is selected from the group consisting of: y2 is selected from the group consisting of:
  10. 10. The compound of any one of claims 1 to 9, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of the compounds shown in table A1, and the compounds shown in table A1 chelated with a radionuclide or a natural metal ion; Table A1
  11. 11. The compound of any one of claims 1 to 7, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein L or OLP is substituted with an albumin binding moiety Z1.
  12. 12. The compound of claim 11, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein L is substituted with an albumin binding moiety Z1.
  13. 13. The compound of any one of claims 1 to 7 and 11 to 12, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the albumin binding moiety Z1 is L1-A1, wherein L1 is a cleavable or non-cleavable linker and A1 is an albumin binding agent.
  14. 14. The compound of any one of claims 1 to 7 and 11 to 12, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein L1 comprises a non-ethoxylated moiety LC attached to L, and optionally an ethoxylated moiety L3 attached to an albumin binder, and wherein Z1 is LC-L3-A1, or LC-A1.
  15. 15. A compound of claim 14, or a stereoisomer or pharmaceutically acceptable salt thereof, LC is selected from the group consisting of: and/or the number of the groups of groups, L3 is selected from the group consisting of:
  16. 16. The compound of any one of claims 13 to 15, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein A1 is selected from the group consisting of:
  17. 17. The compound of any one of claims 1 to 7 and 11 to 16, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the linker is selected from the group consisting of:
  18. 18. The compound of any one of claim 1 to 7 and 11 to 16, or a stereoisomer or pharmaceutically acceptable salt thereof, OLP is -Pa1-Pa2-Pa3-Pa4-Pa5-Pa6-Pa7-Y1, or -Pa1-Pa2-Pa3-Pa4-Pa5-Pa6-Pa7-Pa8-Y2; Wherein, the Pa1, pa2, pa3, pa4, pa5, pa6, pa7, and Pa8 are as defined in claim 2, and Y1 is selected from the group consisting of: And/or Y2 is selected from the group consisting of:
  19. 19. the compound of any one of claims 1 to 7 and 11 to 18, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of the compounds shown in table A2, and the compounds shown in table A2 chelated with a radionuclide or a natural metal ion; Table A2
  20. 20. The compound of any one of claims 1 to 19, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the radionuclide is selected from the group ： 177 Lu、 68 Ga、 212 Pb、 203 Pb、 67 Cu、 64 Cu、 111 In、 225 Ac、 90 Y, or 99m Tc.

Description

Radioligand compounds and uses thereof Technical Field The present invention is in the field of diagnosis and therapy, and in particular relates to radioligand compounds and their use. Background The mammalian bombesin (BBN) receptor family consists of the neuromediator B receptor (NMBR, BB 1), the gastrin releasing peptide receptor (GRPR, BB 2) and the bombesin receptor subtype 3 (BRS-3, bb3). Human GRPR functions as a typical G Protein Coupled Receptor (GPCR) with seven transmembrane structures and has about 90% homology with murine GRPR proteins. Gastrin Releasing Peptide (GRP) is the primary endogenous ligand that binds to GRPR, and interactions between GRPR and GRP mediate a variety of physiological and pathophysiological processes, such as smooth muscle contraction, hormone secretion, cell proliferation and feeding behavior. In normal healthy tissues, GPCRs are widely expressed in the central nervous system, gastrointestinal tract, pancreas, and adrenal cortex. In addition, abnormal overexpression of GRPR is also observed in a variety of primary and metastatic malignant tissues (e.g., prostate cancer, breast cancer, lung cancer, colorectal cancer, gastrinomas, gastrointestinal stromal tumors). Beer et al analyzed benign and malignant prostate samples from 530 patients using immunohistochemistry, found that normal prostate tissue was mostly GRPR negative, with significantly higher GRPR expression seen in primary cancers and metastases. Morgat et al measured the GRPR expression density of a primary breast tumor sample from a patient, and showed that there was 75.8% GRPR overexpression in 1432 tumors and most closely correlated with Estrogen Receptor (ER) positivity. Disclosure of Invention The compounds provided herein are useful for delivering radioactive materials to diseased cells or tissues that highly express a target protein for therapeutic and/or diagnostic purposes. The compounds have a radioactive agent binding portion (RBM) that is linked to a GRPR binding portion (GBM) by a linker (RBM-L-GBM), wherein at least one of L and GBM is optionally substituted with an albumin binding portion (ABM). In some embodiments, the one or more therapeutic or diagnostic agents are delivered to the cancer cell. In some embodiments, the RBM-L-GBM is a compound as described below, such as a compound of formula I or II, or a compound selected from tables A1 and A2. In another aspect, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable excipient and any one of the compounds disclosed herein or a pharmaceutically acceptable salt thereof. A method of treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of any one of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof. A method of diagnosing a disease or disorder in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of any one of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof. Incorporation by reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. Detailed Description The present invention recognizes that GRPR-targeted radiotherapy and imaging can be an effective option for detecting and treating cancers associated with high density expression of GRPR (e.g., prostate and breast cancers). While GRPR-targeted radiopharmaceuticals are reported to be under development and evaluation, no GRPR-targeted radiopharmaceuticals have gained commercially regulatory approval. The present invention recognizes that optimizing the pharmacokinetic and/or pharmacodynamic characteristics of a GRPR-targeted radiopharmaceutical, such as increasing tumor uptake and/or retention for imaging and therapy, is one of the key aspects to improving the efficacy of the GRPR-targeted radiopharmaceutical. Certain terms Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which claimed subject matter belongs. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter as claimed. In the present application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. In the present application, the use of "or" means "and/or" unless stated otherwise. Furthermore, the use of the term "including" and other forms (e.g., "comprising," "