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CN-115484991-B - Methods for radiolabelling PSMA binding ligands and kits therefor

CN115484991BCN 115484991 BCN115484991 BCN 115484991BCN-115484991-B

Abstract

The present disclosure relates to methods of radiolabeling PSMA-binding ligands with radioisotopes, preferably 68 Ga, 67Ga or 64 Cu, and kits thereof.

Inventors

  • D. Babato
  • L. Fugaza
  • M. Tedesco
  • E. Castaldi

Assignees

  • 诺华股份有限公司

Dates

Publication Date
20260505
Application Date
20210428
Priority Date
20200429

Claims (17)

  1. 1. A method of labeling a PSMA binding ligand of formula (II) with a radioisotope, (II) Wherein the radioisotope is 68 Ga、 67 Ga or 64 Cu, the method comprising the steps of: i. Providing a first vial comprising said PSMA-binding ligand and a bulking agent mannitol in dry form, Adding a solution of said radioisotope to said first vial, thereby obtaining a solution of said PSMA binding ligand and said radioisotope, Mixing the solution obtained in ii with a buffer comprising formic acid and sodium hydroxide and incubating for a period of time sufficient to obtain said PSMA-binding ligand labeled with said radioisotope, and Adjusting the pH of the solution.
  2. 2. Use of a solution comprising the PSMA-binding ligand of formula (II) labeled with 68 Ga、 67 Ga or 64 Cu, obtainable or obtained by the method of claim 1, for the preparation of an injectable solution for in vivo detection of a tumor by imaging in a subject in need thereof.
  3. 3. The use of claim 2, wherein the tumor is a PSMA-expressing tumor.
  4. 4. A kit for performing the method of claim 1, the kit comprising I. A first vial having the following components in dry form: i. a PSMA-binding ligand having formula (II): (II), and Bulking agent mannitol, and A second vial comprising a buffer in dry form, the buffer comprising formic acid and sodium hydroxide, and An accessory box for eluting radioisotope produced by a radioisotope generator or cyclotron.
  5. 5. The kit of claim 4, wherein the first vial comprises the following components: i. The PSMA binding ligand of formula (II) in an amount of 10 μg to 100 μg, and Mannitol in an amount of 5 mg to 50 mg.
  6. 6. The kit of claim 5, wherein the amount of PSMA-binding ligand of formula (II) is from 15 μg to 60 μg.
  7. 7. The kit of claim 5, wherein the amount of PSMA-binding ligand of formula (II) is 30 μg.
  8. 8. The kit of claim 5, wherein the amount of mannitol is 10 mg to 30 mg.
  9. 9. The kit of claim 5, wherein the amount of mannitol is 20 mg.
  10. 10. The kit of any one of claims 4-9, wherein the second vial comprises formic acid and sodium hydroxide as buffers for maintaining a pH of 2.5 to 4.0.
  11. 11. The kit of claim 10, wherein the second vial comprises formic acid and sodium hydroxide as buffers for maintaining a pH of 2.8 to 4.0.
  12. 12. The kit of claim 10, wherein the second vial comprises formic acid and sodium hydroxide as buffers for maintaining a pH of 3.0 to 4.0.
  13. 13. The kit of claim 10, wherein the second vial comprises formic acid and sodium hydroxide as buffers for maintaining a pH of 3.2 to 3.8.
  14. 14. The kit of any one of claims 4-9 and 11-13, wherein the kit does not comprise an antioxidant.
  15. 15. The kit of claim 10, wherein the kit does not comprise an antioxidant.
  16. 16. The kit of any one of claims 4-9 and 11-13, wherein the kit does not comprise the antioxidant gentisic acid.
  17. 17. The kit of claim 10, wherein the kit does not comprise the antioxidant gentisic acid.

Description

Methods for radiolabelling PSMA binding ligands and kits therefor Technical Field The present disclosure relates to methods for radiolabeling PSMA-binding ligands and kits thereof. Background Prostate cancer is one of the most common cancers in the united states and europe. In particular, metastatic prostate cancer (mCRPC) is associated with poor prognosis and reduced quality of life. Recently, a new development stream for the treatment of prostate cancer is represented by internal radiotherapy based on PSMA ligand, because PSMA is considered a suitable target for imaging and therapy due to its overexpression in primary cancerous lesions and soft tissue/bone metastatic disease. Furthermore, PSMA expression appears to be higher in the most aggressive castration resistant variants of the disease (which represent an unmet patient population for medical needs). (Marchal et al, histol Histopathol [ histology and histopathology ], month 7 of 2004; 19 (3): 715-8; mease et al, curr Top Med Chem [ current subject of pharmaceutical chemistry ],2013,13 (8): 951-62). Among many small molecule ligands targeting PSMA, urea-based low molecular weight agents are the most widely studied ligands. These agents have proven suitable for clinical assessment of prostate cancer and PRRT therapy (Kiess et al, Q J Nucl Med Mol Imaging [ nuclear medicine & molecular imaging quarterly ],2015; 59:241-68). Some of these agents have glutamate-urea-lysine (GUL) as a targeting scaffold. A class of molecules was created according to the strategy of attaching a linker between the chelator and the GUL moiety. This method allows urea to reach the binding site while keeping the metal chelating moiety outside the binding site. This strategy was successful in xenograft PSMA positive tumors because it showed high uptake and retention and rapid renal clearance (Banerjee et al, J Med Chem J. Pharmaceutical J., 2013; 56:6108-21). It has also been shown that such molecules can be labeled with 68 Ga and used for detection of prostate cancer lesions by PET imaging (Eder et al Pharmaceuticals [ medicine ]2014,7,779-796). However, no optimized method has been developed for labeling PSMA-binding ligands with 68Ga、67 Ga or 64 Cu, thereby obtaining labeled PSMA-binding ligand solutions for imaging purposes in prostate cancer tumors in human patients. In particular, there is a need for a rapid, efficient and safe procedure that will provide labeled PSMA-binding ligands, such as [ 68 Ga ] PSMA-binding ligands, of high radiochemical purity for intravenous injection in a human subject in need thereof. Disclosure of Invention A first aspect of the present disclosure relates to a method for labelling a PSMA binding ligand with a radioisotope, preferably 68Ga、67 Ga or 64 Cu, the method comprising the steps of: i. Providing a first vial comprising said PSMA-binding ligand and optionally a bulking agent in dry form, Adding a solution of said radioisotope to said first vial, thereby obtaining a solution of said PSMA binding ligand and said radioisotope, Mixing the solution obtained in ii with at least a buffer and incubating for a period of time sufficient to obtain said PSMA-binding ligand labeled with said radioisotope, and Optionally, adjusting the pH of the solution. In specific embodiments, the radioisotope is 68 Ga and the radiochemical purity measured in HPLC is at least 92%, and optionally the percentage of free 68Ga3+ (in HPLC) is 2% or less and/or the percentage of uncomplexed 68Ga3+ material (in ITLC) is 3% or less. In other specific embodiments, the radioisotope is 67 Ga and the radiochemical purity measured in HPLC is at least 90%, and optionally the percentage of free 67Ga3+ (in HPLC) is 2% or less and/or the percentage of uncomplexed 67Ga3+ material (in ITLC) is 5% or less. In other specific embodiments, the radioisotope is 64Cu and the radiochemical purity measured in HPLC is at least 92%, and optionally the percentage of free 64Cu2+ (in HPLC) is 2% or less and/or the percentage of uncomplexed 64Cu2+ material (in ITLC) is 3% or less. Preferably, the PSMA-binding ligand is a compound having the formula (I): Wherein: z is tetrazole or COOQ, preferably Z is COOQ; q is independently H or a protecting group, preferably Q is H; m is an integer selected from the group consisting of 1, 2,3, 4 and 5, preferably m is 4; q is an integer selected from the group consisting of 1, 2, 3, 4, 5 and 6, preferably q is 1; R is selected from the group consisting of C 6-C10 aryl and heteroaryl containing 5-10 ring atoms, said aryl and heteroaryl being substituted 1 or more times with X; X is-V-Y; V is a bond or C 1-C6 alkylene, preferably V is a bond; y is halogen; L is a linker selected from the group consisting of: C 1-C6 alkylene, C 3-C6 cycloalkylene and C 6-C10 arylene, said alkylene, cycloalkylene and arylene being optionally substituted with one OR more substituents selected from-OR ', -O, =nr', -N-OR ', -NR' R ', -SR', -halogen 、-SiR'R"R"'、-OC(O)R'、-C(O)R'、-CO2R'、-C