WO2023083209A1 - 一种靶向psma抗原的配体化合物及其螯合物与用于前列腺癌诊断和治疗的应用 - Google Patents

一种靶向psma抗原的配体化合物及其螯合物与用于前列腺癌诊断和治疗的应用 Download PDF

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WO2023083209A1
WO2023083209A1 PCT/CN2022/130833 CN2022130833W WO2023083209A1 WO 2023083209 A1 WO2023083209 A1 WO 2023083209A1 CN 2022130833 W CN2022130833 W CN 2022130833W WO 2023083209 A1 WO2023083209 A1 WO 2023083209A1
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Prior art keywords
ligand compound
psma
integer
pharmaceutically acceptable
solvate
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PCT/CN2022/130833
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English (en)
French (fr)
Chinese (zh)
Inventor
钟志远
袁建栋
杨江涛
皇甫贞元
孙娟
徐斌
陶蕾
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Suzhou Ruihe Medicine Technology Co Ltd
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Suzhou Ruihe Medicine Technology Co Ltd
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Priority to EP22892003.9A priority Critical patent/EP4431503A1/en
Priority to AU2022384375A priority patent/AU2022384375A1/en
Priority to JP2024527096A priority patent/JP2024544870A/ja
Priority to US18/708,905 priority patent/US20260069725A1/en
Priority to CN202280074508.9A priority patent/CN118176188A/zh
Priority to CA3237743A priority patent/CA3237743A1/en
Priority to KR1020247014634A priority patent/KR20240105380A/ko
Publication of WO2023083209A1 publication Critical patent/WO2023083209A1/zh
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    • 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
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0402—Organic compounds carboxylic acid carriers, fatty acids
    • 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
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0497—Organic compounds conjugates with a carrier being an organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • the invention belongs to the field of medicinal chemistry, and in particular relates to a ligand compound targeting PSMA antigen and its chelate, and its application in nuclear medicine as a diagnostic reagent for prostate cancer and for treating different degrees of prostate cancer.
  • the present invention discloses a novel ligand compound targeting PSMA and its chelate combined with radioactive metal.
  • the ligand compound or chelate can be used in nuclear medicine as A reagent for treating or diagnosing prostate cancer, used for treating or diagnosing different degrees of prostate cancer, especially PSMA-positive prostate cancer.
  • the present invention adopts following technical scheme:
  • the present invention discloses a ligand compound targeting PSMA antigen, or a pharmaceutically acceptable salt, ester or solvent compound thereof.
  • the chemical structural formula of the ligand compound targeting PSMA antigen is as follows:
  • a and b are each independently any integer from 1 to 8
  • c and d are each independently any integer from 1 to 4; preferably, a and b are each independently any integer from 2 to 6
  • An integer, c and d are each independently any integer of 1 to 3; more preferably, a and b are 4, c is 2, and d is 1;
  • L is any one of the following chemical structural formulas:
  • L is connected to other fragments in the structural formula of the ligand compound through an amide bond
  • R 6 , R 7 , and R 8 are each independently hydrogen, alkyl, alkoxy, or halogen;
  • R 1 is any one of the following chemical structural formulas:
  • n is any integer from 2 to 20;
  • R 3 , R 4 , and R 5 are each independently any of hydrogen, alkyl, alkoxy, halogen, cycloalkyl, heterocyclyl, and aryl species;
  • p is any integer from 0 to 8;
  • q is any integer from 1 to 10;
  • L2 is an amino acid linker structure;
  • R 2 is an aryl group or a heteroaryl group, preferably an aryl group; Y is a radiometal chelating agent group.
  • the invention discloses a ligand compound targeting PSMA antigen, or a pharmaceutically acceptable salt, ester or solvate thereof.
  • the chemical structural formula of the ligand compound targeting PSMA antigen is as follows:
  • L is any one of the following chemical structural formulas:
  • L is connected to other fragments in the structural formula of the ligand compound through an amide bond
  • R 1 is any one of the following chemical structural formulas:
  • n is any integer from 2 to 20;
  • R 3 , R 4 , and R 5 are each independently selected from one of hydrogen, alkyl, alkoxy, halogen, cycloalkyl, heterocyclic, and aryl species;
  • p is any integer from 0 to 8;
  • q is any integer from 1 to 10;
  • L2 is an amino acid linker structure
  • R2 is an aromatic group or a heteroaryl group, preferably an aromatic group
  • Y is a radioactive metal chelating agent group.
  • Y is a radioactive metal chelating agent group, which can be combined with radioactive metals; preferably, the chelating agent is selected from: DOTA (1,4,7,10-tetraazacyclododecane-1,4, 7,10-tetraacetic acid) or its derivatives, TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid) or its derivatives, SarAR (1- N-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]-eicosane-1,8-diamine) or its derivatives, NOTA( 1,4,7-triazacyclononane-1,4,7-triacetic acid) or its derivatives, TRAP (1,4,7-triazacyclononane-1,4,7-trimethyl (2-carboxyethyl)phosphinic acid) or its derivatives, HBED (N,N'
  • the present invention discloses a ligand compound targeting PSMA antigen based on DOTA, or a pharmaceutically acceptable salt, ester or solvate thereof.
  • the chemical structural formula of the ligand compound targeting PSMA antigen based on DOTA is as follows:
  • L is any one of the following chemical structural formulas:
  • L is connected to other fragments in the structural formula of the ligand compound through an amide bond
  • R 1 is any one of the following chemical structural formulas:
  • n is any integer from 2 to 20;
  • R 3 , R 4 , and R 5 are each independently any of hydrogen, alkyl, alkoxy, halogen, cycloalkyl, heterocyclyl, and aryl species;
  • p is any integer from 0 to 8;
  • q is any integer from 1 to 10;
  • L2 is an amino acid linker structure;
  • R 2 is aryl or heteroaryl, preferably aryl, more preferably naphthyl.
  • the chemical structural formula of the DOTA-based ligand compound targeting PSMA antigen is as follows:
  • L 1 and R 1 are as defined in the chemical structural formula of the above-mentioned DOTA-based ligand compound targeting PSMA antigen.
  • the aromatic group is phenyl, naphthyl or anthracenyl.
  • n is any integer from 4 to 18
  • the alkoxy group is an alkoxy group with 1 to 10 carbons
  • the alkyl group is an alkyl group with 1 to 10 carbons
  • q is 2 to 8 Any integer in
  • p is any integer from 0 to 6;
  • n is any integer from 6 to 16
  • the alkoxy is an alkoxy with 1 to 6 carbons
  • the alkyl is an alkyl with 1 to 6 carbons
  • q is 2 to 5
  • p is any integer from 0 to 4;
  • n is any integer from 8 to 14
  • the alkoxy group is an alkoxy group with 1 to 3 carbons
  • the alkyl group is an alkyl group with 1 to 3 carbons
  • q is 2 or 3
  • p is 0 or 1.
  • the amino acid linker structure refers to the carboxyl group of the amino acid terminal to remove the hydroxyl group, the amino group connected to the methylene adjacent to the carboxyl group to remove a hydrogen, and the remaining structure; the amino group on the amino acid linker and the phenylalkanoic acid group form an amide bond , constituting the R1 structure; the amino acid is arginine, serine, histidine, lysine, glycine or glutamine.
  • the R is the following chemical structural formula:
  • n is any integer of 4-18, preferably any integer of 6-16, more preferably any integer of 8-14.
  • the R is the following chemical structural formula:
  • R 5 is hydrogen, an alkoxy group with 1 to 6 carbons or an alkyl group with 1 to 6 carbons; more preferably, the alkoxy group is an alkoxy group with 1 to 3 carbons, and the alkyl group is 1 to 3 carbon alkyl.
  • the R is the following chemical structural formula:
  • R4 is hydrogen, an alkoxy group with 1 to 6 carbons or an alkyl group with 1 to 6 carbons, q is any integer from 2 to 5, and L2 is an amino acid linker structure;
  • the alkoxy group is an alkoxy group with 1 to 3 carbons
  • the alkyl group is an alkyl group with 1 to 3 carbons
  • q is 2 or 3
  • the amino acid in the amino acid linker is arginine, serine , Histidine, Lysine, Glycine, or Glutamine.
  • the R is the following chemical structural formula:
  • R 3 is hydrogen, alkoxy or alkyl; p is any integer in 0 ⁇ 7;
  • the alkoxy group is an alkoxy group with 1 to 10 carbons
  • the alkyl group is an alkyl group with 1 to 10 carbons
  • p is any integer from 0 to 4;
  • the alkoxy group is an alkoxy group with 1 to 6 carbons
  • the alkyl group is an alkyl group with 1 to 6 carbons
  • p is any integer between 0 and 2;
  • the alkoxy group is an alkoxy group with 1 to 3 carbons
  • the alkyl group is an alkyl group with 1 to 3 carbons
  • p is 0 or 1.
  • the ligand compound targeting PSMA antigen of the present invention or the ligand compound targeting PSMA antigen based on DOTA is PSMA-A, PSMA-B, PSMA-C, PSMA-D, PSMA-E, PSMA - one of F, PSMA-G, PSMA-H, PSMA-I, PSMA-J, PSMA-K, PSMA-L.
  • the present invention discloses a ligand compound of the following structural formula and a pharmaceutically acceptable salt, ester or solvate thereof:
  • the invention discloses a chelate compound, comprising a ligand compound or a pharmaceutically acceptable salt, ester or solvate thereof and a radioactive metal; the ligand compound is the above-mentioned ligand compound targeting PSMA antigen or based on DOTA A ligand compound targeting PSMA antigen, or a ligand compound as a specific preferred example.
  • the radioactive metal is combined with the above-mentioned ligand compound through the radioactive metal chelator group Y, and the radioactive metal is 64 Cu, 67 Cu, 90 Y, 111 In, 68 Ga, 117m Sn, 153 Sm, 149 Tb, 161 Tb, 177 Lu, 225 Ac, 213 Bi, 224 Ra, 212 Bi, 212 Pb, 225 Ac, 227 Th, 223 Ra , 47 Sc, 186 Re, 188 Re, 68 Ga, 64 Cu, 111 In, 89 Zr, 44 Sc, 99m Tc , 86 Y, 152 Tb or 155 Tb.
  • the radiometal when the radiometal is a diagnostic radiometal (including but not limited to 68 Ga, 64 Cu, 111 In, 89 Zr, 44 Sc, 99m Tc, 86 Y, 152 Tb, or 155 Tb), the chelating The compound can be used for diagnosis of prostate cancer, performing imaging diagnosis on PSMA-positive prostate cancer patients; in some embodiments, when the radioactive metal is a therapeutic radioactive metal (including but not limited to 64 Cu, 67 Cu, 90 Y, 111 In , 117m Sn, 153 Sm, 149 Tb, 161 Tb, 177 Lu, 225 Ac, 213 Bi, 224 Ra, 212 Bi, 212 Pb, 225 Ac, 227 Th, 223 Ra, 47 Sc, 186 Re or 188 Re) , these compounds can be used for treating prostate cancer, and treating PSMA-positive prostate cancer patients.
  • a diagnostic radiometal including but not limited to 68 Ga, 64 Cu, 111 In, 89 Zr, 44 Sc, 99m T
  • the radioactive metal is 177 Lu.
  • the chelate includes 177 Lu and a ligand compound with the following structure or a pharmaceutically acceptable salt, ester or solvate of the ligand compound:
  • composition which comprises the above-mentioned chelate, and may also include pharmaceutically acceptable excipients.
  • a reagent for diagnosis or treatment of cancer which uses the above chelate as an active ingredient and may also include pharmaceutically acceptable excipients.
  • the invention discloses the application of the above-mentioned composition, the above-mentioned chelate compound, the above-mentioned ligand compound or a pharmaceutically acceptable salt, ester or solvate thereof in the preparation of cancer diagnosis or treatment reagents.
  • the ligand compound is the above-mentioned ligand compound targeting PSMA antigen or the ligand compound targeting PSMA antigen based on DOTA, or a ligand compound as a specific preferred example.
  • the diagnosis is imaging diagnosis; the treatment is radiotherapy; the cancer is a solid tumor or a hematologic tumor; further, the cancer is prostate cancer, more preferably prostate specific membrane antigen-positive prostate cancer .
  • the invention discloses a method for imaging prostate cancer patients, comprising the following steps: administering (preferably a diagnostically effective amount) the above-mentioned chelate to the patient, or the above-mentioned composition, or the above-mentioned cancer diagnosis or treatment reagent, or comprising The composition of the above-mentioned cancer diagnostic reagent or therapeutic reagent and a pharmaceutically acceptable excipient, and then perform tissue imaging; preferably, the prostate cancer is prostate specific membrane antigen-positive prostate cancer; the imaging is PET imaging or SPECT imaging.
  • the invention discloses a treatment method for prostate cancer patients, comprising the following steps: administering (preferably a therapeutically effective amount) the above-mentioned chelate to the patient, or the above-mentioned composition, or the above-mentioned cancer diagnosis or treatment reagent, or containing the above-mentioned A composition of a cancer diagnostic reagent and a pharmaceutically acceptable excipient; preferably, the prostate cancer is prostate specific membrane antigen-positive prostate cancer; and the treatment is radiotherapy.
  • the above-mentioned cancer diagnosis or treatment reagents, the above-mentioned chelates, the above-mentioned ligand compounds or their pharmaceutically acceptable salts, esters or solvates disclosed in the present invention are used for diagnosing or treating cancer; preferably, the diagnosis is imaging (such as PET imaging or SPECT imaging) diagnosis, the treatment is radiotherapy, and the cancer is a solid tumor or hematological tumor; further, the cancer is prostate cancer, more preferably prostate specific membrane antigen-positive prostate cancer .
  • the ligand compound targeting PSMA antigen disclosed by the present invention has lower normal tissue toxicity after chelating metal, higher exposure to tumor, longer half-life in blood, better antigen affinity and tumor inhibition effect, and Radiochemical purity stability, good in vivo safety, can be used for the diagnosis of prostate cancer patients with positive prostate specific membrane antigen (PSMA) (such as PET or SPECT imaging), can also be used for prostate cancer patients with positive prostate specific membrane antigen Treatment.
  • PSMA prostate specific membrane antigen
  • the coordination between the radioactive metal and the ligand compound targeting PSMA antigen disclosed by the present invention is very stable and will not fall off in vitro and in vivo, which is very beneficial to the production, transportation, storage and diagnosis and treatment of the drug in the later stage.
  • Figure 1 shows the SPECT/CT scanning images of 177 Lu-PSMA-617 in LNCaP tumor-bearing mice and the quantitative distribution of radioactivity in tumors and various tissues.
  • Figure 2 shows the SPECT/CT scanning images of 177 Lu-PSMA-A in LNCaP tumor-bearing mice and the quantitative distribution of radioactivity in tumors and various tissues.
  • Figure 3 shows the SPECT/CT scanning images of 177 Lu-PSMA-B in LNCaP tumor-bearing mice and the quantitative distribution of radioactivity in tumors and various tissues.
  • Figure 4 shows the SPECT/CT scanning images of 177 Lu-PSMA-C in LNCaP tumor-bearing mice and the quantitative distribution of radioactivity in tumors and various tissues.
  • Figure 5 shows the SPECT/CT scanning images of 177 Lu-PSMA-E in LNCaP tumor-bearing mice and the quantitative distribution of radioactivity in tumors and various tissues.
  • Figure 6 shows the SPECT/CT scanning images of 177 Lu-PSMA-F in LNCaP tumor-bearing mice and the quantification of radioactivity distribution in tumors and various tissues.
  • Figure 7 shows the SPECT/CT scanning images of 177 Lu-PSMA-G in LNCaP tumor-bearing mice and the quantification of radioactivity distribution in tumors and various tissues.
  • Figure 8 shows the SPECT/CT scanning images of 177 Lu-PSMA-H in LNCaP tumor-bearing mice and the quantification of radioactivity distribution in tumors and various tissues.
  • Figure 9 shows the SPECT/CT scanning images of 177 Lu-PSMA-I in LNCaP tumor-bearing mice and the quantification of radioactivity distribution in tumors and various tissues.
  • Figure 10 shows the SPECT/CT scanning images of 177 Lu-PSMA-K in LNCaP tumor-bearing mice and the quantification of radioactivity distribution in tumors and various tissues.
  • Figure 11 shows the SPECT/CT scanning images of 177 Lu-PSMA-L in LNCaP tumor-bearing mice and the quantification of radioactivity distribution in tumors and various tissues.
  • Figure 12 shows the binding of177Lu-PSMA-617 and177Lu -PSMA - L to LNCaP cells.
  • Figure 13 shows the pharmacokinetics of 177 Lu-PSMA-617 and 177 Lu-PSMA-L in mice and rats.
  • Figure 14 shows the radiochemical purity stability of 177 Lu-PSMA-L in PBS buffer and 10% mouse serum.
  • Figure 15 shows the effect of 177 Lu-PSMA-L on leukocytes, hemoglobin and platelets in mouse blood.
  • Figure 16 shows the effect of 177 Lu-PSMA-L on the body weight of mice at different dosages.
  • Figure 17 shows the tumor suppressive effect of 177 Lu-PSMA-617 and 177 Lu-PSMA-L on LNCaP tumor-bearing mice and the changes in the body weight of the animals during the treatment.
  • Figure 18 shows the radioactivity at the tumor and the quantitative value of the radioactivity at the tumor during the process of 177 Lu-PSMA-617 and 177 Lu-PSMA-L inhibiting the tumor of LNCaP tumor-bearing mice.
  • Figure 19 is a liquid chromatogram of compound PSMA-L.
  • Figure 20 is the mass spectrum of compound PSMA-L.
  • Fig. 21 is the nuclear magnetic spectrum of compound PSMA-L, 1 H NMR (600MHz, dmso).
  • Figure 22 is the nuclear magnetic spectrum of compound PSMA-H, 1 H NMR (600MHz, dmso).
  • the invention discloses a compound of formula (I), or a salt, an ester or a solvate of the compound, or a pharmaceutically acceptable salt or a solvate thereof; the compound of formula (I) is as follows:
  • Raw material of the present invention is all existing products, and part is expressed as follows:
  • the above reagents were all purchased from conventional commercial channels, and the purity was chemically pure (>99.5%).
  • the animal experiments used BALB/c mice, male, weighing 18-20g; SD rats, male, weighing 180-200g, were randomly divided into groups, and tumor-bearing mice were routinely modeled, which met the requirements of routine animal experiments.
  • the crude product is purified by reverse-phase high-performance liquid chromatography, the chemical structure information of the product is characterized by MALDI-TOF mass spectrometry, and the purity is determined by analytical high-performance liquid chromatography (Agela C18 4.6x250mm, flow rate 1 ml per minute) give.
  • Step (1) Weigh 1 g of Fmoc-Lys(Dde)-Wang resin (1 eq) as an insoluble solid phase carrier and put it into a reactor, and swell it with 30 mL of DCM for 1 h. The liquid in the reactor was filtered off with suction, and 30 mL TEMP/DMF (30%, ie volume ratio 3:10) was added to the resin, and reacted for 20 min to remove the Fmoc protecting group of the amino group.
  • the liquid in the reactor was filtered off with suction, washed 6 times alternately with 30mL DMF and 30mL DCM, and then 8eq Urea(DSC) and 16eq DIEA were added to react for 120min to form Urea(DSC)-Lys(Dde)-Wang resin. Filter out the liquid in the reactor, wash with 30mL DMF and 30mL DCM alternately for 6 times, then add 8eq H-Glu(OtBu) 2 HCl and 16eq DIEA to react with Urea(DSC)-Lys(Dde)-Wang resin for 24h , forming Glu(OtBu) 2 -Urea-Lys(Dde)-Wang resin.
  • the liquid in the reactor was filtered off with suction, washed alternately with 30mL DMF and 30mL DCM for 6 times, added 30mL 3% hydrazine/DMF (volume ratio) solution, and reacted for 20min to remove the Dde protecting group of Lys side chain amino group.
  • the liquid in the reactor was filtered off with suction, washed alternately with 30mL DMF and 30mL DCM for 6 times, and then added with 8eq Fmoc-2-Nal-OH, 8eq HOBT, and 8eq DIC to react for 2h to obtain a peptide chain.
  • the liquid in the reactor was filtered off with suction, washed alternately with 30mL DMF and 30mL DCM for 6 times, then added 30mL TEMP/DMF (30%), and reacted for 20min to remove the Fmoc protecting group of Fmoc-2-Nal-OH.
  • the liquid in the reactor was filtered off by suction, washed alternately with 30mL DMF and 30mL DCM 6 times, and 8eq trans-4-(Fmoc-aminomethyl)cyclohexanecarboxylic acid (X6), 8eq HOBT and 8eq DIC were added to the resin, After reacting for 2 hours, the peptide chain Glu(OtBu) 2 -Urea-Lys[(2-Nal)-X6-Fmoc]-Wang resin was obtained.
  • Step (2) Wash the peptide chain Glu(OtBu) 2 -Urea-Lys ⁇ (2-Nal)-X6- ⁇ Dde-Lys(Fmoc)] ⁇ -Wang resin alternately with 30mL DMF and 30mL DCM for 6 times, then add 30 mL of 30% TEMP/DMF (volume ratio), reacted for 20 min, and removed the Fmoc protecting group.
  • the liquid in the reactor was filtered off with suction, washed alternately with 30mL DMF and 30mL DCM for 6 times, then added 8eq DOTA, 8eq HOBT, 8eq DIC, and reacted for 4h to obtain the peptide chain Glu(OtBu) 2 -Urea-Lys ⁇ (2- Nal)-X6-[Dde-Lys(DOTA)] ⁇ -Wang resin.
  • the liquid in the reactor was filtered off by suction, washed alternately with 30mL DMF and 30mL DCM for 6 times, and 30mL of 3% hydrazine/DMF (volume ratio) solution was added to react for 20min to remove the Dde protecting group.
  • the liquid in the reactor was filtered off by suction, washed alternately with 30mL DMF and 30mL DCM for 6 times, then 8eq amino acid raw material R, 8eq HOBT, and 8eq DIC were added to react for 2h to obtain the peptide chain Glu(OtBu) 2 -Urea-Lys[(2 -Nal)-X6-Lys(DOTA)-R].
  • the liquid in the reactor was filtered off with suction, washed alternately with 30 mL DMF and 30 mL DCM for 6 times, then 30 mL TEMP/DMF (30%) was added, and reacted for 20 min to remove the Fmoc protecting group of R.
  • the liquid in the reactor was filtered off with suction, washed alternately with 30mL DMF and 30mL DCM for 6 times, then 8eq p-methoxybenzenebutyric acid (X8), 8eq HOBT, and 8eq DIC were added, and reacted for 2h to obtain a peptide chain.
  • the liquid in the reactor was filtered off by suction, and washed alternately with 30mL DMF and 30mL DCM for 6 times.
  • the product is compound PSMA-A with a molecular weight of 1502.78;
  • the product is PSMA-B with a molecular weight of 1483.73;
  • the product is PSMA-C with a molecular weight of 1474.76;
  • the product is PSMA-D with a molecular weight of 1433.65;
  • the product is PSMA-E with a molecular weight of 1474.2.
  • Step (1) Weigh 1 g of Fmoc-Lys(Dde)-Wang resin (1 eq) as an insoluble solid phase carrier and put it into a reactor, and swell it with 30 mL of DCM for 1 h. The liquid in the reactor was filtered off with suction, and 30 mL TEMP/DMF (30%, ie volume ratio 3:10) was added to the resin, and reacted for 20 min to remove the Fmoc protecting group of the amino group.
  • the liquid in the reactor was filtered off with suction, washed 6 times alternately with 30mL DMF and 30mL DCM, and then 8eq Urea(DSC) and 16eq DIEA were added to react for 120min to form Urea(DSC)-Lys(Dde)-Wang resin. Filter out the liquid in the reactor, wash with 30mL DMF and 30mL DCM alternately for 6 times, then add 8eq H-Glu(OtBu) 2 HCl and 16eq DIEA to react with Urea(DSC)-Lys(Dde)-Wang resin for 24h , forming Glu(OtBu) 2 -Urea-Lys(Dde)-Wang resin.
  • the liquid in the reactor was filtered off with suction, washed alternately with 30mL DMF and 30mL DCM for 6 times, added 30mL 3% hydrazine/DMF (volume ratio) solution, and reacted for 20min to remove the Dde protecting group of Lys side chain amino group.
  • the liquid in the reactor was filtered off with suction, washed alternately with 30mL DMF and 30mL DCM for 6 times, and then added with 8eq Fmoc-2-Nal-OH, 8eq HOBT, and 8eq DIC to react for 2h to obtain a peptide chain.
  • the liquid in the reactor was filtered off with suction, washed alternately with 30mL DMF and 30mL DCM for 6 times, then added 30mL TEMP/DMF (30%), and reacted for 20min to remove the Fmoc protecting group of Fmoc-2-Nal-OH.
  • the liquid in the reactor was filtered off by suction, washed alternately with 30mL DMF and 30mL DCM 6 times, and 8eq trans-4-(Fmoc-aminomethyl)cyclohexanecarboxylic acid (X6), 8eq HOBT and 8eq DIC were added to the resin, After reacting for 2h, the peptide chain Glu(OtBu) 2 -Urea-Lys[(2-Nal)-X6-Fmoc]-Wang resin was obtained.
  • Step (2) Wash the peptide chain Glu(OtBu) 2 -Urea-Lys ⁇ (2-Nal)-X6- ⁇ Dde-Lys(Fmoc)] ⁇ -Wang resin alternately with 30mL DMF and 30mL DCM for 6 times, then add 30 mL of 30% TEMP/DMF (volume ratio), reacted for 20 min, and removed the Fmoc protecting group of Dde-Lys (Fmoc).
  • the liquid in the reactor was filtered off with suction, washed alternately with 30mL DMF and 30mL DCM for 6 times, then added 8eq DOTA, 8eq HOBT, 8eq DIC, and reacted for 4h to obtain the peptide chain Glu(OtBu) 2 -Urea-Lys ⁇ (2- Nal)-X6-[Dde-Lys(DOTA)] ⁇ -Wang resin.
  • the liquid in the reactor was filtered off by suction, washed alternately with 30mL DMF and 30mL DCM for 6 times, and 30mL of 3% hydrazine/DMF (volume ratio) solution was added to react for 20min to remove the Dde protecting group.
  • the liquid in the reactor was filtered off by suction, washed alternately with 30mL DMF and 30mL DCM for 6 times, and then added 8eq R 1 precursor compound, 8eq HOBT, 8eq DIC to react for 2h to obtain the peptide chain Glu(OtBu) 2 -Urea-Lys[ (2-Nal)-X6-Lys(DOTA)-R 1 ].
  • the product is PSMA-F with a molecular weight of 1439.51 and a purity of 93.65%;
  • the product is PSMA-G with a molecular weight of 1411.88 and a purity of 95.85%;
  • the product is PSMA-H with a molecular weight of 1383.22 and a purity of 97.32%;
  • the product is PSMA-I with a molecular weight of 1304.56 and a purity of 96.83%;
  • Step (1) Weigh 1 g of Fmoc-Lys(Dde)-Wang resin (1 eq) as an insoluble solid phase carrier and put it into a reactor, and swell it with 30 mL of DCM for 1 h. The liquid in the reactor was filtered off with suction, and 30 mL TEMP/DMF (30%, ie volume ratio 3:10) was added to the resin, and reacted for 20 min to remove the Fmoc protecting group of the amino group.
  • the liquid in the reactor was filtered off with suction, washed 6 times alternately with 30mL DMF and 30mL DCM, and then 8eq Urea(DSC) and 16eq DIEA were added to react for 120min to form Urea(DSC)-Lys(Dde)-Wang resin. Filter out the liquid in the reactor, wash with 30mL DMF and 30mL DCM alternately for 6 times, then add 8eq H-Glu(OtBu) 2 HCl and 16eq DIEA to react with Urea(DSC)-Lys(Dde)-Wang resin for 24h Glu(OtBu) 2 -Urea-Lys(Dde)-Wang resin was formed.
  • the liquid in the reactor was filtered off with suction, washed alternately with 30mL DMF and 30mL DCM for 6 times, added 30mL 3% hydrazine/DMF (volume ratio) solution, and reacted for 20min to remove the Dde protecting group of Lys side chain amino group. Filter out the liquid in the reactor, wash with 30mL DMF and 30mL DCM alternately for 6 times, then add 8eq Fmoc-2-Nal-OH, 8eq HOBT, 8eq DIC to react for 2h to obtain the peptide chain Glu(OtBu) 2 -Urea- Lys(2-Nal)-Wang resin.
  • the liquid in the reactor was filtered off with suction, washed alternately with 30mL DMF and 30mL DCM for 6 times, then 30mL TEMP/DMF (30%) was added, and reacted for 20min to remove the Fmoc protecting group of X9. Filter out the liquid in the reactor, wash it alternately with 30mL DMF and 30mL DCM for 6 times, then add 8eq Dde-Lys(Fmoc)-OH, 8eq HOBT and 8eq DIC, and react for 4h to obtain the peptide chain Glu(OtBu) 2 -Urea -Lys ⁇ (2-Nal)-X9- ⁇ Dde-Lys(Fmoc)] ⁇ -Wang resin.
  • Step (2) Wash the peptide chain Glu(OtBu) 2 -Urea-Lys ⁇ (2-Nal)-X9- ⁇ Dde-Lys(Fmoc)] ⁇ -Wang resin alternately with 30mL DMF and 30mL DCM for 6 times, then add 30 mL of 30% TEMP/DMF (volume ratio), reacted for 20 min, and removed the Fmoc protecting group.
  • the liquid in the reactor was filtered off with suction, washed alternately with 30mL DMF and 30mL DCM for 6 times, then added 8eq DOTA, 8eq HOBT, 8eq DIC, and reacted for 4h to obtain the peptide chain Glu(OtBu) 2 -Urea-Lys ⁇ (2- Nal)-X9-[Dde-Lys(DOTA)] ⁇ -Wang resin.
  • the liquid in the reactor was filtered off by suction, washed alternately with 30mL DMF and 30mL DCM for 6 times, and 30mL of 3% hydrazine/DMF (volume ratio) solution was added to react for 20min to remove the Dde protecting group.
  • the liquid in the reactor was filtered off by suction, washed alternately with 30mL DMF and 30mL DCM for 6 times, and then added 8eq R 1 precursor compound, 8eq HOBT, 8eq DIC to react for 2h to obtain the peptide chain Glu(OtBu) 2 -Urea-Lys[ (2-Nal)-X9-Lys(DOTA)-R 1 ].
  • the product is PSMA-J with a molecular weight of 1309.29 and a purity of 96.00%;
  • the product is PSMA-L with a molecular weight of 1536.37 and a purity of 96.13%.
  • X56 has the following structure:
  • the precursor (ligand compound targeting PSMA antigen) was diluted to 100 ng/ ⁇ L with 0.5M sodium acetate buffer solution at pH 4.5, which was the precursor solution.
  • 0.5M sodium acetate buffer solution at pH 4.5
  • the precursor solution Take 37MBq (1mCi) 177 LuCl 3 solution (about 50pmol), add 15 times the equivalent of the precursor solution, make up to 50 ⁇ L of sodium acetate buffer, and react at 95°C and 800rpm for 30min to obtain the precursor compound labeled with 177Lu . form exists.
  • Use 1% EDTA as developing agent to perform TLC purity test if the purity is greater than 95%, no subsequent treatment is required. If the purity is less than 95%, follow-up purification is required: use a C18 column for desalting to remove uncoordinated 177 Lu.
  • the 177 Lu-labeled precursor compound was diluted to 7.4MBq (200 ⁇ Ci)/200 ⁇ L with physiological saline, and about 7.4MBq (200 ⁇ Ci) of the drug was administered to each tumor-bearing mouse by tail vein injection.
  • the mice were anesthetized continuously with diflurane, and the mice were lying prone on the examination bed for SPECT/CT scanning.
  • the acquisition methods were static 12min SPECT and medium-resolution whole-body CT.
  • the animal body weight, injection dose, injection time, and residual dose were recorded according to the record sheet, and the time for measuring the injected dose and the time for measuring the residual dose were recorded respectively.
  • the PMOD software analyzes and outlines various organs and tissues, quantifies the distribution of drugs, saves the images and data, and further statistically analyzes the data.
  • Figures 1 to 11 present 177 Lu labeled compounds PSMA-617, PSMA-A, PSMA-B, PSMA-C, PSMA-E, PSMA-F, PSMA-G, PSMA-H, PSMA-I, PSMA- SPECT/CT scans of K and PSMA-L and quantitative values of drug distribution in each tissue.
  • PSMA-D is the predicted value
  • PSMA-L can greatly increase the drug exposure of LNCaP tumors while maintaining low drug exposure in normal tissues. It is a compound with more potential than PSMA-617.
  • PSMA-positive cells LNCaP were expanded and cultured, and seeded in a 24-well plate at a density of 10 5 cells/well after digestion. After the cells adhered to the wall, the medium was aspirated, and the 177 Lu-labeled compound containing gradient radioactive counting and the positive control PSMA-617 were added. Among them, the highest concentration is 5 ⁇ 10 6 cpm/0.5mL, and it is serially diluted according to the dilution factor of 1/3. After adding the labeled compound, incubate at 37°C for 1 h, aspirate the medium, wash the cells three times with PBS, and add 0.2 mL of 1M NaOH solution to lyse the cells. The lysate is drawn into the immunotube, and the gamma counter detects the radioactive count of each sample tube. Data analysis, comparing the binding ability of the candidate compound and the positive control compound PSMA-617 and PSMA positive cells.
  • Figure 12 presents the binding of 177 Lu-PSMA-617 and 177 Lu-PSMA-L to LNCaP cells. It can be seen that the binding ability of 177 Lu-PSMA-L to LNCaP cells is stronger than that of 177 Lu-PSMA-617, indicating that 177 Lu-PSMA-L Lu-PSMA-L has higher antigen affinity than 177 Lu-PSMA-617.
  • mice Male, weighing 18-20 g. SD rats, male, weighing 180-200g. Randomly grouped, 3 in each group.
  • 1.85 MBq (50 ⁇ Ci) of the compound labeled with 177 Lu was injected into the tail vein respectively.
  • 20 ⁇ L of orbital blood was collected and put into a pre-weighed centrifuge tube. Measure the radioactive count of the blood in the centrifuge tube and the weight of the centrifuge tube with blood, and calculate the percentage of the radioactive count in the blood per unit weight to the dose.
  • Draw a drug-time chart to calculate the blood exposure of the compound of the present invention and the positive control compound PSMA-617.
  • Figure 13 presents the pharmacokinetics of 177 Lu-PSMA-617 and 177 Lu-PSMA-L in mice and rats. It can be seen that the metabolic rate of 177 Lu-PSMA-L in mice and rats is slower than that of 177 Lu-PSMA-617, and its blood half-life is longer and drug exposure is higher. Moreover, this higher blood drug concentration is only maintained for 1 hour after administration, after which 177 Lu-PSMA-L is basically cleared out of the blood, which can increase the concentration and time of the drug and tumor without increasing the effect on normal cells. Tissue toxicity.
  • Figure 14 presents the radiochemical purity stability of 177 Lu-PSMA-L in PBS buffer and 10% mouse serum. It can be seen that the radiochemical purity of 177 Lu-PSMA-L is maintained at 100% within 96 hours in PBS buffer and 10% mouse serum, which is very stable. Combined with the scanning results, it shows that the coordination of 177 Lu and PSMA-L is very stable and will not fall off in vitro and in vivo, which is very beneficial to the production, transportation, storage, diagnosis and treatment of drugs in the later stage.
  • mice were randomly divided into groups according to body weight, with 5 mice in each group. Each mouse was given 177 Lu-labeled compound 7.4 MBq (200 ⁇ Ci) or 14.8 MBq (400 ⁇ Ci) by tail vein injection, and the control group was given PBS. After 7 days, the animal was anesthetized, and more than 1 mL of blood was collected and placed in an anticoagulant tube, and the content of white blood cells, hemoglobin and platelets in the blood was detected by a blood biochemical analyzer dedicated to mice. Compare the control group and the administration group to understand the degree of drug suppression on bone marrow.
  • Figure 15 presents the effect of 177 Lu-PSMA-L on leukocytes, hemoglobin and platelets in mouse blood. It can be seen that under the doses of 7.4MBq (200 ⁇ Ci) and 14.8MBq (400 ⁇ Ci), the contents of white blood cells, hemoglobin and platelets in the blood of the mice were not significantly different from those of the control PBS group, indicating that the blood toxicity of 177 Lu-PSMA-L Very low, weak bone marrow suppression. This is related to the pharmacokinetic properties of 177Lu -PSMA-L. 177Lu -PSMA-0057 only maintains a high blood concentration for 1 hour after administration, and then quickly clears it from the blood, thereby reducing the effect on normal cells in the blood. s damage.
  • mice were randomly divided into groups according to body weight, with 5 mice in each group. Each mouse was given 14.8 MBq (400 ⁇ Ci) or 29.6 MBq (800 ⁇ Ci) of the 177 Lu-labeled compound through tail vein injection, and the control group was given solvent. The body weight of the mice was measured every 3 days after administration, and the death of the mice was recorded. Compare the control group and the treatment group to understand the maximum tolerated dose of the drug for the mice.
  • Figure 16 presents the effect of 177 Lu-PSMA-L on the body weight of mice at different dosages. It can be seen that under the dosage of 14.8MBq (400 ⁇ Ci) or 29.6MBq (800 ⁇ Ci), the body weight of the mice did not decrease significantly, indicating that the mice have a very high dose tolerance to 177Lu -PSMA-L, 177Lu -PSMA -L is good for security.
  • the PSMA-positive LNCaP cells were expanded, and the cells were collected and inoculated subcutaneously in mice at an amount of 1 ⁇ 10 7 /mouse.
  • the tumor grows to 200-400 mm 3 , they are randomly divided into groups according to the tumor size, 3-4 animals in each group, and given 400 ⁇ Ci of the compound of the present invention labeled with 177 Lu or the positive control compound PSMA-617 labeled with 177 Lu through tail vein injection.
  • the tumor size and body weight of the mice were measured every 3 days after administration, and the death of the mice was recorded. Comparing the control group and each drug administration group, understand the inhibition of different drugs on LNCaP tumors.
  • SPECT/CT scanning was performed on the administration group to understand the exposure of different drugs at the tumor during the treatment.
  • Figure 17 presents the tumor suppressive effect of 177 Lu-PSMA-617 and 177 Lu-PSMA-L on LNCaP tumor-bearing mice and the changes in animal body weight during treatment. It can be seen that 177 Lu-PSMA-L has a stronger tumor inhibitory effect on LNCaP tumor-bearing mice than 177 Lu-PSMA-617. During the treatment, there was no significant difference in the body weight of the animals in each group, indicating that the mice could tolerate both 14.8 MBq (400 ⁇ Ci) of 177 Lu-PSMA-617 and 14.8 MBq (400 ⁇ Ci) of 177 Lu-PSMA-L.
  • Figure 18 presents the radioactivity at the tumor and its quantitative value during the process of 177 Lu-PSMA-617 and 177 Lu-PSMA-L inhibiting the tumor of LNCaP tumor-bearing mice. It can be seen that the exposure of 177 Lu-PSMA-L at the tumor site on the 6th day after administration is higher than that of 177 Lu-PSMA-617, which is also consistent with the drug's effect on tumor inhibition.
  • Fig. 19 is the liquid phase chromatogram of above-mentioned compound PSMA-L;
  • Fig. 20 is the mass spectrogram of above-mentioned compound PSMA-L;
  • Figure 21 is the nuclear magnetic spectrum of the above-mentioned compound PSMA-L, 1 H NMR (600MHz, dmso);
  • Fig. 22 is the nuclear magnetic spectrum, 1 H NMR (600MHz, dmso) of the above-mentioned compound PSMA-H.
  • Prostate cancer is a cancer that occurs in the prostate, a small, walnut-shaped gland in the pelvis of men.
  • CRPC castration-resistant prostate cancer
  • tumors show signs of growth despite the use of testosterone-lowering hormone therapy.
  • Radioligand therapy combines a targeting compound that binds to markers expressed by the tumor with a radioactive isotope that causes DNA damage and inhibits tumor growth and replication. This treatment approach enables targeted delivery of radiation to tumors while limiting damage to surrounding normal tissue.
  • Lu-PSMA-617 is a PSMA-targeted radioligand therapy for the treatment of metastatic castration-resistant prostate cancer (mCRPC), which has entered clinical research.
  • the chelate composed of the ligand compound of the present invention and radioactive metals has lower normal tissue toxicity, higher exposure to tumors, longer half-life in blood, better antigen affinity and tumor inhibitory effect. Better, moreover, it has stable radiochemical purity and good safety in vivo, and has high application value in the diagnosis and treatment of prostate cancer.

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WO2026002208A1 (zh) * 2024-06-28 2026-01-02 思路迪生物医药(上海)有限公司 前列腺特异性膜抗原小分子抑制剂及其放射性核素配合物的制备及应用

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