CN115260155B - Glutamic acid-urea derivative containing triazole ring and hydrazinonigulamido and application thereof - Google Patents
Glutamic acid-urea derivative containing triazole ring and hydrazinonigulamido and application thereof Download PDFInfo
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- 125000001425 triazolyl group Chemical group 0.000 title claims abstract description 20
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 34
- 238000002360 preparation method Methods 0.000 claims abstract description 26
- 230000002285 radioactive effect Effects 0.000 claims abstract description 17
- 206010060862 Prostate cancer Diseases 0.000 claims abstract description 12
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims abstract description 12
- 238000003745 diagnosis Methods 0.000 claims abstract description 9
- SEQKRHFRPICQDD-UHFFFAOYSA-N N-tris(hydroxymethyl)methylglycine Chemical compound OCC(CO)(CO)[NH2+]CC([O-])=O SEQKRHFRPICQDD-UHFFFAOYSA-N 0.000 claims description 92
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 20
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 claims description 20
- IFQUWYZCAGRUJN-UHFFFAOYSA-N ethylenediaminediacetic acid Chemical compound OC(=O)CNCCNCC(O)=O IFQUWYZCAGRUJN-UHFFFAOYSA-N 0.000 claims description 10
- 229960003512 nicotinic acid Drugs 0.000 claims description 10
- 235000001968 nicotinic acid Nutrition 0.000 claims description 10
- 239000011664 nicotinic acid Substances 0.000 claims description 10
- DVECLMOWYVDJRM-UHFFFAOYSA-N pyridine-3-sulfonic acid Chemical compound OS(=O)(=O)C1=CC=CN=C1 DVECLMOWYVDJRM-UHFFFAOYSA-N 0.000 claims description 10
- PAEXAIBDCHBNDC-UHFFFAOYSA-N 2-pyridin-4-ylacetic acid Chemical compound OC(=O)CC1=CC=NC=C1 PAEXAIBDCHBNDC-UHFFFAOYSA-N 0.000 claims description 5
- MPFLRYZEEAQMLQ-UHFFFAOYSA-N dinicotinic acid Chemical compound OC(=O)C1=CN=CC(C(O)=O)=C1 MPFLRYZEEAQMLQ-UHFFFAOYSA-N 0.000 claims description 5
- VYFPSYVVFFFYBF-UHFFFAOYSA-N sodium;triphenylphosphane Chemical compound [Na].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 VYFPSYVVFFFYBF-UHFFFAOYSA-N 0.000 claims description 5
- 239000012216 imaging agent Substances 0.000 claims description 3
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- 102100041003 Glutamate carboxypeptidase 2 Human genes 0.000 abstract description 20
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- 239000007997 Tricine buffer Substances 0.000 description 38
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- 238000009835 boiling Methods 0.000 description 8
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- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 241000699660 Mus musculus Species 0.000 description 4
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
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- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- UYRPRYSDOVYCOU-UHFFFAOYSA-N 2-diphenylphosphanylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UYRPRYSDOVYCOU-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
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- 230000009286 beneficial effect Effects 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 238000012925 biological evaluation Methods 0.000 description 1
- FATUQANACHZLRT-KMRXSBRUSA-L calcium glucoheptonate Chemical compound [Ca+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O FATUQANACHZLRT-KMRXSBRUSA-L 0.000 description 1
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- TVMXDCGIABBOFY-UHFFFAOYSA-N n-Octanol Natural products CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 238000000163 radioactive labelling Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- 239000011755 sodium-L-ascorbate Substances 0.000 description 1
- 235000019187 sodium-L-ascorbate Nutrition 0.000 description 1
- NTUROZDXWLPVHB-UHFFFAOYSA-M sodium;3-diphenylphosphanylbenzenesulfonate Chemical compound [Na+].[O-]S(=O)(=O)C1=CC=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NTUROZDXWLPVHB-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Classifications
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- 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
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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
- A61K51/041—Heterocyclic compounds
- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
- A61K51/0455—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
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- Proteomics, Peptides & Aminoacids (AREA)
- Optics & Photonics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The invention relates to the technical fields of radiopharmaceuticals and clinical nuclear medicine, in particular to a glutamic acid-urea derivative containing triazole rings and hydrazino-ninicolamide groups and application thereof. The radioactive preparation obtained by labeling the glutamic acid-urea derivative containing triazole ring and hydrazinonigulamido with radionuclide has high uptake in tumors, has good tumor/non-target ratio, is specifically combined with prostate specific membrane antigen, and can be used as a novel tumor radioactive medicament with popularization and application values for prostate cancer diagnosis.
Description
Technical Field
The invention relates to the fields of radiopharmaceuticals and nuclear medicine, in particular to a glutamic acid-urea derivative containing triazole rings and hydrazinonigulamido and application thereof.
Background
Prostate cancer is one of the most common malignant forms of men, with the second leading cancer in men worldwide. With the aging of population and the change of life habits, the prevalence of prostate cancer in China is continuously increasing in recent years. Metastasis, recurrence and castration resistance are the leading causes of death in prostate cancer patients. The prognostic effect is closely related to the stage of the tumor, so early diagnosis of prostate cancer and detection of recurrent lesions are critical to optimizing treatment. The Prostate Specific Membrane Antigen (PSMA) is highly specifically expressed in prostate cancer cells and is positively correlated with the degree of tumor deterioration and cancer stage, so that the PSMA has important research value in the fields of prostate cancer molecular image diagnosis and targeted therapy. In particular, the radionuclide marked PSMA small molecule inhibitor as a targeting molecule has shown obvious advantages and wide clinical prospect in the diagnosis and treatment of the prostate cancer.
Recent studies have shown that the structure is based on the glutamic acid-urea (Glu-urea) skeletonThe small molecule compounds exhibit high affinity and specificity for PSMA on the surface of prostate cancer cells. The radionuclide marked PSMA inhibitor containing glutamic acid-urea skeleton molecules can accurately locate the prostatic cancer lesion area and distinguish the cancer exacerbation degree, and becomes a research hot spot of international radiopharmaceuticals. However, because PSMA is highly expressed in the kidneys, most radionuclides label PSMA inhibitors containing a glutamate-urea backbone molecule with high renal uptake and no negligible radiation damage to the patient's kidneys. 99m Tc is taken as SPECT imaging nuclide with the most wide clinical application, has proper nuclide property and can be obtained by 99 Mo/ 99m The Tc generator is leached and obtained, and 99m tc marked medicine is convenient for medicine box production and easy for clinical popularization and use, so that a novel PSMA-targeted prostate cancer specific diagnosis is developed 99m Tc radiopharmaceuticals have important practical significance.
It has been reported that the introduction of triazole rings reduces the uptake of these inhibitors by the kidneys and thus reduces the radiation damage to the kidneys of patients (Ying Chen, ala List, samit Chatterjee, et al. [ et al ] 18 F]Fluoroethyl triazole substituted PSMA inhibitor exhibiting rapid normal organ clearance. Bioconjugate chem.2016,27, 1655-1662.). Hydrazinony Gu Xianan (HYNIC) is 99m A bifunctional linker commonly used in Tc-labeled radiopharmaceutical studies. Based on the background, the invention synthesizes the glutamic acid-urea derivative containing triazole ring and hydrazinonigulamido, and carries out the synthesis in the presence of other co-ligands 99m Tc marks to search for novel tumor radiopharmaceuticals specifically targeting PSMA, and has important scientific significance and wide clinical application prospect.
Disclosure of Invention
The invention provides a glutamic acid-urea derivative containing triazole ring and hydrazino-ninicoamide, which has the advantages of good stability, simple preparation, high tumor uptake and good target/non-target ratio, is used for prostate tumor diagnosis and treatment after radiolabeling, and has important scientific significance and application prospect in the tumor diagnosis and treatment field.
Specifically, the invention provides the following technical scheme:
a glutamic acid-urea derivative containing triazole ring and hydrazinonigulamido, wherein the structural formula is (I):
wherein m represents an integer of 1 or more and n represents an integer of 1 or more.
Preferably, in the above glutamic acid-urea derivative containing a triazole ring and a hydrazinium amide group, when m=2, n=3, the structural formula of the glutamic acid-urea derivative containing a triazole ring and a hydrazinium amide group is one of the following (II), and the corresponding derivative is prepared therefrom 99m Tc complex is combined with PSMA specifically, has very low uptake in non-target organs, has high tumor uptake value, tumor/blood and tumor/muscle ratio, and can obtain very good effect on prostate tumor diagnosis and treatment.
The present invention also provides a radioactive preparation comprising the above-mentioned glutamic acid-urea derivative containing a triazole ring and a hydrazinonigulamido group, which is labeled with a radionuclide.
Preferably, in the above-mentioned radioactive preparation, the radionuclide moiety is a metal radionuclide.
Preferably, in the above radioactive preparation, the metal radionuclide is 99m Tc、 99 Tc、 94m Tc、 94 Tc、 52 Mn、 186 Re or 188 Re。
Most preferably, in the above radioactive preparation, the radionuclide is 99m Tc, the structural formula of the radioactive preparation is (III):
wherein: m represents 1 or an integer of 1 or more, and n represents1 or an integer of 1 or more, L is 99m Tc formation stabilization 99m The co-ligand components in Tc complexes are N-tris (hydroxymethyl) methylglycine (Tricine) and ethylenediamine-N, N' -diacetic acid (EDDA), N-tris (hydroxymethyl) methylglycine (Tricine) and triphenylphosphine sodium tri-m-sulfonate (TPPTS), N-tris (hydroxymethyl) methylglycine (Tricine) and diphenylphosphinophenone-3-sulfonate (TPPMS), N-tris (hydroxymethyl) methylglycine (Tricine) and 2- (pyridin-4-yl) acetic acid (PA), N-tris (hydroxymethyl) methylglycine (Tricine) and nicotinic acid (NIC), N-tris (hydroxymethyl) methylglycine (Tricine) and isonicotinic acid (ISONIC), N-tris (hydroxymethyl) methylglycine (Tricine) and 3, 5-pyridinedicarboxylic acid (PDA), N-tris (hydroxymethyl) methylglycine (Tricine) and 3-pyridinesulfonic acid (PSA).
The invention also provides application of the radioactive preparation in the field of prostate tumor diagnosis and/or prostate tumor treatment. The invention has the beneficial effects that: the invention provides a glutamic acid-urea derivative containing triazole ring and hydrazino-ninicolamide group, and a radioactive preparation obtained by labeling the glutamic acid-urea derivative with a radionuclide has high uptake in prostate tumor, and meanwhile, the tumor/non-target ratio is good, so that the glutamic acid-urea derivative is a novel tumor radioactive drug with popularization significance.
Detailed Description
The invention provides a glutamic acid-urea derivative containing triazole ring and hydrazino-nigulamido and application thereof, in a preferred embodiment, the invention provides a structural general formula 99m Radioactive preparation of Tc-GTH-L:
wherein: m represents 2, n represents 3, L is 99m Tc formation stabilization 99m The co-ligand components of Tc complex are N-tris (hydroxymethyl) methylglycine (Tricine) and ethylenediamine-N, N' -diacetic acid (EDDA), N-tris (hydroxymethyl) methylglycine (Tricine) and triphenylphosphine sodium tri-m-sulfonate (TPPTS), N-tris (hydroxymethyl) methylglycine (Tricine) and diphenylphosphinobenzene-3-sulfonate sodium (TPPMS), N-tris (hydroxymethyl) methylglycine (Tricine) and 2- (pyridin-4-yl) ethyl acetateAcid (PA), N-tris (hydroxymethyl) methylglycine (Tricine) and nicotinic acid (NIC), N-tris (hydroxymethyl) methylglycine (Tricine) and isonicotinic acid (ISONIC), N-tris (hydroxymethyl) methylglycine (Tricine) and 3, 5-pyridinedicarboxylic acid (PDA), N-tris (hydroxymethyl) methylglycine (Tricine) and 3-pyridinesulfonic acid (PSA).
The preparation method comprises the following steps:
a. synthesis of ligand GTH
25mL of a three port round bottom flask was taken at N 2 Adding a proper amount of CuSO under protection 4 ·5H 2 After the O and the L-sodium ascorbate aqueous solution are stirred uniformly, adding the DMF solution of the compound 1 and the DMF solution of the compound 2, reacting for 24 hours at room temperature, removing the solvent by rotary evaporation, and purifying the crude product by column chromatography to obtain the compound 3. And (3) dissolving the compound 3 in a mixed solution of dichloromethane and trifluoroacetic acid (the volume ratio is 3:1), stirring at room temperature for 5h, and removing the solvent by rotary evaporation to obtain the ligand GTH.
The specific synthetic route is as follows:
b. 99m preparation of Tc-GTH-L Complex
Dissolving GTH and Tricine in physiological saline, adding EDDA or TPPTS or TPPMS or PA or NIC or ISONIC or PDA or PSA, adding SnCl 2 ·2H 2 O, adjusting the pH of the solution to about 5.0-7.0, and then adding freshly leached Na thereto 99m TcO 4 The solution is reacted for 20 to 30 minutes at the temperature of 100 ℃ to obtain the product 99m Tc-GTH-L complex.
Prepared by the above method 99m The Tc-GTH-L complex has radiochemical purity higher than 90%, is hydrophilic and has excellent in vitro stability. 99m Tc-GTH-L complex has specific uptake in kidney and can be obviously inhibited by inhibitor, uptake and tumor/non-target ratio are better at tumor site of tumor-bearing mice, tumor uptake can be obviously inhibited by inhibitor, and the novel targeted PSMA tumor imaging agent is worth popularizing and applying.
The following examples are illustrative of the invention and are not intended to limit the scope of the invention. The specific techniques or conditions are not identified in the examples and are described in the literature in this field or are carried out in accordance with the product specifications.
The invention is illustrated by the following examples: the method comprises the following steps of 99m Tc-marked glutamic acid-urea derivative containing triazole ring and hydrazino-nigulamido, which can be used for SPECT/CT imaging of targeted PSMA and has a structural general formula of 99m Tc-GTH-L。
Wherein m represents 2, and n represents 3.L is 99m Tc formation stabilization 99m The co-ligand components in Tc complex are N-tris (hydroxymethyl) methylglycine (Tricine) and ethylenediamine-N, N' -diacetic acid (EDDA), N-tris (hydroxymethyl) methylglycine (Tricine) and triphenylphosphine sodium tri-m-sulfonate (TPPTS), N-tris (hydroxymethyl) methylglycine (Tricine) and diphenylphosphinophenone-3-sulfonate (TPPMS), N-tris (hydroxymethyl) methylglycine (Tricine) and 2- (pyridin-4-yl) acetic acid (PA), N-tris (hydroxymethyl) methylglycine (Tricine) and nicotinic acid (NIC), N-tris (hydroxymethyl) methylglycine (Tricine) and isonicotinic acid (ISONIC), N-tris (hydroxymethyl) methylglycine (Tricine) and 3, 5-pyridinedicarboxylic acid (PDA), N-tris (hydroxymethyl) methylglycine (Tricine) and 3-pyridinesulfonic acid (PSA) and the like.
99m The preparation of Tc-GTH-L is as follows, but is not limited to the illustrated complexes:
a. synthesis of ligand GTH
25mL of a three port round bottom flask was taken at N 2 7.4mg (0.030 mmol) of CuSO are added under protection 4 ·5H 2 O and 17.7mg (0.089 mmol) of sodium L-ascorbate. After stirring well, 203.0mg (0.358 mmol) of compound 1 and 99.9mg (0.298 mmol) of compound 2 in DMF are added, the solvent is removed by rotary evaporation after reaction at room temperature for 24h, and the crude product is purified by column chromatography (dichloromethane/methanol=10:1, R f =0.4) to give compound 3 in a yield of 93.6%. Compound 3 was dissolved in a mixed solution of dichloromethane and trifluoroacetic acid (volume ratio 3:1), at room temperatureStirring for 5h, and removing the solvent by rotary evaporation to obtain the ligand GTH. 1 H-NMR(400MHz,CD 3 OD)δ(ppm):8.52(d,J＝2.2Hz,1H),8.22–8.08(m,1H),7.79(d,J＝ 11.9Hz,1H),6.96–6.88(m,1H),4.52–4.44(m,2H),4.30(dt,J＝11.0,5.5Hz,1H),4.24(dd,J＝ 8.4,4.9Hz,1H),3.41(t,J＝6.7Hz,2H),3.19–3.10(m,2H),2.97(t,J＝7.3Hz,2H),2.54(q,J＝ 7.5Hz,2H),2.42(ddd,J＝9.5,8.3,5.8Hz,2H),2.24–2.11(m,2H),1.95–1.85(m,1H),1.84– 1.76(m,1H),1.63(dt,J＝21.2,7.3Hz,1H),1.52–1.44(m,2H),1.37(d,J＝7.2Hz,3H).HR-MS (ESI)for C 26 H 39 N 10 O 9 [M+H] + :found 635.2906,calcd 635.2895.
b. 99m Preparation of Tc-GTH-EDDA Complex
Taking 10 μg ligand GTH,250 μl ethylenediamine-N, N' -diacetic acid (EDDA, 40mg/mL,0.2mol/L NaOH), 20mg N-tris (hydroxymethyl) methylglycine (Tricine), 100 μg SnCl 2 ·2H 2 O,20mg mannitol and 0.5mL PBS (0.2 mol/L, pH=6.0), 0.15mL sterile injectable water was added to dissolve, then 0.1mL Na was added 99m TcO 4 The leacheate reacts with boiling water for 20min to obtain the target complex 99m Tc-GTH-EDDA。
c. 99m Preparation of Tc-GTH-TPPTS complex
10 μg of ligand GTH,1mg of N-tris (hydroxymethyl) methylglycine (Tricine), 2mg of triphenylphosphine sodium trimetaphosphate (TPPTS) and 100 μg of SnCl are taken 2 ·2H 2 O,20mg mannitol and 0.5mL succinate buffer (0.5 mol/L, pH=5.0), 0.4mL sterile injectable water was added to dissolve, then 0.1mL Na was added 99m TcO 4 The leacheate reacts with boiling water for 30min to obtain the target complex 99m Tc-GTH-TPPTS。
d. 99m Tc-GTH-TPPMS complexIs prepared from
10. Mu.g of ligand GTH,1mg of N-tris (hydroxymethyl) methylglycine (Tricine), 2mg of diphenylphosphinobenzene-3-sodium sulfonate (TPPMS) and 30. Mu.g of SnCl are taken 2 ·2H 2 O,0.4mL succinate buffer (0.5 mol/L, pH=5.0), 0.5mL sterile water for injection was added to dissolve, followed by 0.1mL Na 99m TcO 4 The leacheate reacts with boiling water for 30min to obtain the target complex 99m Tc-GTH-TPPMS。
e. 99m Preparation of Tc-GTH-PA complexes
10 μg of ligand GTH,5mg of N-tris (hydroxymethyl) methylglycine (Tricine), 4mg of 2- (pyridin-4-yl) acetic acid (PA) and 30 μg of SnCl were taken 2 ·2H 2 O,0.4mL PBS (0.2 mol/L, pH=6.5), 0.5mL sterile water for injection was added to dissolve, then 0.1mL Na was added 99m TcO 4 The leacheate reacts with boiling water for 20min to obtain the target complex 99m Tc-GTH-PA。
f. 99m Preparation of Tc-GTH-NIC complex
10 μg ligand GTH,5mg N-tris (hydroxymethyl) methylglycine (Tricine), 2mg nicotinic acid (NIC), 30 μg SnCl were taken 2 ·2H 2 O,0.4mL succinate buffer (0.5 mol/L, pH=5.0), 0.5mL sterile water for injection was added to dissolve, followed by 0.1mL Na 99m TcO 4 The leacheate reacts with boiling water for 20min to obtain the target complex 99m Tc-GTH-NIC。
g. 99m Preparation of Tc-GTH-ISONIC complex
Taking 10 μg ligand GTH,5mg N-tris (hydroxymethyl) methylglycine (Tricine),4mg isonicotinic acid (ISONIC), 30. Mu.g SnCl 2 ·2H 2 O,0.4mL succinate buffer (0.5 mol/L, pH=5.0), 0.5mL sterile water for injection was added to dissolve, followed by 0.1mL Na 99m TcO 4 The leacheate reacts with boiling water for 20min to obtain the target complex 99m Tc-GTH-ISONIC。
h. 99m Preparation of Tc-GTH-PDA complex
10 μg of ligand GTH,5mg of N-tris (hydroxymethyl) methylglycine (Tricine), 4mg of 3, 5-pyridinedicarboxylic acid (PDA), 30 μg of SnCl were taken 2 ·2H 2 O,0.4mL succinate buffer (0.5 mol/L, pH=5.0), 0.5mL sterile water for injection was added to dissolve, followed by 0.1mL Na 99m TcO 4 The leacheate reacts with boiling water for 20min to obtain the target complex 99m Tc-GTH-PDA。
i. 99m Preparation of Tc-GTH-PSA Complex
10 μg ligand GTH,5mg N-tris (hydroxymethyl) methylglycine (Tricine), 4mg 3-pyridinesulphonic acid (PSA), 30 μg SnCl 2 ·2H 2 O,0.4mL succinate buffer (0.5 mol/L, pH=5.0), 0.5mL sterile water for injection was added to dissolve, followed by 0.1mL Na 99m TcO 4 The leacheate reacts with boiling water for 20min to obtain the target complex 99m Tc-GTH-PSA。
Experiments show that the complex 99m The performance of Tc-GTH-L is as follows:
1. identification of complexes
a. Thin Layer Chromatography (TLC) identification
The unfolding system is as follows: polyamide sheetFilm as support, ammonium acetate (1 mol/L)/methanol=2: 1 (V/V) as a developing agent, R of each radioactive component under the system f The values are shown in the following table.
TABLE 1 chromatographic results of the components of the complexes (R f Value of
The radiochemical purity of the markers as determined by the chromatographic assay described above is greater than 90%.
2. Determination of the lipid partition coefficient of the Complex
0.8mL of n-octanol and 0.7mL of phosphate buffer solution with pH=7.4 (0.025 mol/L) are taken in a 2mL centrifugal test tube, 0.1mL of complex solution is added into the centrifugal test tube, a plug is covered, vortex is fully mixed, and the mixture is centrifuged for 5min (3000 r/min). 0.1mL of each of the organic and aqueous phases was removed, the radioactivity count of the two phases was determined, and the log P value (p=radioactivity of the organic phase/radioactivity of the aqueous phase) was calculated. The results of the lipid partition coefficients of the complexes are shown in the following table:
table 2 results of the lipid partition coefficient of the complexes
The results of the lipid water distribution coefficients show that the complexes are all water-soluble substances.
3. In vitro stability determination of complexes
The radiochemical purity of the labeled complex is measured after the labeled complex is placed in mouse serum at room temperature and 37 ℃ for 6 hours, and experimental results show that the radiochemical purity of the complex is more than 90% after the labeled complex is placed in mouse serum at room temperature and 37 ℃ for 6 hours, which indicates that the in vitro stability of the labeled complex is good.
4. Experiment of the Complex in mouse biodistribution
To verify that the complex was a tumor imaging agent that specifically targets PSMA, inhibition experiments were performed with the PSMA inhibitor ZJ-43. Each normal Kunming male mouse was injected with 500 μg ZJ-43 by tail vein 30min in advance, followed by a further injection of 0.10mL of complex solution (0.185 MBq,15 pmol). Mice were sacrificed 2h after dosing, their kidneys, blood and muscles were removed, and their radioactivity counts were weighed after wiping and measured using a gamma Counter to calculate the percent injected dose per gram (% ID/g) for each organ. The biodistribution results are shown in tables 3-10.
TABLE 3 Table 3 99m Results of biological distribution of Tc-GTH-EDDA in normal Kunming male mice (2h.p.i., n=5,% ID/g)
TABLE 4 Table 4 99m Biological distribution results of Tc-GTH-TPPTS in normal Kunming Male mice (2h.p.i., n=5,% ID/g)
TABLE 5 99m Biological distribution results of Tc-GTH-TPPMS in normal Kunming Male mice (2h.p.i., n=5,% ID/g)
TABLE 6 99m Biological distribution results of Tc-GTH-PA in normal Kunming male mice (2h.p.i., n=5,% ID/g)
TABLE 7 99m Biological distribution results in normal Kunming male mice by Tc-GTH-NIC (2h.p.i., n=5,% ID/g)
TABLE 8 99m Results of biological distribution of Tc-GTH-ISONIC in normal Kunming Male mice (2h.p.i., n=5,% ID/g)
TABLE 9 99m Results of biological distribution of Tc-GTH-PDA in normal Kunming male mice (2h.p.i., n=5,% ID/g)
Table 10 99m Biological distribution results of Tc-GTH-PSA in normal Kunming Male mice (2h.p.i., n=5,% ID/g)
As can be seen from tables 3-10, in the control group, the kidneys were the organs for higher expression of PSMA, and the complexes exhibited high renal uptake at 2h, while blood and muscle uptake were low. After 30min in advance of injection of the inhibitor ZJ-43, the renal uptake is obviously reduced, and the inhibition effect is obvious, which indicates that the complex is specifically combined with PSMA.
In the above complex, select 99m Tc-GTH-TPPTS 99m Biological evaluation of the Tc-GTH-PA on the BALB/c male nude mice bearing 22Rv1 tumor was performed. Male nude mice bearing 22Rv1 tumor BALB/c were injected with 500. Mu.g ZJ-43 30min in advance, followed by 0.10mL of complex solution (0.185 MBq,15 pmol). Mice were sacrificed 2h after administration, tissues and organs such as kidneys, hearts, lungs, blood, muscles were taken, the animals were weighed after wiping, their radioactivity counts were measured using a gamma Counter, and the percent injection dose (% ID/g) per gram of each tissue and organ was calculated.
TABLE 11 99m Tc-GTH-TPPTS in the presence of BALB/c male with 22Rv1 tumorBiological distribution results in sex nude mice (2h.p.i., n=4,% ID/g)
Table 12 99m Biological distribution results of Tc-GTH-PA in BALB/c Male nude mice bearing 22Rv1 tumor (2h.p.i., n=4,% ID/g)
The 22Rv1 tumor is a tumor model with intermediate expression of PSMA, and the experimental result of tumor-bearing animals shows that, 99m Tc-GTH-TPPTS 99m Tc-GTH-PA complex has higher uptake, tumor/muscle and tumor/blood ratio in tumor, and after 30min advance injection of inhibitor ZJ-43, tumor uptake is obviously reduced, and inhibition effect is obvious, which indicates that the complex is specifically targeted and combined with PSMA.
While the invention has been described in detail in the foregoing general description and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that modifications and improvements can be made thereto. Thus, the radionuclide labeling of the glutamic acid-urea derivatives and the co-ligands L containing triazole rings and hydrazinonigulide groups, except for the glutamic acid-urea derivatives containing triazole rings and hydrazinonigulide groups, which are related to the present invention, is within the scope of the present invention, except that the corresponding co-ligands L are N-tris (hydroxymethyl) methylglycine (Tricine) and disodium 3,3' - (phenylphosphinediyl) bis (benzene-1-sulfonate) (TPPDS), N-tris (hydroxymethyl) methylglycine (Tricine) and glucoheptonate, N-tris (hydroxymethyl) methylglycine (Tricine) and glucosamine, N-tris (hydroxymethyl) methylglycine (Tricine) and mannitol, N-tris (hydroxymethyl) methylglycine (Tricine) and diphenylphosphinobenzoic acid.
Claims (5)
1. A glutamic acid-urea derivative containing a triazole ring and hydrazinonigulamido, which is characterized in that the structural formula of the glutamic acid-urea derivative containing the triazole ring and the hydrazinonigulamido is (I):
wherein m represents an integer of 1 or more;
n represents an integer of 1 or more.
2. A radioactive preparation comprising a glutamic acid-urea derivative containing a triazole ring and a hydrazinonigulamido group according to claim 1 labeled with a radionuclide.
3. The radioactive preparation according to claim 2, characterized in that the radionuclide is 99m Tc、 99 Tc、 94m Tc、 94 Tc、 52 Mn、 186 Re or 188 Re。
4. The radioactive preparation according to claim 3, wherein the radioactive preparation has a structural formula (II):
wherein: m represents an integer of 1 or more, N represents an integer of 1 or more, L is N-tris (hydroxymethyl) methylglycine and ethylenediamine-N, N' -diacetic acid, N-tris (hydroxymethyl) methylglycine and triphenylphosphine sodium trimetaphosphate, N-tris (hydroxymethyl) methylglycine and diphenylphosphinophenone-3-sulfonate, N-tris (hydroxymethyl) methylglycine and 2- (pyridin-4-yl) acetic acid, N-tris (hydroxymethyl) methylglycine and nicotinic acid, N-tris (hydroxymethyl) methylglycine and isonicotinic acid, N-tris (hydroxymethyl) methylglycine and 3, 5-pyridinedicarboxylic acid, N-tris (hydroxymethyl) methylglycine and 3-pyridinesulfonic acid.
5. Use of a radioactive preparation according to any one of claims 2-4 for the preparation of a tumor imaging agent in the field of diagnosis of prostate cancer and/or in the field of tumor therapy.
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