CN116874489A - Technetium-99 m marked folic acid derivative containing D-proline modification and preparation method and application thereof - Google Patents
Technetium-99 m marked folic acid derivative containing D-proline modification and preparation method and application thereof Download PDFInfo
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- CN116874489A CN116874489A CN202310690009.9A CN202310690009A CN116874489A CN 116874489 A CN116874489 A CN 116874489A CN 202310690009 A CN202310690009 A CN 202310690009A CN 116874489 A CN116874489 A CN 116874489A
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- hydroxymethyl
- methylglycine
- tris
- dpfa
- folic acid
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- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- 229930182820 D-proline Natural products 0.000 title claims abstract description 16
- ONIBWKKTOPOVIA-SCSAIBSYSA-N D-Proline Chemical compound OC(=O)[C@H]1CCCN1 ONIBWKKTOPOVIA-SCSAIBSYSA-N 0.000 title claims abstract description 15
- 150000002224 folic acids Chemical class 0.000 title claims abstract description 15
- 230000004048 modification Effects 0.000 title claims abstract description 14
- GKLVYJBZJHMRIY-OUBTZVSYSA-N Technetium-99 Chemical compound [99Tc] GKLVYJBZJHMRIY-OUBTZVSYSA-N 0.000 title description 6
- 229940056501 technetium 99m Drugs 0.000 title description 6
- 238000002715 modification method Methods 0.000 title description 2
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 34
- 230000002285 radioactive effect Effects 0.000 claims abstract description 22
- 102000006815 folate receptor Human genes 0.000 claims abstract description 20
- 108020005243 folate receptor Proteins 0.000 claims abstract description 20
- 238000012986 modification Methods 0.000 claims abstract description 12
- 239000012216 imaging agent Substances 0.000 claims abstract description 5
- SEQKRHFRPICQDD-UHFFFAOYSA-N N-tris(hydroxymethyl)methylglycine Chemical compound OCC(CO)(CO)[NH2+]CC([O-])=O SEQKRHFRPICQDD-UHFFFAOYSA-N 0.000 claims description 89
- UZMAPBJVXOGOFT-UHFFFAOYSA-N Syringetin Natural products COC1=C(O)C(OC)=CC(C2=C(C(=O)C3=C(O)C=C(O)C=C3O2)O)=C1 UZMAPBJVXOGOFT-UHFFFAOYSA-N 0.000 claims description 39
- 239000007997 Tricine buffer Substances 0.000 claims description 39
- KCFYHBSOLOXZIF-UHFFFAOYSA-N dihydrochrysin Natural products COC1=C(O)C(OC)=CC(C2OC3=CC(O)=CC(O)=C3C(=O)C2)=C1 KCFYHBSOLOXZIF-UHFFFAOYSA-N 0.000 claims description 39
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 24
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 claims description 24
- 229960003512 nicotinic acid Drugs 0.000 claims description 12
- 235000001968 nicotinic acid Nutrition 0.000 claims description 12
- 239000011664 nicotinic acid Substances 0.000 claims description 12
- 239000011734 sodium Substances 0.000 claims description 12
- DVECLMOWYVDJRM-UHFFFAOYSA-N pyridine-3-sulfonic acid Chemical compound OS(=O)(=O)C1=CC=CN=C1 DVECLMOWYVDJRM-UHFFFAOYSA-N 0.000 claims description 10
- MPFLRYZEEAQMLQ-UHFFFAOYSA-N dinicotinic acid Chemical compound OC(=O)C1=CN=CC(C(O)=O)=C1 MPFLRYZEEAQMLQ-UHFFFAOYSA-N 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 4
- IFQUWYZCAGRUJN-UHFFFAOYSA-N ethylenediaminediacetic acid Chemical compound OC(=O)CNCCNCC(O)=O IFQUWYZCAGRUJN-UHFFFAOYSA-N 0.000 claims description 3
- PAEXAIBDCHBNDC-UHFFFAOYSA-N 2-pyridin-4-ylacetic acid Chemical compound OC(=O)CC1=CC=NC=C1 PAEXAIBDCHBNDC-UHFFFAOYSA-N 0.000 claims description 2
- AZSFNUJOCKMOGB-UHFFFAOYSA-K cyclotriphosphate(3-) Chemical compound [O-]P1(=O)OP([O-])(=O)OP([O-])(=O)O1 AZSFNUJOCKMOGB-UHFFFAOYSA-K 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 2
- 150000001875 compounds Chemical class 0.000 claims 1
- 241000699670 Mus sp. Species 0.000 abstract description 18
- 230000008685 targeting Effects 0.000 abstract description 7
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
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- 229940121896 radiopharmaceutical Drugs 0.000 abstract description 6
- 230000002799 radiopharmaceutical effect Effects 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 4
- 239000003112 inhibitor Substances 0.000 abstract description 4
- 238000002372 labelling Methods 0.000 abstract description 4
- 238000009206 nuclear medicine Methods 0.000 abstract description 2
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- 210000003734 kidney Anatomy 0.000 description 20
- 239000003446 ligand Substances 0.000 description 16
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- 238000004809 thin layer chromatography Methods 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 238000000034 method Methods 0.000 description 8
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- 239000000243 solution Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000001384 succinic acid Substances 0.000 description 6
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 238000002603 single-photon emission computed tomography Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
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- 210000000936 intestine Anatomy 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- 238000005192 partition Methods 0.000 description 4
- 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 description 4
- -1 D-proline modified folic acid derivatives Chemical class 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 241000699660 Mus musculus Species 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000003745 diagnosis Methods 0.000 description 3
- 235000019152 folic acid Nutrition 0.000 description 3
- 239000011724 folic acid Substances 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
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- 210000003205 muscle Anatomy 0.000 description 3
- 238000011580 nude mouse model Methods 0.000 description 3
- 230000005855 radiation Effects 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 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 3
- 230000006641 stabilisation Effects 0.000 description 3
- 238000011105 stabilization Methods 0.000 description 3
- GBHSCKFAHCEEAZ-UHFFFAOYSA-N 2-[hydroxymethyl(methyl)amino]acetic acid Chemical compound OCN(C)CC(O)=O GBHSCKFAHCEEAZ-UHFFFAOYSA-N 0.000 description 2
- 102000010451 Folate receptor alpha Human genes 0.000 description 2
- 108050001931 Folate receptor alpha Proteins 0.000 description 2
- 229930182821 L-proline Natural products 0.000 description 2
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- KBPLFHHGFOOTCA-UHFFFAOYSA-N caprylic alcohol Natural products CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
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- 229910052751 metal Inorganic materials 0.000 description 2
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- 239000003068 molecular probe Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229960002429 proline Drugs 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 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
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 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 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 102100041003 Glutamate carboxypeptidase 2 Human genes 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 101000892862 Homo sapiens Glutamate carboxypeptidase 2 Proteins 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- VEJXYBLYLRPHPK-UHFFFAOYSA-N [Mo].[Tc] Chemical compound [Mo].[Tc] VEJXYBLYLRPHPK-UHFFFAOYSA-N 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
- 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
- 239000003054 catalyst Substances 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
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- 210000002987 choroid plexus Anatomy 0.000 description 1
- 238000007813 chromatographic assay Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229940014144 folate Drugs 0.000 description 1
- 230000005251 gamma ray Effects 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 229930004094 glycosylphosphatidylinositol Natural products 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
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- 238000002386 leaching Methods 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N n-Octanol Natural products CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
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- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920001481 poly(stearyl methacrylate) Polymers 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
- C07D475/04—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
-
- 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
- A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
- A61K51/0482—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group chelates from cyclic ligands, e.g. DOTA
-
- 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
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic Table
- C07F13/005—Compounds without a metal-carbon linkage
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Physics & Mathematics (AREA)
- 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 chemistry and clinical nuclear medicine, in particular to a folic acid derivative containing D-proline modification and application thereof. The radioactive preparation obtained by labeling the D-proline-modified folic acid derivative with radionuclide can be prepared through medicine box formation, has high radiochemical purity and good stability, can be obviously absorbed by tumor sites of tumor-bearing mice, can be obviously inhibited by inhibitors, has a good target/non-target ratio, has low renal absorption, and can be used as a novel tumor imaging agent targeting folic acid receptors.
Description
Technical Field
The invention belongs to the technical fields of radiopharmaceuticals and clinical nuclear medicine, and particularly relates to a technetium-99 m marked folic acid derivative containing D-proline modification, a preparation method and application thereof.
Background
Folate Receptor (FR) is a glycoprotein with a molecular weight of about 38-40kDa, linked to the cell membrane by glycosyl phosphatidylinositol, and mainly comprises the three subtypes α, β and γ. Among them, the folate-alpha receptor is expressed in a small number of healthy tissues such as the proximal tubule of the kidney and epithelial cells of the intestinal, pulmonary and choroid plexus, and the folate-alpha receptor in other healthy tissues is located on the apical surface of polarized epithelial cells, and is difficult to bind with externally taken folate, so that the expression of folate-alpha receptor in healthy tissue cells other than the kidney is highly conserved. However, it has been found that FR-alpha is highly expressed in many epithelial malignant cells, such as ovarian cancer, breast cancer, endometrial cancer, lung cancer, and nasopharyngeal cancer cells, and the degree of expression is correlated with the degree of tissue differentiation of malignant tumors, and is low in tissue differentiation or malignant tumors in the development stage, and that the FR-alpha expression level is higher. Therefore, FR- α subtype has become a hotspot for the study of radiotargeted molecular probes in the diagnosis and treatment of related high-expression tumors.
99m Tc is the most widely clinically applied nuclide in the single photon nuclide at present, has half-life of 6.02h, proper gamma-ray energy (140 keV) and coordination chemistry diversity, and can be obtained by leaching a molybdenum technetium generator, and is cheap and easy to obtain, thus developing a novel FR-targeting model 99m Tc tumor radiopharmaceuticals have important practical significance. Has been reported at present 99m Tc marks the radioactive complex of the targeting FR, although most have higher uptake and good target/non-target ratio in the tumor site of positive expression FR, these complexes have very high radioactive accumulation in the kidney of the mouse, cause it to cause certain radiation damage to the kidney, and multiple medicaments need to use the high performance liquid chromatography to separate and purify before injecting, the preparation step is tedious, inconvenient for clinical popularization, because ofThe need for developing a novel drug which is easy to popularize and suitable for kidney uptake 99m Tc marks tumor imaging agent targeting FR.
The linker (linker) has attached to it a targeting group and a chelating group attached to the radionuclide and plays an important role in modulating the pharmacokinetics and pharmacodynamics of the radiopharmaceutical. The invention uses D-proline as a connecting agent, and aims to reduce radiation damage to the kidney by improving the pharmacokinetic property of the complex, on one hand, keeping the complex high in tumor uptake and on the other hand, reducing the uptake of the complex in the kidney. Hydrazinony Gu Xianan (HYNIC) is 99m A bifunctional linker commonly used in Tc-labeled radiopharmaceutical studies. Based on the background, the invention synthesizes the folic acid derivative containing D-proline and hydrazinonigulamido, and carries out the folic acid derivative under the participation of other co-ligands 99m Tc labeling is used for searching for novel tumor radiopharmaceuticals with specific targeting to FR, has important scientific significance and wide clinical application prospect, and is also an important task facing the field.
Disclosure of Invention
The invention aims to provide a technetium-99 m marked folic acid derivative containing D-proline modification, which is simple and convenient to prepare, has high radiochemical purity, specifically targets FR and is suitable for kidney uptake, and a preparation method thereof.
Specifically, the invention provides the following technical scheme: a technetium-99 m marked folic acid derivative containing D-proline modification has the following structural formula (I):
from the derivatives, the corresponding products are prepared 99m Tc complex is combined with FR specifically, has high tumor uptake, low non-target uptake, excellent target to non-target ratio, low kidney uptake and satisfactory effect on diagnosis and treatment of high-expression FR tumor.
The present invention also provides a radioactive preparation comprising a folic acid derivative containing a D-proline modification as described above, labelled 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 (II):
wherein: l is 99m Tc formation stabilization 99m The co-ligand components in Tc complex are 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 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), etc.
The invention also provides application of the radioactive preparation in the diagnosis field and/or the treatment field of FR high expression tumor.
The invention has the beneficial effects that: the invention provides a derivative containing D-proline modification, a preparation method and application thereof, and a radioactive preparation obtained by labeling the derivative with radionuclide has high uptake in folic acid receptor high-expression tumors, and meanwhile, the ratio of tumor to non-target is good, and kidney uptake is proper, so that the derivative is a novel tumor radioactive drug which is safe, effective and has popularization significance.
Detailed Description
The invention provides a preparation method and application of a technetium-99 m marked folic acid derivative containing D-proline modification, and in a preferred embodiment, the invention providesThe general formula of the structure is 99m Radioactive preparation of Tc-DPFA-L:
wherein: l is 99m Tc formation stabilization 99m The co-ligand components in Tc complex are 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 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), etc.
The preparation method comprises the following steps:
ligand DPFA synthesis:
weighing a proper amount of compound 1 into a 25mL round bottom three-necked flask, adding a proper amount of dimethyl sulfoxide (DMSO) for dissolution, then adding a proper amount of triethylamine, adding a proper amount of compound 2 under the protection of nitrogen, and reacting overnight at room temperature under the condition of avoiding light. And (3) repeatedly washing with cold diethyl ether and dichloromethane after the reaction is finished, and drying in vacuum to obtain the ligand DPFA.
The specific synthetic route is as follows:
b: 99m preparation of Tc-DPFA-L complex:
dissolving DPFA, tricine in physiological saline, adding TPPTS, TPPMS, NIC, ISONIC, PDA or PSA, and SnCl 2 ·2H 2 O, adjust the pH of the solution to 5.0, then add fresh rinsed Na thereto 99m TcO 4 The solution is reacted for 30min at the temperature of 100 ℃ to obtain the catalyst 99m Tc-DPFA-L complex.
Prepared by the above method 99m The radiochemical purity of the Tc-DPFA-L complex is more than 90 percent and isHydrophilic substances and good in vitro stability. The biodistribution results indicate that 99m Tc-DPFA-L has higher tumor uptake, can be remarkably inhibited, has high target to non-target ratio and lower kidney uptake, and SPECT/CT imaging results show that the tumor has obvious radioactive concentration and can also be remarkably inhibited, so that the novel FR-targeting tumor imaging agent is worthy of popularization and application.
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.
Example 1
The present embodiment provides a method of 99m Tc marked folic acid derivative containing D-proline modification, which is called as short as 99m Tc-DPFA-L has the following structural formula:
wherein: l is 99m Tc formation stabilization 99m The co-ligand components in Tc complex are 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 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), etc.
The preparation method is as follows, but is not limited to the illustrated complexes:
a. synthesis of ligand DPFA
73mg of Compound 1 (0.15 mmol) was weighed into a 25mL round bottom three-necked flask, 3mL of dimethyl sulfoxide (DMSO) was added to dissolve, then 75mg of triethylamine (0.75 mmol) was added, 96mg of Compound 2 (0.18 mmol) was added under nitrogen protection, and the reaction was carried out overnight at room temperature under a dark condition. After the reaction, cold diethyl ether and dichloromethane are usedRepeated washing and vacuum drying gave ligand DPFA 86mg in 63.7% yield. 1 H NMR(600MHz,DMSO-d 6 )δ(ppm):8.98(s,1H),8.60(s,1H),8.34(d,J＝23.3Hz,1H),7.97(d,J＝7.5Hz,2H),7.83(s,2H),7.73(d,J＝7.8Hz,1H),7.63(d,J＝7.9Hz,1H),7.31(s,1H),7.25(d,J＝6.0Hz,1H),7.20(s,1H),6.88(s,1H),6.59(d,J＝8.0Hz,1H),4.44(s,2H),4.30(s,1H),3.62(s,1H),3.51(d,J＝17.5Hz,2H),3.08(s,2H),2.95(s,1H),2.17(d,J＝47.8Hz,2H),1.79(d,J＝36.9Hz,6H),1.09(dd,J＝14.6,7.2Hz,1H).HR-MS for C 39 H 40 N 13 O 10 S[M-Na] - :found 882.2753,calcd 882.2747.
b. 99m Preparation of Tc-DPFA-TPPTS complex
Taking 5 mug ligand DPFA,2mg N-tri (hydroxymethyl) methyl glycine (Tricine), 2mg triphenylphosphine trimetaphosphate (TPPTS) dissolved in proper physiological saline, adding 30 mug SnCl 2 ·2H 2 O and 0.1mL succinic acid buffer (ph=5.0) then fresh rinsed Na was added 99m TcO 4 Reacting at 100deg.C for 30min to obtain target complex 99m Tc-DPFA-TPPTS, the radiochemical purity of which is more than 90 percent by adopting TLC and HPLC methods.
c. 99m Preparation of Tc-DPFA-TPPMS Complex
Taking 5 mug ligand DPFA,2mg N-tri (hydroxymethyl) methylglycine (Tricine), 2mg diphenylphosphinobenzene-3-sodium sulfonate (TPPMS) dissolved in proper physiological saline, and adding 30 mug SnCl 2 ·2H 2 O and 0.1mL succinic acid buffer (ph=5.0) then fresh rinsed Na was added 99m TcO 4 Reacting at 100deg.C for 30min to obtain target complex 99m Tc-DPFA-TPPMS with radiochemical purity higher than 90% measured by TLC and HPLC methods.
d. 99m Preparation of Tc-DPFA-NIC complex
Taking 5 μg ligand DPFA,2mg N-tris (hydroxymethyl) methylglycine (Tricine), 2mg nicotinic acid (NIC), dissolving in appropriate amount of physiological saline, and adding 30 μg SnCl 2 ·2H 2 O and 0.1mL succinic acid buffer (ph=5.0) then fresh rinsed Na was added 99m TcO 4 Reacting at 100deg.C for 30min to obtain target complex 99m Tc-DPFA-NIC has a radiochemical purity of more than 90% as determined by TLC and HPLC.
e. 99m Preparation of Tc-DPFA-ISONIC complex
Taking 5 μg ligand DPFA,2mg N-tris (hydroxymethyl) methylglycine (Tricine), 2mg isonicotinic acid (ISONIC), dissolving in appropriate amount of physiological saline, and adding 30 μg SnCl 2 ·2H 2 O and 0.1mL succinic acid buffer (ph=5.0) then fresh rinsed Na was added 99m TcO 4 Reacting at 100deg.C for 30min to obtain target complex 99m Tc-DPFA-ISONIC, the radiochemical purity of which is more than 90% by TLC and HPLC method.
f. 99m Preparation of Tc-DPFA-PDA complex
Taking 5 μg ligand DPFA,2mg N-tris (hydroxymethyl) methylglycine (Tricine), 2mg 3, 5-Pyridine Dicarboxylic Acid (PDA), dissolving in appropriate amount of physiological saline, and adding 30 μg SnCl 2 ·2H 2 O and 0.1mL succinic acid buffer (ph=5.0) then fresh rinsed Na was added 99m TcO 4 Reacting at 100deg.C for 30min to obtain target complex 99m Tc-DPFA-PDA with radiochemical purity higher than 90% measured by TLC and HPLC.
g. 99m Preparation of Tc-DPFA-PSA Complex
Taking 5 μg ligand DPFA,2mg N-tris (hydroxymethyl) methylglycine (Tricine), 2mg 3-Pyridine Sulfonic Acid (PSA), dissolving in appropriate amount of physiological saline, and adding 30 μg SnCl 2 ·2H 2 O and 0.1mL succinic acid buffer (ph=5.0) then fresh rinsed Na was added 99m TcO 4 Reacting at 100deg.C for 30min to obtain target complex 99m Tc-DPFA-PSA with a radiochemical purity of more than 90% measured by TLC and HPLC.
Experiments show that the complex 99m The performance of Tc-DPFA-L is as follows:
1. identification of complexes
(1) TLC method
Determination of the radiochemical yield and radiochemical purity of the markers by Thin Layer Chromatography (TLC) using developed System 1 as whatman filter paper-raw salt and System 2 as Polyamide film-acetonitrile under which R of the respective radioactive components f The values are shown in table 1.
TABLE 1R of the radioactive components under the respective systems f Value of
As measured by the chromatographic assay described above 99m The Tc-DPFA-L complex has radiochemical yield and radiochemical purity greater than 90% and may be used in subsequent experiment without further purification.
(2) HPLC method
The identification of the radiochemical purity of the markers was carried out by High Performance Liquid Chromatography (HPLC) using pure water containing 0.1% trifluoroacetic acid (phase A) and acetonitrile containing 0.1% trifluoroacetic acid (phase B) as mobile phases, and the elution gradient is shown in Table 2 below.
TABLE 2 HPLC elution gradient
The HPLC identification result shows that, 99m the retention time of Tc-DPFA-L complex is 9.0-10.0 min.
2. Determination of the lipid partition coefficient of the Complex
1.9mL of phosphate buffer (0.025 mol/L) having pH 7.4 was taken in a 5mL centrifuge tube, and 2.0mL of n-octanol and 0.1mL of the buffer were added to the centrifuge tube 99m Tc-DPFA-L solution, capped with a plug, vortexed for 5min, centrifuged for 5min (3000 r/min). Then 3×0.1mL were taken out of the organic and aqueous phases, respectively, the radioactivity counts of the two phases were determined, and the partition coefficient D (d=radioactivity of the organic phase/radioactivity of the aqueous phase) was calculated and repeated three times, and the lipid partition coefficient results of the complex are shown in the following table:
table 3 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 labeled complex 99m Tc-DPFA-L was measured for its radiochemical purity after 4 hours at room temperature and in 37℃mouse serum, respectively, and the results of the experiments showed that the radiochemical purity of the complex was more than 90% after 4 hours at room temperature and in 37℃mouse serum, respectivelyIt has good in vitro stability.
4. Biodistribution experiments of complexes in mice
To verify that a series of complexes are tumor imaging agents specifically targeting FR, while kidney is an organ with high FR expression, to a certain extent, can be one of the target organs, normal uptake and inhibition experiments were performed in normal female white mice with folic acid FA as an inhibitor. Each mouse was injected with 0.1mL of the complex solution (about 7.4X10) 5 Bq), wherein the inhibition group was injected with 100 μg FA 30min ahead. Mice were sacrificed 2h after dosing, related tissues and organs such as heart, liver, lung, kidney, spleen, bone, intestine, stomach, muscle, blood, etc., were removed, rubbed off, weighed, and their radioactivity counts were measured on a gamma Counter to calculate the percent injection dose per gram (% ID/g) for each tissue. The number of mice per phase was 5. The biodistribution results are shown in tables 4-9.
TABLE 4 Table 4 99m Biological distribution results of Tc-DPFA-TPPTS in normal Kunming Male mice (n=5)
TABLE 5 99m Biological distribution results of Tc-DPFA-TPPMS in normal Kunming Male mice (n=5)
TABLE 6 99m Results of Tc-DPFA-NIC biodistribution in normal Kunming male mice (n=5)
TABLE 7 99m Tc-DPFA-ISONIC in normal Kunming Male SmallMurine biodistribution results (n=5)
TABLE 8 99m Results of biological distribution of Tc-DPFA-PDA in normal Kunming male mice (n=5)
TABLE 9 99m Results of biological distribution of Tc-DPFA-PSA in Normal Kunming Male mice (n=5)
As can be seen from tables 4-9, in the control group, the kidney was used as an organ with high PSMA expression, and the complex showed a certain renal uptake at 2h, while the uptake of blood and muscle was very low, the target to non-target ratio was high, and the non-specific binding clearance was fast. After the inhibitor FA is injected 30min in advance, the renal uptake is obviously reduced, and the inhibition effect is obvious, which indicates that the complexes are specifically targeted to FR.
In the above-mentioned complex, the reaction product, 99m Tc-DPFA-TPPTS is suitable for uptake in kidney with FR high expression, can be significantly inhibited, and has low uptake in non-target organs such as intestine, blood and the like, thus selecting 99m Tc-DPFA-TPPTS was used as one of the representatives for intensive studies in KB tumor-bearing Balb/c female nude mice. Tumor-bearing mice were divided into normal and inhibitory groups, and each mouse was injected with 0.1mL of the complex solution (about 7.4X10 5 Bq), wherein the inhibition group was injected with 100 μg FA 30min ahead. Mice were sacrificed 2h after administration, and the heart, liver, lung, kidney, spleen, bone, intestine, stomach, muscle, blood, tumor, etc. were collectedTissues and organs were weighed after wiping and their radioactivity counts were measured on a gamma Counter and the percent injected dose per gram (% ID/g) for each tissue was calculated. The biodistribution results of tumor-bearing mice are shown in table 10.
Table 10 99m Biological distribution result of Tc-DPFA-TPPTS in KB tumor-bearing Balb/c female nude mice (n=4)
KB tumors are positive tumors with high FR expression. 99m Tc-DPFA-TPPTS complexes have higher tumor uptake in KB tumors and can be significantly inhibited by inhibitor FA, thus demonstrating that the complexes bind specifically to FR. The ingestion of the kidney is also lower, the ingestion value of the kidney after 2 hours of injection is 5.94+/-0.48 ID%/g, and the radiation damage to the kidney is avoided.
5. SPECT/CT imaging experiment of complex in tumor-bearing mice
Imaging experiments were divided into normal and inhibition groups. Tail intravenous injection of KB tumor-bearing nude mice 99m Tc-DPFA-TPPTS complex solution (about 18.5 MBq), wherein the inhibition group was injected with 100. Mu.g FA folic acid solution 30min earlier. 2h after dosing, mice were anesthetized with isoflurane at 1.5% concentration, scan parameters were set, SPECT scan for 15min, ct scan for 4min, and finally scan images were obtained by HiSPECT software and vivoquant2.5 software. Mice were fixed prone and SPECT/CT visualizations were performed.
The SPECT imaging result shows that, 99m Tc-DPFA-TPPTS has obvious concentration at tumor sites in normal mice, other non-target organs such as liver, intestine and the like have lower uptake except for a certain concentration in kidneys, and the uptake is obviously reduced in tumors and kidneys of inhibition mice, which shows that 99m Tc-DPFA-TPPTS can be used as a tumor molecular probe for specifically targeting FR.
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, these modifications or improvements, which are made without departing from the spirit of the invention, are made in the radioactive areas of the radionuclides of the invention where, in addition to the D-proline modified folic acid derivatives to which the invention relates, L-proline modified folic acid derivatives and the corresponding co-ligands M are N-tris (hydroxymethyl) methylglycine (Tricine) and ethylenediamine-N, N' -diacetic acid (EDDA), N-tris (hydroxymethyl) methylglycine (Tricine) and triphenylphosphine sodium trimetaphosphate (TPPTS), N-tris (hydroxymethyl) methylglycine (Tricine) and diphenylphosphinobenzene-3-sodium 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 2- (pyridin-4-yl) acetic acid (Tricine) are labelled. In addition, radioactive preparations obtained by radionuclide labeling of folic acid derivatives containing D-proline or L-proline modification and the co-ligand M as N-tris (hydroxymethyl) methylglycine (Tricine) and 3,3' - (phenylphosphinediyl) disodium (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 are also within the scope of the claimed invention.
Claims (5)
1. A folic acid derivative containing a D-proline modification, characterized in that the compound has the structural formula (I):
2. a radioactive preparation comprising a D-proline-containing modified folic acid derivative according to claim 1, labelled 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: l is sodium N-tris (hydroxymethyl) methylglycine and triphenylphosphine trimetaphosphate, sodium N-tris (hydroxymethyl) methylglycine and diphenylphosphinophenone-3-sulfonate, 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, N-tris (hydroxymethyl) methylglycine and ethylenediamine-N, N' -diacetic acid, N-tris (hydroxymethyl) methylglycine (Tricine) and 2- (pyridin-4-yl) acetic acid.
5. Use of a radioactive preparation according to any one of claims 2-4 for the preparation of a folate receptor targeted tumor imaging agent.
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