CN113583066A - 一种甘露糖衍生物及其应用 - Google Patents
一种甘露糖衍生物及其应用 Download PDFInfo
- Publication number
- CN113583066A CN113583066A CN202110839524.XA CN202110839524A CN113583066A CN 113583066 A CN113583066 A CN 113583066A CN 202110839524 A CN202110839524 A CN 202110839524A CN 113583066 A CN113583066 A CN 113583066A
- Authority
- CN
- China
- Prior art keywords
- tumor
- mannose derivative
- mannose
- radioactive
- integer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000002703 mannose derivatives Chemical class 0.000 title claims abstract description 23
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 40
- 238000002360 preparation method Methods 0.000 claims abstract description 16
- 230000002285 radioactive effect Effects 0.000 claims abstract description 14
- 239000012217 radiopharmaceutical Substances 0.000 claims abstract description 7
- 229940121896 radiopharmaceutical Drugs 0.000 claims abstract description 7
- 230000002799 radiopharmaceutical effect Effects 0.000 claims abstract description 7
- 238000003745 diagnosis Methods 0.000 claims description 7
- 238000009472 formulation Methods 0.000 claims 3
- 239000000203 mixture Substances 0.000 claims 3
- 150000002527 isonitriles Chemical class 0.000 abstract description 5
- 238000009206 nuclear medicine Methods 0.000 abstract description 4
- 238000002372 labelling Methods 0.000 abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 238000000034 method Methods 0.000 description 7
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000003384 imaging method Methods 0.000 description 6
- 210000000056 organ Anatomy 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 239000003446 ligand Substances 0.000 description 5
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-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
- 239000003550 marker Substances 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- CBOJBBMQJBVCMW-UHFFFAOYSA-N D-(+)-Galactosamine Chemical compound Cl.O=CC(N)C(O)C(O)C(O)CO CBOJBBMQJBVCMW-UHFFFAOYSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000012216 imaging agent Substances 0.000 description 3
- 230000001965 increasing effect Effects 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 210000003205 muscle Anatomy 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 239000005695 Ammonium acetate Substances 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 235000013878 L-cysteine Nutrition 0.000 description 2
- 239000004201 L-cysteine Substances 0.000 description 2
- 239000004952 Polyamide Substances 0.000 description 2
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 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
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000013399 early diagnosis Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 2
- 238000005192 partition Methods 0.000 description 2
- 229920002647 polyamide Polymers 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 2
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 1
- XDIYNQZUNSSENW-KZXKDKCNSA-N (2s,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)C=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)C=O XDIYNQZUNSSENW-KZXKDKCNSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- -1 carbon monosaccharide Chemical class 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 125000002462 isocyano group Chemical group *[N+]#[C-] 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 239000003068 molecular probe Substances 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N n-Octanol Natural products CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000000163 radioactive labelling Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000002603 single-photon emission computed tomography Methods 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
-
- 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
- A61K51/0491—Sugars, nucleosides, nucleotides, oligonucleotides, nucleic acids, e.g. DNA, RNA, nucleic acid aptamers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/005—Sugars; Derivatives thereof; Nucleosides; Nucleotides; Nucleic acids
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/08—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals directly attached to carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
- C07H5/04—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to nitrogen
- C07H5/06—Aminosugars
-
- 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
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Physics & Mathematics (AREA)
- Medicinal Chemistry (AREA)
- Optics & Photonics (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
本发明涉及放射性药物化学和临床核医学技术领域,具体涉及一种甘露糖衍生物及其应用。所述甘露糖衍生物是含有不同连接基团X的如通式(I)所示结构的含异腈的甘露糖衍生物,将其用放射性核素标记得到的放射性制剂,在肿瘤中摄取高且肿瘤/非靶比值好,是一种值得推广的新型肿瘤放射性药物。
Description
技术领域
本发明涉及放射性药物化学和临床核医学技术领域,具体涉及一种甘露糖衍生物及其应用。
背景技术
当前,在临床医学领域中,恶性肿瘤严重危害人类身体健康。肿瘤早期诊断对于挽救病人的生命和延长病人生存期具有十分重要的现实意义。目前,用于肿瘤早期诊断的方法主要有:组织学活检法、X射线法、 CT、MRI及放射性核素显像等方法。放射性核素显像可以反映肿瘤的生理、病理、代谢和功能的变化,并且放射性核素显像法是一种无创性检测方法,诸多优点使得放射性核素显像已经成为肿瘤诊断的主要方法之一。尤其是随着正电子发射断层扫描术(PET)和单光子发射断层扫描术(SPECT)与CT等技术的融合使用,放射性核素肿瘤显像已经成为核医学诊断的优势之一。
D-甘露糖(D-Mannose)是葡萄糖C-2的差向异构体,也是一种六碳单糖。甘露糖具有调节免疫系统,增加伤口愈合,避免某些细菌感染,还可以抑制肿瘤生长与转移,增加癌症存活率。基于这一特性,结合核医学显像,可以将甘露糖类衍生物用放射性核素进行标记以用于肿瘤显像。异腈是一类通式为RNC的有机化合物,异腈中的碳原子能够与99mTc(I)配位形成正一价的[99mTc-(CNR)6]+配合物,其中作为心肌灌注显像剂的99mTc-甲氧基异丁基异腈(99mTc-MIBI)在临床上也可以作为肿瘤显像剂。异氰基(-NC)可作为双功能连接剂把99mTc和甘露糖分子连接起来,使靶向肿瘤的糖分子与99mTc示踪功能合为一体。基于以上背景,研发探求一种性能优良的99mTc标记甘露糖类肿瘤分子探针,将D-甘露糖胺盐酸盐转化为含异腈的甘露糖衍生物(简称为:CNDM),然后利用异腈配体中的碳原子与99mTc配位,得到稳定的99mTc标记含异腈的甘露糖衍生物用作肿瘤显像剂有重要的科学意义和广阔的应用前景。
发明内容
本发明提供了一种甘露糖衍生物及其应用,该甘露糖衍生物稳定性好,制备简便,进行放射性标记后用于肿瘤诊疗,肿瘤摄取高且靶/非靶比值好,在肿瘤诊疗领域具有重要的科学意义和应用前景。
具体地,本发明提供以下技术方案:
一种甘露糖衍生物,所述的结构式为(I):
n表示2或2以上的整数;
a表示0或0以上的整数;
b表示0或0以上的整数。
优选的,上述甘露糖衍生物中,当n=7时,所述甘露糖衍生物的结构式为下面一种,由该衍生物制备得到的99mTc配合物在非靶器官中有很低的摄取,有高的肿瘤摄取值和满意的肿瘤/血和肿瘤/肌肉比值,能够针对肿瘤诊疗取得很好的效果。
本发明还提供一种放射性制剂,所述放射性制剂包含用放射性核素标记的上述甘露糖衍生物。
优选的,上述放射性制剂中,所述放射性核素部分为金属放射性核素。
优选的,上述放射性制剂中,所述金属放射性核素为99mTc、99Tc、94mTc、94Tc、52Mn、186Re或188Re。
优选的,所述放射性制剂的结构式为(II):
本发明还提供上述放射性制剂在肿瘤诊断领域和/或肿瘤治疗领域中的应用。
本发明的有益效果在于:本发明提供一种甘露糖衍生物,将其用放射性核素标记得到的放射性制剂,在肿瘤中具有高摄取,同时肿瘤/非靶比值好,是一种有推广意义的新型肿瘤放射性药物。
具体实施方式
本发明提供了一种甘露糖衍生物及其应用,在一种优选的实施方式中,本发明提供结构通式为99mTc-CNDM 的放射性制剂:
式中:
n表示2或2以上的整数;
a表示0或0以上的整数;
b表示0或0以上的整数。
其制备步骤如下:
(1)配体的合成
称取适量D-甘露糖胺盐酸盐和NaOH于25mL圆底烧瓶中,加入无水甲醇,室温下搅拌至固体完全溶解,然后向其中加入化合物1a或1b或1c的甲醇溶液,滴加完毕后继续在室温下反应24h,反应结束后减压蒸馏除去溶剂,柱层析纯化(二氯甲烷/甲醇=5/1)得到配体CNDM。
具体合成路线为:
式中,n表示2或2以上的整数;
式中,a表示0或0以上的整数,b表示0或0以上的整数;
式中,a表示0或0以上的整数,b表示0或0以上的整数。
(2)99mTc-CNDM的制备
将适量柠檬酸钠、L-半胱氨酸溶于适量生理盐水中,向其中加入适量SnCl2·2H2O,调节溶液pH为6.0,然后依次向其中加入适量配体CNDM和新鲜淋洗的Na99mTcO4,100℃下反应20min即可得到99mTc-CNDM配合物。
通过上述方法制备的99mTc-CNDM配合物的放射化学纯度大于90%,体内外稳定性良好,其在荷瘤小鼠肿瘤部位有较高的摄取和良好的滞留,靶/非靶比值好,利于作为新型肿瘤显像剂推广应用。
以下实施例用于说明本发明,但不用来限制本发明的范围。实施例中未注明具体技术或条件者,按照本领域内的文献所描述的技术或条件,或者按照产品说明书进行。
本发明中,所用仪器等未注明生产厂商者,均为可通过正规渠道商购买得到的常规产品。所述方法如无特别说明均为常规方法,所述原材料如无特别说明均能从公开商业途径而得。
实施例1
本实施例提供一种99mTc标记的甘露糖衍生物,简称为99mTc-CN7DM,结构式如下:
其制备步骤如下:
1、CN7DM的合成:
称取氢氧化钠0.088g(2.2mmol)于100mL圆底烧瓶中,加入20mL甲醇溶解,然后加入D-甘露糖胺盐酸盐0.431g(2.0mmol)和化合物1a 0.761g(n=7,2.4mmol),室温过夜反应。反应结束后减压蒸馏除去溶剂,柱层析纯化(二氯甲烷/甲醇=5:1),得到配体0.248g,产率38%。1H NMR(400MHz,Methanol-d4)δ4.96(d, J=1.6Hz,1H),4.89–4.84(m,1H),4.30–4.21(m,1H),3.98(dd,J=9.7,4.7Hz,1H),3.80(dd,J=3.9,2.5Hz, 1H),3.78–3.70(m,2H),3.56(t,J=9.6Hz,1H),3.44(ddt,J=6.6,3.8,2.0Hz,3H),2.25(td,J=7.3,2.1Hz,2H),1.67–1.60(m,4H),1.45–1.31(m,8H);13C NMR(101MHz,Methanol-d4)δ176.78,175.64,153.90(t,J= 6.3Hz),93.68,76.91,73.25,72.11,69.27,67.17,66.79,60.94,60.75,54.45,53.71,41.06(t,J=6.0Hz),35.70, 35.53,28.81,28.72,28.68,28.19,25.95,25.49,25.45;IR(KBr)/cm-1 2150.72(-N≡C);HR-MS(ESI)for C15H27N2O6[M+H]+:found331.1861,calcd331.1863.
2、99mTc-CN7DM的合成:
将2.6mg柠檬酸钠、1mg L-半胱氨酸溶于适量生理盐水中,向其中加入0.10mgSnCl2·2H2O,调节溶液pH 为6.0,然后依次向其中加入0.5mg CN7DM和1mL新鲜淋洗的Na99mTcO4,100℃下反应20min即得到本实施例所述的99mTc-CN7DM。
试验例
1、实施例1提供的放射性制剂的层析鉴定
(1)TLC法
采用薄层色谱层析法(TLC)进行标记物放射化学产率和放射化学纯度的测定,所用展开体系为聚酰胺薄膜- 醋酸铵(1M)/甲醇(体积比:2/1),该体系下,各放射性组分的Rf值如表1所示。
表1放射性组分在聚酰胺薄膜-醋酸铵(1M)/甲醇(体积比:2/1)体系下的Rf值
由上述层析鉴定所测得的99mTc-CN7DM配合物的放射化学产率和放射化学纯度均大于90%,未经进一步纯化即用于后续实验。
(2)HPLC法
采用高效液相色谱(HPLC)进行标记物放射化学纯度的鉴定:SHIMADZU高效液相色谱仪(CL-20AVP), Kromasil C18反相柱(5μm,250×4.6mm),Gabi raytest放射性检测器。淋洗梯度如表2所示,流速为1 mL/min,A相为含0.1%三氟乙酸的纯水,B相为含0.1%三氟乙酸的乙腈。
表2配合物的梯度洗脱条件
HPLC鉴定结果表明99mTc-CN7DM的保留时间为9.5min。
2、脂水分配系数的测定
取标记液100μL(10μCi)置于5mL的离心管里,然后向其中加入1mL正辛醇和900μLPBS(0.025M, pH 7.4),涡旋3min(2500rpm),静置待溶液分层后于离心机中离心5min(9000rpm),从两相中各取出3份100μL,于γ-counter中分别测定其放射性计数。脂水分配系数P=有机相放射性计数/水相放射性计数,通常以log P作为脂水分配系数的表示。经测定99mTc-CN7DM的log P值为-3.15±0.06,说明它是水溶性物质。
3、稳定性测定
将99mTc-CN7DM在室温下生理盐水中和在37℃下小鼠血清中放置4小时后通过TLC测定其放射化学纯度,实验结果表明其在室温下生理盐水中和在37℃下小鼠血清中放置4小时后放射化学纯度均大于90%,说明其具有良好的体外稳定性。
4、荷瘤小鼠体内生物分布测定
将99mTc-CN7DM标记液(0.1mL,370kBq)通过尾静脉注入荷S180肿瘤的小鼠体内,记下注射时间后在不同的时间点(30min,120min)将小鼠断颈处死(每个时相5只小鼠),解剖后取出心、肝、肺、肾、脾、骨、肌肉、小肠、血液和肿瘤等感兴趣组织或器官,用γ-counter分别测定各脏器的放射性计数,并通过各脏器的质量换算后得到各个脏器的摄取值(以%ID/g为单位),标记物在荷瘤小鼠体内的生物分布结果见表3。
表3 99mTc-CN7DM在荷S180肿瘤小鼠体内生物分布结果(n=5,mean±SD,%ID/g)
从结果可以看出,99mTc-CN7DM在肿瘤中摄取高且滞留好,而在非靶器官中快速代谢,给药120min后,肿瘤/肌肉和肿瘤/血液比值高。尤其是其在血液中的清除很快,从而大大提高了肿瘤/血液比值。
虽然,上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述,但在本发明基础上,可以对之作一些修改或改进,这对本领域技术人员而言是显而易见的。因此,在不偏离本发明精神的基础上所做的这些修改或改进,利用除葡萄糖和甘露糖外的其它单糖进行结构修饰后得到的配体经放射性核素标记后得到的放射性制剂均属于本发明要求保护的范围。
Claims (5)
2.一种放射性制剂,其特征在于,所述放射性制剂包含用放射性核素标记的权利要求1任一项所述的甘露糖衍生物。
3.根据权利要求2所述的放射性制剂,其特征在于,所述放射性核素为99mTc、99Tc、94mTc、94Tc、52Mn、186Re或188Re。
5.权利要求2-4任一项所述的放射性制剂在肿瘤诊断领域和/或肿瘤治疗领域中的应用。
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110839524.XA CN113583066B (zh) | 2021-07-23 | 2021-07-23 | 一种甘露糖衍生物及其应用 |
PCT/CN2022/104832 WO2023001004A1 (zh) | 2021-07-23 | 2022-07-11 | 一种甘露糖衍生物及其应用 |
US18/513,283 US20240109929A1 (en) | 2021-07-23 | 2023-11-17 | Mannose derivative and application thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110839524.XA CN113583066B (zh) | 2021-07-23 | 2021-07-23 | 一种甘露糖衍生物及其应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN113583066A true CN113583066A (zh) | 2021-11-02 |
CN113583066B CN113583066B (zh) | 2023-03-14 |
Family
ID=78249380
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202110839524.XA Active CN113583066B (zh) | 2021-07-23 | 2021-07-23 | 一种甘露糖衍生物及其应用 |
Country Status (3)
Country | Link |
---|---|
US (1) | US20240109929A1 (zh) |
CN (1) | CN113583066B (zh) |
WO (1) | WO2023001004A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023001004A1 (zh) * | 2021-07-23 | 2023-01-26 | 北京师范大学 | 一种甘露糖衍生物及其应用 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107245087A (zh) * | 2017-06-15 | 2017-10-13 | 北京师宏药物研制中心 | 99mTc标记含异腈的葡萄糖衍生物及制备方法和应用 |
CN111138504A (zh) * | 2020-01-13 | 2020-05-12 | 北京师范大学 | 一种99mTc-CNPEDG配合物及其制备方法和应用 |
CN112175025A (zh) * | 2020-10-13 | 2021-01-05 | 北京师范大学 | 一种含苯环的葡萄糖衍生物及其应用 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113583066B (zh) * | 2021-07-23 | 2023-03-14 | 北京师范大学 | 一种甘露糖衍生物及其应用 |
CN114031652B (zh) * | 2021-11-04 | 2023-05-26 | 北京师范大学 | 一种含环己烷的葡萄糖衍生物及其应用 |
-
2021
- 2021-07-23 CN CN202110839524.XA patent/CN113583066B/zh active Active
-
2022
- 2022-07-11 WO PCT/CN2022/104832 patent/WO2023001004A1/zh unknown
-
2023
- 2023-11-17 US US18/513,283 patent/US20240109929A1/en active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107245087A (zh) * | 2017-06-15 | 2017-10-13 | 北京师宏药物研制中心 | 99mTc标记含异腈的葡萄糖衍生物及制备方法和应用 |
CN111138504A (zh) * | 2020-01-13 | 2020-05-12 | 北京师范大学 | 一种99mTc-CNPEDG配合物及其制备方法和应用 |
CN112175025A (zh) * | 2020-10-13 | 2021-01-05 | 北京师范大学 | 一种含苯环的葡萄糖衍生物及其应用 |
Non-Patent Citations (1)
Title |
---|
SHAUN,等: "Metabolic glycan imaging by isonitrile-tetrazine click chemistry.", 《CHEMBIOCHEM : A EUROPEAN JOURNAL OF CHEMICAL BIOLOGY》 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023001004A1 (zh) * | 2021-07-23 | 2023-01-26 | 北京师范大学 | 一种甘露糖衍生物及其应用 |
Also Published As
Publication number | Publication date |
---|---|
WO2023001004A1 (zh) | 2023-01-26 |
CN113583066B (zh) | 2023-03-14 |
US20240109929A1 (en) | 2024-04-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN112175025B (zh) | 一种含苯环的葡萄糖衍生物及其应用 | |
US11628228B2 (en) | 99mTc-labeled isonitrile-containing glucose derivative and preparation method and use thereof | |
CN111138504B (zh) | 一种99mTc-CNPEDG配合物及其制备方法和应用 | |
CN112209970B (zh) | 一种锝-99m标记含异腈的谷氨酸-脲衍生物的制备方法和应用 | |
CN111518137B (zh) | 锝-99m标记含异腈的氨基酸衍生物及制备方法和应用 | |
CN112625065A (zh) | 锝-99m标记含肼基尼古酰胺基的FAPI衍生物及制备方法和应用 | |
CN110078767B (zh) | 一种锝-99m标记含肼基尼古酰胺基的2-硝基咪唑类配合物及其制备方法和应用 | |
CN110183493B (zh) | 一种99m锝标记配合物及其在诊断非小细胞肺癌中的应用 | |
CN107522673B (zh) | 用于生物正交反应的1,2,4,5-四嗪化合物及其制备方法与应用 | |
CN113583066B (zh) | 一种甘露糖衍生物及其应用 | |
CN114163478A (zh) | 锝-99m标记含D-脯氨酸修饰的FAPI衍生物及制备方法和应用 | |
CN113200960A (zh) | 锝-99m标记含异腈的PEG链修饰的FAPI衍生物及制备方法和应用 | |
CN102977174B (zh) | 99mTc(CO)3核标记大环多胺三唑环类葡萄糖基配合物及制备方法和应用 | |
CN114031652B (zh) | 一种含环己烷的葡萄糖衍生物及其应用 | |
CN101891791B (zh) | 一种标记胆汁酸衍生物及其参照化合物、制备方法和应用 | |
CN113150032B (zh) | 一种锝-99m标记含异腈的叶酸衍生物及其制备方法和应用 | |
CN102146098B (zh) | 一种99mTc标记D-葡萄糖配合物的制备方法及应用 | |
CN102827208B (zh) | 99mTcO核标记蛋氨酸氨荒酸盐配合物的制备方法和应用 | |
CN116987128A (zh) | 一种含(D)-α-亚氨基酸修饰的甘露糖衍生物及其应用 | |
CN105001274B (zh) | 一种氨基葡萄糖衍生配体化合物及制备方法、三羰基锝‑99m标记的配合物、制备方法及用途 | |
CN115160293B (zh) | 锝-99m标记含L-脯氨酸修饰的谷氨酸-脲衍生物及制备方法和应用 | |
CN112250680B (zh) | 一种新型黄连素衍生物及其合成方法和应用 | |
CN109438265B (zh) | 一种与棕色脂肪组织具有亲和力的化合物及其制备方法和应用 | |
CN105524113A (zh) | 99mTcN核标记含三唑环的葡萄糖氨荒酸盐配合物及制备方法和应用 | |
CN117924415A (zh) | 一种含寡肽链DPro-Gly修饰的谷氨酸-脲衍生物及其应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |