WO2023001004A1 - 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 PDF

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WO2023001004A1
WO2023001004A1 PCT/CN2022/104832 CN2022104832W WO2023001004A1 WO 2023001004 A1 WO2023001004 A1 WO 2023001004A1 CN 2022104832 W CN2022104832 W CN 2022104832W WO 2023001004 A1 WO2023001004 A1 WO 2023001004A1
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tumor
mannose derivative
mannose
application
radioactive
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PCT/CN2022/104832
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张俊波
阮晴
尹广星
王学斌
张站斌
唐志刚
陆洁
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北京师范大学
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Publication of WO2023001004A1 publication Critical patent/WO2023001004A1/zh
Priority to US18/513,283 priority Critical patent/US20240109929A1/en

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    • 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
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    • 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
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    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
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    • 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
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    • 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

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  • the invention relates to the technical fields of radiopharmaceutical chemistry and clinical nuclear medicine, in particular to a mannose derivative and its application.
  • Radionuclide imaging can reflect changes in the physiology, pathology, metabolism and function of tumors, and radionuclide imaging is a non-invasive detection method with many advantages that make radionuclide imaging one of the main methods for tumor diagnosis one.
  • PET positron emission tomography
  • SPECT single photon emission tomography
  • D-Mannose is the epimer of glucose C-2 and also a six-carbon monosaccharide. Mannose can regulate the immune system, increase wound healing, avoid certain bacterial infections, inhibit tumor growth and metastasis, and increase cancer survival rates. Based on this characteristic, combined with nuclear medicine imaging, mannose derivatives can be labeled with radionuclides for tumor imaging. Isonitrile is a class of organic compounds with the general formula RNC.
  • the carbon atom in isonitrile can coordinate with 99m Tc(I) to form a positive monovalent [ 99m Tc-(CNR) 6 ] + complex, in which as myocardial perfusion
  • the imaging agent 99m Tc-methoxyisobutyl isonitrile ( 99m Tc-MIBI) can also be used as a tumor imaging agent clinically.
  • the isocyano group (-NC) can be used as a bifunctional linker to connect 99m Tc and mannose molecules, so that the tumor-targeting sugar molecule can be integrated with the tracer function of 99m Tc.
  • CNDM isocyanide-containing mannose derivatives
  • the invention provides a mannose derivative and its application.
  • the mannose derivative has good stability and is easy to prepare. It can be used for tumor diagnosis and treatment after radioactive labeling. The tumor uptake is high and the target/non-target ratio is good. In the field of tumor diagnosis and treatment It has important scientific significance and application prospects.
  • the present invention provides the following technical solutions:
  • a kind of mannose derivative, described structural formula is (I):
  • n an integer of 2 or more
  • a represents an integer of 0 or more
  • b represents an integer of 0 or more.
  • the structural formula of the mannose derivative is one of the following, and the 99m Tc complex prepared from the derivative has very low uptake in non-target organs , has a high tumor uptake value and satisfactory tumor/blood and tumor/muscle ratios, and can achieve good results for tumor diagnosis and treatment.
  • the present invention also provides a radioactive preparation comprising the above-mentioned mannose derivative labeled with a radionuclide.
  • the radionuclide moiety is a metal radionuclide.
  • the metal radionuclide is 99m Tc, 99 Tc, 94m Tc, 94 Tc, 52 Mn, 186 Re or 188 Re.
  • the structural formula of the radioactive preparation is (II):
  • the present invention also provides the application of the above-mentioned radioactive preparation in the field of tumor diagnosis and/or tumor treatment.
  • the beneficial effect of the present invention is that: the present invention provides a kind of mannose derivative, the radioactive preparation obtained by labeling it with radionuclide, has high uptake in tumor, and at the same time the ratio of tumor/non-target is good, it is a kind of popularization significance new tumor radiopharmaceuticals.
  • the present invention provides a mannose derivative and its application.
  • the present invention provides a radioactive preparation whose general structural formula is99mTc -CNDM:
  • n an integer of 2 or more
  • a represents an integer of 0 or more
  • b represents an integer of 0 or more.
  • n represents an integer of 2 or more
  • a represents an integer of 0 or more
  • b represents an integer of 0 or more
  • a represents an integer of 0 or greater
  • b represents an integer of 0 or greater
  • the radiochemical purity of the 99m Tc-CNDM complex prepared by the above method is greater than 90%, and the stability in vivo and in vitro is good. It has high uptake and good retention in the tumor site of tumor-bearing mice, and the target/non-target ratio is good. It is conducive to popularization and application as a new tumor imaging agent.
  • used instrument etc. do not indicate manufacturer's person, all are the conventional products that can be purchased through formal channel trader.
  • the methods are conventional methods unless otherwise specified, and the raw materials can be obtained from open commercial channels unless otherwise specified.
  • TLC Thin-layer chromatography
  • the radiochemical yield and radiochemical purity of the 99m Tc-CN7DM complex determined by the above chromatographic identification were both greater than 90%, and it was used in subsequent experiments without further purification.
  • High-performance liquid chromatography was used to identify the radiochemical purity of markers: SHIMADZU high-performance liquid chromatography (CL-20AVP), Kromasil C18 reverse-phase column (5 ⁇ m, 250 ⁇ 4.6mm), Gabi raytest radioactive detector.
  • the elution gradient is shown in Table 2, the flow rate is 1 mL/min, phase A is pure water containing 0.1% trifluoroacetic acid, and phase B is acetonitrile containing 0.1% trifluoroacetic acid.
  • Lipid-water partition coefficient P organic phase radioactive count/water phase radioactive count, usually expressed as log P as the lipid-water partition coefficient.
  • the measured log P value of 99m Tc-CN7DM is -3.15 ⁇ 0.06, indicating that it is a water-soluble substance.
  • the 99m Tc-CN7DM labeling solution (0.1mL, 370kBq) was injected into the mice bearing S180 tumors through the tail vein, and the mice were killed by neck dislocation at different time points (30min, 120min) after recording the injection time (every hour 5 mice), the tissues or organs of interest such as heart, liver, lung, kidney, spleen, bone, muscle, small intestine, blood, and tumor were taken out after dissection, and the radioactive counts of each organ were measured with a ⁇ -counter, and The uptake value (in %ID/g) of each organ was obtained after conversion of the mass of each organ, and the biodistribution results of the markers in tumor-bearing mice are shown in Table 3.
  • the invention provides a mannose derivative and application thereof.
  • the mannose derivatives are isonitrile-containing mannose derivatives containing different linking groups X with the structure shown in the general formula (I), and the radioactive preparation obtained by labeling it with a radionuclide has a high uptake in tumors. And the tumor/non-target ratio is good, it is a new type of tumor radiopharmaceutical worthy of promotion, and has good economic value and application prospect.

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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

一种甘露糖衍生物及其应用
交叉引用
本申请要求2021年7月23日提交的专利名称为“一种甘露糖衍生物及其应用”的第202110839524.X号中国专利申请的优先权，其全部公开内容通过引用整体并入本文。
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)：
Figure PCTCN2022104832-appb-000001
式中X为：
Figure PCTCN2022104832-appb-000002
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。
Figure PCTCN2022104832-appb-000003
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)：
Figure PCTCN2022104832-appb-000004
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：
Figure PCTCN2022104832-appb-000005
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：
Figure PCTCN2022104832-appb-000006
式中，n表示2或2以上的整数；
Figure PCTCN2022104832-appb-000007
式中，a表示0或0以上的整数，b表示0或0以上的整数；
Figure PCTCN2022104832-appb-000008
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SnCl 2·2H 2O，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Na 99mTcO 4，100℃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：
Figure PCTCN2022104832-appb-000009
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1a0.761g(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-d 4)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-d 4)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 C 15H 27N 2O 6[M+H] +:found 331.1861,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0.10mg SnCl 2·2H 2O，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Na 99mTcO 4，100℃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R f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R f值
Figure PCTCN2022104832-appb-000010
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1mL/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
Figure PCTCN2022104832-appb-000011
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900μL PBS(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)
Figure PCTCN2022104832-appb-000012
Figure PCTCN2022104832-appb-000013
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。
工业实用性
本发明提供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，具有较好的经济价值和应用前景。
Figure PCTCN2022104832-appb-000014

Claims (5)

  1. 一种甘露糖衍生物，其特征在于，所述甘露糖衍生物的结构式为(I)：
    Figure PCTCN2022104832-appb-100001
    式中X为：
    Figure PCTCN2022104832-appb-100002
    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。
  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。
  4. 根据权利要求3所述的放射性制剂，其特征在于，所述放射性制剂的结构式为(II)：
    Figure PCTCN2022104832-appb-100003
    式中：X、n、a、b是如权利要求1所定义的。
  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。
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