CN117105987A - 锝-99m标记含双药效基团的FAPI衍生物及制备方法和应用 - Google Patents
锝-99m标记含双药效基团的FAPI衍生物及制备方法和应用 Download PDFInfo
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- 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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- A—HUMAN NECESSITIES
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- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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- Y02P20/00—Technologies relating to chemical industry
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Abstract
本发明公开了一种结构通式为[99mTc]Tc‑(HYNIC‑PEG4‑2F46)(Tricine/TPPTS)的锝‑99m标记含双药效基团的FAPI衍生物及制备方法和应用。通过配体HYNIC‑PEG4‑2F46的合成以及[99mTc]Tc‑(HYNIC‑PEG4‑2F46)(Tricine/TPPTS)的制备两个步骤，得到[99mTc]Tc‑(HYNIC‑PEG4‑2F46)(Tricine/TPPTS)配合物。该配合物制备简便，放射化学纯度高，稳定性好，在U87MG荷瘤小鼠肿瘤部位有很高的摄取和高的靶与非靶比值，且在肿瘤中与FAP有特异性结合，是一种有临床应用价值的新型肿瘤放射性药物。
Description
技术领域
本发明属于放射性药物领域，特别涉及锝-99m标记含双药效基团的FAPI衍生物及制备方法和应用。
背景技术
肿瘤微环境在肿瘤的发生、发展过程中发挥着极其重要的作用。肿瘤相关成纤维细胞是构成肿瘤微环境的重要组成部分，在肿瘤细胞的增殖、迁移、免疫逃逸、放化疗抵抗和能量代谢中扮演着重要的角色。成纤维细胞激活蛋白(FAP)是肿瘤相关成纤维细胞表面重要的分子标志物，因其选择性地表达于大多数实体瘤基质的成纤维细胞的细胞膜上，成为肿瘤检测和治疗的重要靶点。
基于(4-喹啉酰基)-甘氨酰-2-氰基吡咯烷的FAP小分子抑制剂(FAPI)具有高亲力和高选择性。通过对结构的不断修饰和改进，一系列68Ga标记的FAPI配合物被报道，并用于在原发病灶和转移病灶的肿瘤显像。其中，[68Ga]Ga-FAPI-04表现出良好生物分布，在肿瘤中摄取迅速，图像对比度良好。在癌症病人体内研究表明，原发性不明原因癌、肉瘤、胆管癌、食管癌、乳腺癌和肺癌中均有较高的摄取。在FAPI-04的基础上进行结构改进，[68Ga]Ga-FAPI-46表现出比[68Ga]Ga-FAPI-04更高的肿瘤摄取和滞留，其在正常器官中的摄取也明显降低。人体显像数据显示，[68Ga]Ga-FAPI-46在原发性肿瘤和转移灶中迅速积累，正常组织中的示踪剂摄取量低,能够产生高对比度图像。从目前的报道来看，[68Ga]Ga-FAPI-46表现出最佳的效果，因此其药效基团也被进一步的研究。
[68Ga]Ga-DOTA-2P(FAPI)2含有两个FAPI-46药效基团，荷瘤小鼠生物分布显示，相较于[68Ga]Ga-FAPI-46，[68Ga]Ga-DOTA-2P(FAPI)2表现出了更高的肿瘤摄取和更高的肿瘤/肾脏的比值。在患者的PET/CT显像可以看出，[68Ga]Ga-DOTA-2P(FAPI)2的肿瘤摄取要高于[68Ga]Ga-FAPI-46。这表明含有两个药效基团的分子探针可以有效提高肿瘤特异性摄取，降低非靶摄取，提高靶与非靶比值。
目前关于靶向FAP分子探针的报道中，68Ga标记配合物最多，约占92％，此外，18F标记的FAPI分子探针[18F]AlF-NOTA-FAPI、[18F]F-FAPI-74和[18F]AlF-P-FAPI等，具有较高的特异性肿瘤摄取和优良的显像效果。但是上述探针均为PET(正电子发射断层成像术，Positron Emission Tomography)显像剂，价格昂贵，临床应用推广受到一定限制。而基于99mTc的SPECT(单光子发射计算机断层成像术,Single-Photon Emission ComputedTomography)诊断技术具有以下优势：99mTc是一种由99Mo/99mTc发生器制备得到的SPECT类核素，方便易得，由于全球SPECT设备数量多，约为27000台，所以能够被更为广泛的市场应用，药盒化的生产工艺更加简便可控；价格低廉且已经纳入医保可以使更多患者受益。近年来基于碲锌镉(CZT)技术的SPECT/CT以及软件的发展，螺旋定量SPECT/CT生产，进一步提升显像质量和缩短显像时间，SPECT/CT显像再次迎来了曙光。
目前99mTc标记的SPECT类靶向FAP分子探针报道较少，其中[99mTc]Tc-FAPI-34和[99mTc][Tc-(CN-PEG4-FAPI)6]+有较高的亲和力和较高的肿瘤摄取，但是腹部非靶脏器摄取较高在一定程度上制约其应用。为了开发优良的靶向FAP的SPECT类肿瘤分子探针，2021年，我们研制了一种99mTc标记FAPI衍生物(专利号：ZL2021115355016)，其以D-脯氨酸修饰的含HYNIC基团的FAPI衍生物(HYNIC-DP-FAPI)和协同配体三羟甲基甘氨酸(Tricine)及三苯基膦三磺酸钠(TPPTS)与99mTc配位形成稳定的99mTc(HYNIC-DP-FAPI)(Tricine/TPPTS)。该配合物具有良好的体内外稳定性与FAP亲和性，生物分布显示荷瘤小鼠肿瘤部位有很高的摄取，在非靶器官如心、肝、肌肉等摄取较低，但是由于血液摄取较高，肿瘤/血比值有待提高。
为了有效解决99mTc标记靶向FAP肿瘤分子探针的肿瘤摄取以及肿瘤/血比值有待提高的问题，本专利在FAPI-46的药效基团的基础上进行结构修饰得到含有两个FAPI-46药效基团的配体(HYNIC-PEG4-2F46)，然后和协同配体Tricine/TPPTS与99mTc配位形成稳定的制备稳定性高、靶向性强、靶与非靶比值好且易于推广的靶向FAP的肿瘤分子探针[99mTc]Tc-(HYNIC-PEG4-2F46)(Tricine/TPPTS)，以用于肿瘤早期诊断、分期和疗效评价，将为转化医学和精准医疗的实现奠定良好的基础。
发明内容
本发明的目的是提供锝-99m标记含双药效基团的FAPI衍生物及制备方法和应用。
为了实现上述目的，本发明提供的锝-99m标记含双药效基团的FAPI衍生物[99mTc]Tc-(HYNIC-PEG4-2F46)(Tricine/TPPTS)，其结构如式(I)所示：
该结构式中：HYNIC-PEG4-2F46分子中肼基上的氮原子、共配体TPPTS中的磷原子以及Tricine中的氧原子和氮原子与99mTc配位得到[99mTc]Tc-(HYNIC-PEG4-2F46)(Tricine/TPPTS)配合物。
锝-99m标记含双药效基团的FAPI衍生物的制备方法，其制备步骤如下：
a:配体HYNIC-PEG4-2F46的合成:
将化合物1和化合物2溶解于适量的N,N-二甲基甲酰胺(DMF)中，再加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)和N-乙基二异丙胺(DIPEA)，置于室温下搅拌反应，反应完成后旋干反应液，加入25％三乙胺/四氢呋喃(TEA/THF)，室温下反应3h，用反相制备液相分离纯化得化合物3；将化合物4溶解于DMF中，再加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDCI)和1-羟基苯并三唑(HOBt)，室温下反应，再加入化合物3和N-甲基吗啉(NMM)，室温下反应，旋干溶剂，再溶解于三氟乙酸(TFA)中，室温反应30min，再将反应液加入到冰乙醚中，大量固体析出，离心，所得固体用反相制备液相纯化，得到化合物5；称取适量化合物5于圆底烧瓶中，加入适量DMF溶解，然后依次加入DIPEA和化合物6，室温下反应6h，旋干溶剂，用反相制备液相分离纯化得HYNIC-PEG4-2F46。具体合成路线为：
b:[99mTc]Tc-(HYNIC-PEG4-2F46)(Tricine/TPPTS)配合物的制备：
称取适量的Tricine、TPPTS、HYNIC-PEG4-2F46配体溶于生理盐水中，调节溶液pH为5.0，向其中加入适量的新鲜淋洗的Na99mTcO4，沸水浴加热30min即可得到所述的[99mTc]Tc-(HYNIC-PEG4-2F46)(Tricine/TPPTS)配合物。
通过上述方法制备的[99mTc]Tc-(HYNIC-PEG4-2F46)(Tricine/TPPTS)配合物的放射化学纯度大于95％，为亲水性物质，体外稳定性良好。其在荷瘤小鼠肿瘤部位有很高的摄取与良好的滞留(注射后1h:21.07±1.70％ID/g；4h:15.09±2.13％ID/g)，注射FAP抑制剂进行抑制后，肿瘤摄取显著性降低(由21.07±1.70％ID/g降低到4.91±0.48％ID/g)，表明其在肿瘤中的摄取与FAP具有特异性。与锝-99m标记的含HYNIC基团的FAPI衍生物(99mTc(HYNIC-DP-FAPI)(Tricine/TPPTS))相比，在注射1小时后，该药物在U87MG肿瘤的摄取显著性提高(由16.26±2.71％ID/g提高到21.07±1.70％ID/g)，且靶与非靶比值明显提升(肿瘤/肌肉比值由6.20上升到8.18；肿瘤/血液比值由2.42上升到3.10)，达到预期效果。显像结果表明其在肿瘤部位有明显浓集，非靶组织摄取低，且在肿瘤中的摄取可以被FAP抑制剂显著地抑制，是性能优良的可用于肿瘤显像的新型SPECT分子探针。
具体实施方式
下面通过实施例详述本发明：一种锝-99m标记以锝-99m标记含双药效基团的FAPI衍生物，结构通式为[99mTc]Tc-(HYNIC-PEG4-2F46)(Tricine/TPPTS)，其结构式如下：
该结构式中：HYNIC-PEG4-2F46分子中肼基上的氮原子、共配体TPPTS中的磷原子以及Tricine中的氧原子和氮原子与99mTc配位得到[99mTc]Tc-(HYNIC-PEG4-2F46)(Tricine/TPPTS)配合物。
[99mTc]Tc-(HYNIC-PEG4-2F46)(Tricine/TPPTS)配合物的制备方法，其制备步骤如下：
a.HYNIC-PEG4-2F46的合成
将化合物1(200mg)和化合物2(195mg)溶解于10mL DMF中，再加入HATU(182mg)和DIPEA(215uL)，置于室温下搅拌反应1h，TLC监测反应完成，用旋蒸旋干反应液，再加入10mL25％TEA/THF，室温下反应3h，旋干，用反相制备液相分离纯化得化合物3(215mg,72％)；
将化合物4(32mg)溶解于5mL DMF中，再加入EDCI(30mg)和HOBt(21mg)，室温下反应10min，再加入化合物3(215mg)和NMM(42uL)，室温下反应2h，旋干溶剂，再溶解于5mL TFA中，室温反应30min，再将反应液加入到50mL冰乙醚中，大量固体析出，离心，所得固体用反相制备液相纯化，得到化合物5(131mg，63％)；
将化合物5(131mg)溶解于5mL DMF中，再加入DIPEA(44uL)，最后加入化合物6(44mg)，室温下反应6h，旋干溶剂，用反相制备液相分离纯化得HYNIC-PEG4-2F46(76mg,46％)。1H NMR(400MHz,Methanol-d4)δ9.02(s,1H),8.63(d,J＝5.1Hz,3H),8.37(s,1H),8.18(d,J＝7.8Hz,1H),8.08(s,1H),7.98(d,J＝9.5Hz,3H),7.89(d,J＝7.5Hz,1H),7.66(dd,J＝8.1,5.3Hz,6H),7.61(s,3H),7.53-7.38(m,3H),7.17(s,1H),5.16-5.12(m,3H),4.39-4.20(m,12H),4.11(dt,J＝20.3,10.1Hz,4H),3.83-3.76(m,5H),3.67(q,J＝6.5Hz,12H),3.54-3.51(m,34H),3.15(d,J＝2.5Hz,11H),2.62(s,6H),2.48-2.40(m,4H),2.27(s,3H),2.14(s,6H).MS：M(Formula:C95H124F4N21NaO21S；MW:2027.21),[M-Na+4H]/3:found669.3,calcd 669.3。
合成路线为：
b.[99mTc]Tc-(HYNIC-PEG4-2F46)(Tricine/TPPTS)配合物的制备
称取1mg Tricine和2mg TPPTS溶于0.5mL生理盐水中，加入pH为5.0的琥珀酸盐缓冲液调节溶液pH为5.0，向其中依次加入20μg配体HYNIC-PEG4-2F46和0.5mL新鲜淋洗的Na99mTcO4(约370MBq)，沸水浴加热30min即可得到所述的[99mTc]Tc-(HYNIC-PEG4-2F46)(Tricine/TPPTS)配合物。
本发明[99mTc]Tc-(HYNIC-PEG4-2F46)(Tricine/TPPTS)配合物的性能测定：
1.配合物的鉴定
[99mTc]Tc-(HYNIC-PEG4-2F46)(Tricine/TPPTS)采用高效液相色谱(HPLC)法鉴定：用C18反向柱，SCL-10AVP型高压液相色谱仪，A相为水(含0.1％三氟乙酸)，B相为乙腈(含0.1％三氟乙酸)，梯度为0-2min B相为10％，2-10min B相由10％变为90％，10-15min B相为90％，15-20min B相由90％变为10％，20-30min B相为10％。进样量为20μL，流速为1mL/min。测定[99mTc]Tc-(HYNIC-PEG4-2F46)(Tricine/TPPTS)保留时间(Rt)为：10.27min。
2.配合物的脂水分配系数的测定
取0.9mL pH 7.4的磷酸盐缓冲液(0.025mol/L)于5mL离心试管中，在离心试管中加入1mL正辛醇和0.1mL[99mTc]Tc-(HYNIC-PEG4-2F46)(Tricine/TPPTS)溶液，盖上塞子，充分摇匀，离心5min(5000r/min)。然后分别从有机相和水相中取出3×0.1mL，测定二相的放射性计数，并计算其分配系数D(D＝有机相的放射性活度/水相的放射性活度)，重复五组。测得[99mTc]Tc-(HYNIC-PEG4-2F46)(Tricine/TPPTS)配合物的脂水分配系数(logD)为-3.10±0.06，表明其为亲水性物质。
3.配合物的稳定性测定
将配合物分别在室温下放置和37℃小鼠血清中放置4小时后测定其放射化学纯度，结果表明[99mTc]Tc-(HYNIC-PEG4-2F46)(Tricine/TPPTS)配合物在室温下和37℃小鼠血清中放置4小时后放射化学纯度均大于90％，说明其体外稳定性良好。
4.配合物在荷瘤小鼠中的生物分布实验
从荷U87MG肿瘤Balb/c模型小鼠的尾静脉注射0.10mL[99mTc]Tc-(HYNIC-PEG4-2F46)(Tricine/TPPTS)标记液(约3.7×105Bq)，注射后1h和4h时麻醉后处死小鼠。此外，使用FAPI对[99mTc]Tc-(HYNIC-PEG4-2F46)(Tricine/TPPTS)进行小鼠体内抑制实验，方法如下：将100μL含有100μgFAPI的生理盐水溶液尾静脉注射小鼠体内，30min后注射0.10mL[99mTc]Tc-(HYNIC-PEG4-2F46)(Tricine/TPPTS)标记液(约3.7×105Bq)，1h后麻醉后处死小白鼠。取其心、肝、肺、肾、脾、骨、小肠、胃、肌肉、血、肿瘤等有关组织和器官，擦净后称重，并在γ-Counter上测其放射性计数，计算各组织的每克百分注射剂量(％ID/g)。每个时项的小鼠数为4只。结果见表1。
表1[99mTc]Tc-(HYNIC-PEG4-2F46)(Tricine/TPPTS)在荷U87MG肿瘤Balb/c裸鼠的生物分布(％ID/g，n＝4)
5.配合物在荷瘤小鼠的SPECT显像
从荷U87MG肿瘤Balb/c模型小鼠的尾静脉注射[99mTc]Tc-(HYNIC-PEG4-2F46)(Tricine/TPPTS)溶液0.2mL(约37MBq)，1小时后，使用异氟烷气体麻醉。抑制组需要提前30min注射100μL含有100μg FAPI的生理盐水溶液，然后注射[99mTc]Tc-(HYNIC-PEG4-2F46)(Tricine/TPPTS)配合物0.2mL(约37MBq)，1小时后，使用异氟烷气体麻醉。将小鼠俯卧固定，使用SPECT/CT进行显像。SPECT显像结果表明在实验组中[99mTc]Tc-(HYNIC-PEG4-2F46)(Tricine/TPPTS)在肿瘤中浓集明显，而在抑制组中肿瘤的摄取明显降低，进一步说明其在肿瘤中的摄取具有特异性，表明其可作为亲肿瘤性能优良的新型SPECT分子探针。
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，改变不同的连接剂，如氨基酸、肽链、聚乙二醇(PEG)链、脂肪链等，或利用N-三(羟甲基)甲基甘氨酸(Tricine)和乙二胺-N,N'-二乙酸(EDDA)、N-三(羟甲基)甲基甘氨酸(Tricine)和二苯基膦苯-3-磺酸钠(TPPMS)、N-三(羟甲基)甲基甘氨酸(Tricine)和3,3'-(苯基膦二基)二(苯-1-磺酸)二钠(TPPDS)、N-三(羟甲基)甲基甘氨酸(Tricine)和烟酸(NIC)、N-三(羟甲基)甲基甘氨酸(Tricine)和异烟酸(ISONIC)、N-三(羟甲基)甲基甘氨酸(Tricine)和3,5-吡啶二羧酸(PDA)、N-三(羟甲基)甲基甘氨酸(Tricine)和3-吡啶磺酸(PSA)、N-三(羟甲基)甲基甘氨酸(Tricine)和葡庚糖酸盐、N-三(羟甲基)甲基甘氨酸(Tricine)和葡糖胺、N-三(羟甲基)甲基甘氨酸(Tricine)和甘露糖醇、N-三(羟甲基)甲基甘氨酸(Tricine)和二苯基膦苯甲酸等共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 (3)
1.一种锝-99m标记含双药效基团的FAPI衍生物，结构通式为[99mTc]Tc-(HYNIC-PEG4-2F46)(Tricine/TPPTS)，其结构如下式所示：
该结构式中：HYNIC-PEG4-2F46分子中肼基上的氮原子、共配体TPPTS中的磷原子以及Tricine中的氧原子和氮原子与99mTc配位得到[99mTc]Tc-(HYNIC-PEG4-2F46)(Tricine/TPPTS)配合物。
2.一种制备方法，其用于获得权利要求1所述的锝-99m标记含双药效基团的FAPI衍生物，其特征在于，其工艺步骤如下：
a:配体HYNIC-PEG4-2F46的合成:
将化合物1和化合物2溶解于适量的N,N-二甲基甲酰胺(DMF)中，再加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)和N-乙基二异丙胺(DIPEA)，置于室温下搅拌反应，反应完成后旋干反应液，加入25％三乙胺/四氢呋喃(TEA/THF)，室温下反应3h，用反相制备液相分离纯化得化合物3；将化合物4溶解于DMF中，再加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDCI)和1-羟基苯并三唑(HOBt)，室温下反应，再加入化合物3和N-甲基吗啉(NMM)，室温下反应，旋干溶剂，再溶解于三氟乙酸(TFA)中，室温反应30min，再将反应液加入到冰乙醚中，大量固体析出，离心，所得固体用反相制备液相纯化，得到化合物5；称取适量化合物5于圆底烧瓶中，加入适量DMF溶解，然后依次加入DIPEA和化合物6，室温下反应6h，旋干溶剂，用反相制备液相分离纯化得HYNIC-PEG4-2F46；
具体合成路线为：
b:[99mTc]Tc-(HYNIC-PEG4-2F46)(Tricine/TPPTS)配合物的制备：
称取适量的N-三(羟甲基)甲基甘氨酸(Tricine)、三苯基膦三间磺酸钠(TPPTS)、HYNIC-PEG4-2F46配体溶于生理盐水中，调节溶液pH为5.0，向其中加入适量的新鲜淋洗的Na99mTcO4，沸水浴加热30min即可得到所述的[99mTc]Tc-(HYNIC-PEG4-2F46)(Tricine/TPPTS)配合物。
3.如权利要求1所述的锝-99m标记含双药效基团的FAPI衍生物在制备肿瘤显像剂中的应用。
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