WO2024000648A1 - Psma荧光分子探针、制备方法及试剂盒 - Google Patents

Psma荧光分子探针、制备方法及试剂盒 Download PDF

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WO2024000648A1
WO2024000648A1 PCT/CN2022/105197 CN2022105197W WO2024000648A1 WO 2024000648 A1 WO2024000648 A1 WO 2024000648A1 CN 2022105197 W CN2022105197 W CN 2022105197W WO 2024000648 A1 WO2024000648 A1 WO 2024000648A1
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psma
molecular probe
fluorescent molecular
solution
fitc
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赵静
杨丽蓉
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戴格普瑞生物科技(苏州)有限公司
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    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
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    • G—PHYSICS
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    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/645—Specially adapted constructive features of fluorimeters
    • G01N21/6456—Spatial resolved fluorescence measurements; Imaging
    • G01N21/6458—Fluorescence microscopy
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    • C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
    • C09K2211/10—Non-macromolecular compounds
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    • C09K2211/1088—Heterocyclic compounds characterised by ligands containing oxygen as the only heteroatom
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • G01N2021/6439—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" with indicators, stains, dyes, tags, labels, marks

Definitions

  • the present invention relates to detection technology, in particular to a PSMA fluorescent molecular probe, preparation method and kit.
  • Prostate cancer is often difficult to detect early due to its relatively slow progression.
  • Prostate-specific antigen (PSA) combined with magnetic resonance imaging and needle biopsy can effectively diagnose PCa.
  • PSA Prostate-specific antigen
  • PET/CT integrates PET's highly sensitive and specific nuclear medicine molecular imaging and CT's fine anatomical images. It has been used in the preoperative diagnosis of primary prostate cancer. It has great potential in many aspects such as staging and treatment decision-making.
  • radical prostatectomy is one of the most effective methods for treating localized and locally advanced prostate cancer.
  • the surgeon’s determination of the margin range mainly relies on preoperative imaging examinations, intraoperative macroscopic findings and exploration, and the surgeon own experience. Excessive surgical resection will damage normal tissues and affect normal functions such as urinary control; while too small a resection range will result in positive margins and patients are prone to recurrence. Therefore, how to preserve normal tissues and functions as much as possible during surgery while completely resecting the area invaded by prostate cancer is a problem that clinicians often need to face and solve.
  • PSMA prostate-specific membrane antigen
  • PSMA is overexpressed in 90% of prostate cancers, while only a small amount of expression is found in normal tissues such as lacrimal salivary glands and kidney proximal tubules.
  • the expression level of PSMA in prostate cancer is highly correlated with tumor invasion and malignancy. Therefore, PSMA has become an ideal biomarker for precise localization imaging and intraoperative navigation of prostate cancer lesions.
  • the near-infrared fluorescence surgical navigation technology targeting PSMA mainly uses near-infrared dyes, which have the advantages of longer wavelength, strong tissue penetration, and small scattering.
  • the optical-nuclear medicine dual-modality molecular imaging probe can combine the advantages of the two imaging modalities. It can identify and locate diseased tissue through nuclear medicine modality with high sensitivity and accuracy before surgery, and accurately fluorescence during surgery. Marking the location of the lesion guides surgical resection.
  • the purpose of the present invention is to provide a PSMA fluorescent molecular probe, preparation method and kit, which optimizes the molecular structure of the probe, has the characteristics of good solubility, strong fluorescence penetration, good applicability, and adopts optimized
  • the selected synthesis scheme has higher synthesis yield and efficiency, improving the cost performance and promotion and application performance of the product.
  • embodiments of the present invention provide a PSMA fluorescent molecular probe, the general formula is Wherein R2 is p-methylphenylbutyryl or -CO(CH 2 ) 16 COOH, and the fluorescent molecular probe is specifically selected from:
  • the method for preparing PSMA fluorescent molecular probes includes the following steps: preparing a raw material solution containing raw materials, a first solution and a FITC solution (FITC, CAS: 3326-32-7),
  • the first solution is a hydrogen phosphate solution with pH 8-9
  • the raw materials are adaptively selected from:
  • the FITC solution is then added, and the reaction, separation, and purification are completed.
  • the raw material liquid is an aqueous solution, and the concentration of the raw material is: 0.01-0.1 mg/ ⁇ L.
  • the solute of the first solution is selected from K2HPO4, Na2HPO4.
  • the first solution is an aqueous solution or a DMSO solution.
  • the solvent in the FITC solution is selected from: DMSO, DMF, and DME.
  • the concentration of FITC in the FITC solution is: 0.010-0.05 mg/ ⁇ L.
  • the reaction conditions are stirring at 15-35°C in the dark.
  • the reaction time of the reaction is 1-4 h.
  • the stirring speed is 100-1000 rpm.
  • the kit includes the aforementioned PSMA fluorescent molecular probe.
  • the PSMA fluorescent molecular probe, preparation method and kit according to the embodiments of the present invention optimize the molecular structure of the probe, have the characteristics of good solubility, strong fluorescence penetration, and have good applications.
  • the optimized synthesis scheme is adopted to achieve higher synthesis yield and efficiency, which improves the cost performance and promotion and application performance of the product.
  • Figure 1 is a mass spectrum of a PSMA fluorescent molecular probe according to an embodiment of the present invention
  • Figure 2 is a mass spectrum of a PSMA fluorescent molecular probe according to another embodiment of the present invention.
  • Figure 3 is a comparison chart of the binding capacity of the PSMA fluorescent molecular probe (compound 2) according to an embodiment of the present invention, in which PC3 is a PSMA-negative cell and 22RV1 is a PSMA-positive cell;
  • Figure 4 is a fluorescence imaging of PSMA fluorescent molecular probe (Compound 2) stained in 22RV1 and PC3 cells according to an embodiment of the present invention, where PC3 is a PSMA-negative cell and 22RV1 is a PSMA-positive cell;
  • Figure 5 is the fluorescence imaging of the PSMA fluorescent molecular probe (compound 2) in tumors according to an embodiment of the present invention, in which PC3 is a PSMA-negative cell and 22RV1 is a PSMA-positive cell;
  • Figure 6 is the fluorescence imaging of the PSMA fluorescent molecular probe (Compound 2) in tumors according to an embodiment of the present invention, in which PC3 is a PSMA-negative cell and 22RV1 is a PSMA-positive cell;
  • Figure 7 is fluorescence imaging of PSMA fluorescent molecular probe (Compound 2) in tumors and different organs according to an embodiment of the present invention.
  • the PSMA fluorescent molecular probe (compound 1) is:
  • the synthesis scheme of this example is: add 0.01M Na2HPO4 (150 ⁇ L, pH 8.4) to 50 ⁇ L of the aqueous solution of compound 1 (concentration: 0.01 mg/ ⁇ L) to obtain a mixed solution.
  • FITC (0.25 mg) was dissolved in 10 ⁇ L DMSO, then added to the aforementioned mixed solution, stirred at 200 rpm for 2 hours at 20°C in the dark, and passed through a high-performance liquid chromatograph (Agilent 588915-902, HC-C18 (2) 4.6 ⁇ 150mm, 5 ⁇ m, 0-5 minutes: 5% acetonitrile, 5-45 minutes: 5-95% methanol, flow rate: 1 ml per minute) Purification (product purity is 90%, yield is 85%) Its chemical structure Characterized by Waters' LC-MS, the spectrum is shown in Figure 1 (M/2+1).
  • IVIS in vivo fluorescence imaging was performed at different time points (1, 1.5, 3, 6 and 9h).
  • the imaging parameters were excitation 750nm and emission 800nm.
  • the results show that compound 1 has high expression of PSMA and high sensitivity.
  • the synthesis scheme of this example is: add Na2HPO4 (150 ⁇ L) of pH 8 to 50 ⁇ L of the aqueous solution of compound 1 (concentration: 0.05 mg/ ⁇ L) to obtain a mixed solution.
  • FITC 0.1 mg was dissolved in 10 ⁇ L DMSO, then added to the aforementioned mixed solution, stirred at 1000 rpm for 3 hours at 15°C in the dark, and passed through a high performance liquid chromatograph (Agilent 588915-902, HC-C18 (2) 4.6 ⁇ 150mm, 5 ⁇ m, 0-5 minutes: 5% acetonitrile, 5-45 minutes: 5-95% methanol, flow rate: 1 ml per minute) Purification (product purity is 93%, yield is 84%) Its chemical structure is given by Waters' LC-MS was used for characterization, and the spectrum is shown in Figure 1 (M/2+1).
  • the synthesis scheme of this example is: add K2HPO4 (150 ⁇ L) of pH 9 to 50 ⁇ L of the aqueous solution of compound 1 (concentration: 0.1 mg/ ⁇ L) to obtain a mixed solution.
  • FITC 0.5 mg was dissolved in 10 ⁇ L DME, then added to the aforementioned mixed solution, stirred at 800 rpm for 1 hour at 35°C in the dark, and passed through a high-performance liquid chromatograph (Agilent 588915-902, HC-C18 (2) 4.6 ⁇ 150mm, 5 ⁇ m, 0-5 minutes: 5% acetonitrile, 5-45 minutes: 5-95% methanol, flow rate: 1 ml per minute) Purification (product purity is 91%, yield is 86%) Its chemical structure is given by Waters' LC-MS was used for characterization, and the spectrum is shown in Figure 1 (M/2+1).
  • the synthesis scheme of this example is: add K2HPO4 (150 ⁇ L) of pH 8.6 to 50 ⁇ L of the aqueous solution of compound 1 (concentration: 0.08 mg/ ⁇ L) to obtain a mixed solution.
  • FITC (0.25 mg) was dissolved in 10 ⁇ L DMF, then added to the aforementioned mixed solution, stirred at 100 rpm for 4 hours at 30°C in the dark, and passed through a high-performance liquid chromatograph (Agilent 588915-902, HC-C18 (2) 4.6 ⁇ 150mm, 5 ⁇ m, 0-5 minutes: 5% acetonitrile, 5-45 minutes: 5-95% methanol, flow rate: 1 ml per minute) Purification (product purity is 87%, yield is 80%) Its chemical structure is given by Waters' LC-MS was used for characterization, and the spectrum is shown in Figure 1 (M/2+1).
  • the synthesis scheme of this comparative example is: add FITC solution (0.25 mg FITC dissolved in 10 ⁇ L DMF) to 50 ⁇ L of the aqueous solution of compound 1 (concentration: 0.08 mg/ ⁇ L) to obtain a mixed solution.
  • the synthesis scheme of this comparative example is: after blending 50 ⁇ L of the aqueous solution of compound 1 (concentration: 0.08 mg/ ⁇ L), K2HPO4 at pH 8.6 (150 ⁇ L) and FITC solution (0.25 mg FITC dissolved in 10 ⁇ L DMF), the mixture was heated at 30°C. Under dark conditions, stir at 100 rpm for 4 hours, and pass through high performance liquid chromatography (Agilent 588915-902, HC-C18 (2) 4.6 ⁇ 150 mm, 5 ⁇ m, 0-5 minutes: 5% acetonitrile, 5-45 minutes: 5- 95% methanol, flow rate: 1 ml per minute) purification (product purity is 73%, yield 55%). Its chemical structure is characterized by Waters' LC-MS, and the chromatogram is shown in Figure 1 (M/2+1) .
  • the PSMA fluorescent molecular probe (compound 2) is:
  • IVIS in vivo fluorescence imaging was performed at different time points (1, 1.5, 3, 6 and 9h).
  • the imaging parameters were excitation 750nm and emission 800nm.
  • the imaging results are shown in Figures 5 and 6, and the fluorescence display of the dissected organs is shown in Figure 7.
  • the synthesis scheme of this example is: add Na2HPO4 (150 ⁇ L) of pH 8 to 50 ⁇ L of the aqueous solution of compound 3 (concentration: 0.05 mg/ ⁇ L) to obtain a mixed solution.
  • FITC 0.1 mg was dissolved in 10 ⁇ L DMSO, then added to the aforementioned mixed solution, stirred at 1000 rpm for 3 hours at 15°C in the dark, and passed through a high performance liquid chromatograph (Agilent 588915-902, HC-C18 (2) 4.6 ⁇ 150mm, 5 ⁇ m, 0-5 minutes: 5% acetonitrile, 5-45 minutes: 5-95% methanol, flow rate: 1 ml per minute) Purification (product purity is 91%, yield is 83%) Its chemical structure is given by Waters' LC-MS was used for characterization, and the spectrum is shown in Figure 2 (M/2+1).
  • the synthesis scheme of this example is: add K2HPO4 (150 ⁇ L) of pH 9 to 50 ⁇ L of the aqueous solution of compound 3 (concentration: 0.1 mg/ ⁇ L) to obtain a mixed solution.
  • FITC 0.5 mg was dissolved in 10 ⁇ L DME, then added to the aforementioned mixed solution, stirred at 800 rpm for 1 hour at 35°C in the dark, and passed through a high-performance liquid chromatograph (Agilent 588915-902, HC-C18 (2) 4.6 ⁇ 150mm, 5 ⁇ m, 0-5 minutes: 5% acetonitrile, 5-45 minutes: 5-95% methanol, flow rate: 1 ml per minute) Purification (product purity is 90%, yield is 84%) Its chemical structure Characterized by Waters' LC-MS, the spectrum is shown in Figure 2 (M/2+1).
  • the synthesis scheme of this example is as follows: add K2HPO4 (150 ⁇ L) of pH 8.6 to 50 ⁇ L of the aqueous solution of compound 3 (concentration: 0.08 mg/ ⁇ L) to obtain a mixed solution.
  • FITC (0.25 mg) was dissolved in 10 ⁇ L DMF, then added to the aforementioned mixed solution, stirred at 100 rpm for 4 hours at 30°C in the dark, and passed through a high-performance liquid chromatograph (Agilent 588915-902, HC-C18 (2) 4.6 ⁇ 150mm, 5 ⁇ m, 0-5 minutes: 5% acetonitrile, 5-45 minutes: 5-95% methanol, flow rate: 1 ml per minute) Purification (product purity is 93%, yield is 82%) Its chemical structure Characterized by Waters' LC-MS, the spectrum is shown in Figure 2 (M/2+1).
  • the synthesis scheme of this comparative example is: add FITC solution (0.25 mg FITC dissolved in 10 ⁇ L DMF) to 50 ⁇ L of the aqueous solution of compound 3 (concentration: 0.08 mg/ ⁇ L) to obtain a mixed solution.
  • the synthesis scheme of this comparative example is: after blending 50 ⁇ L of the aqueous solution of compound 3 (concentration: 0.08 mg/ ⁇ L), K2HPO4 at pH 8.6 (150 ⁇ L) and FITC solution (0.25 mg FITC dissolved in 10 ⁇ L DMF), the mixture was heated at 30°C. Under dark conditions, stir at 100 rpm for 4 hours, and pass through high performance liquid chromatography (Agilent 588915-902, HC-C18 (2) 4.6 ⁇ 150 mm, 5 ⁇ m, 0-5 minutes: 5% acetonitrile, 5-45 minutes: 5- 95% methanol, flow rate: 1 ml per minute) was purified (product purity was 91%, yield was 53%). Its chemical structure was characterized by Waters' LC-MS, and the chromatogram is shown in Figure 2 (M/2+1) .

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Abstract

本发明是关于PSMA荧光分子探针、制备方法及试剂盒，其中探针的通式为I，其中R2为对甲基苯丁酰基或II。本发明方案优化了探针的分子结构，具有溶解性好，荧光穿透性强的特点，具有良好的应用性。

Description

PSMA荧光分子探针、制备方法及试剂盒
本发明要求2022年07月01日向中国专利局提交的、申请号为202210763244X、发明名称为“PSMA荧光分子探针、制备方法及试剂盒”的中国专利申请的优先权，该申请的全部内容通过引用结合在本文中。
技术领域
本发明关于检测技术，特别是关于一种PSMA荧光分子探针、制备方法及试剂盒。
背景技术
前列腺癌早期的准确检测对患者的治疗效果和生存至关重要。前列腺癌由于进展相对缓慢往往较难及早发现，前列腺特异性抗原(PSA)联合磁共振成像以及穿刺活检能有效诊断PCa，但目前缺乏能界定其生物学行为的高灵敏度及特异性的功能性成像设备，近十年来PET/CT得到了长足的发展，PET/CT整合了PET兼具高灵敏度与特异度的核医学分子影像以及CT精细的解剖图像，已在原发性前列腺癌的术前诊断与分期以及治疗决策制定等多个方面发挥出巨大的潜力。在治疗上，根治性前列腺癌切除术是治疗局限性及局部进展前列腺癌最有效的方法之一，术者确定切缘范围主要依靠术前影像学检查、术中肉眼所见及探查和术者自身经验。手术切除范围过大会损伤正常组织，影响尿控等正常功能；而切除范围过小会导致阳性切缘，患者容易出现复发。因此，如何在手术中尽可能保留正常组织和功能，同时对前列腺癌侵犯区域进行彻底切除是临床医生经常需要面对和解决的问题。
靶向荧光术中导航技术正是解决这一问题的良方，在前列腺癌领域，存在高特异性的前列腺癌分子标志物—前列腺特异性膜抗原(PSMA)。PSMA在90％的前列腺癌中过度表达，而正常组织如泪腺唾液腺、肾脏近端小管中仅有少量表达。PSMA在前列腺癌中的表达水平与肿瘤的侵袭和恶性程度高度相关。因此，PSMA成为前列腺癌病灶精准定位显像和术中导航的理想生物标志物。靶向PSMA的近红外荧光手术导航技术主要利用近红外染料具有波长较长、组织穿透力较强、散射较小等优点，可在术中点亮病灶，让术者清晰地了解病灶的范围，从而对其进行更加完整有效的切除，因此，靶向PSMA的近红外荧光手术导航将是治疗前列腺癌的一种非常有前景的手术方式。进一步，光学-核医学双模态的分子影像探针可结合两种显像模态的优势，高灵敏 度、高精确度在手术前通过核医学模态识别和定位病变组织、在手术中精准荧光标记病灶位置引导外科手术的切除。
目前临床实验中使用的靶向PSMA的核素诊疗和手术导航药物都是以谷氨酸-脲基为基本骨架。这些探针对PSMA具有良好的靶向性和亲和力，但是存在膀胱内核素滞留严重及肾脏内核素背景高的问题，膀胱内大量核素滞留严重影响前列腺癌早期诊断准确率，而双肾高核素背景对肾脏具有一定的毒副作用。因此亟需通过改变药物结构，开发高特异性、低肾脏排泄的PSMA分子影像探针，对于实现前列腺癌病灶的精准定位与分级具有重要意义。但是目前现有探针的溶解度、染料穿透性等方面的不足限定了应用推广的前景。
公开于该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解，而不应当被视为承认或以任何形式暗示该信息构成已为本领域一般技术人员所公知的现有技术。
发明内容
本发明的目的在于提供一种PSMA荧光分子探针、制备方法及试剂盒，优化了探针的分子结构，具有溶解性好，荧光穿透性强的特点，具有良好的应用性，同时采用优化选择的合成方案具有更高的合成产率和效率，改善产品的成本性能和推广应用性能。
为实现上述目的，本发明的实施例提供了PSMA荧光分子探针，通式为
Figure PCTCN2022105197-appb-000001
其中R2为对甲基苯丁酰基或-CO(CH 2) 16COOH，荧光分子探针具体选自：
Figure PCTCN2022105197-appb-000002
(标记为化合物1)或
Figure PCTCN2022105197-appb-000003
(标记为化合物2)。注意这里EuK为靶头。
在本发明的一个或多个实施方式中，PSMA荧光分子探针的制备方法，包括如下步骤：准备含有原料的原料液、第一溶液以及FITC溶液(FITC，CAS:3326-32-7)，第一溶液为pH 8-9的磷酸氢盐溶液，原料适应性地选自：
Figure PCTCN2022105197-appb-000004
Figure PCTCN2022105197-appb-000005
第一溶液加到原料液后，再加入FITC溶液，反应、分离、纯化即可。
在本发明的一个或多个实施方式中，原料液为水溶液，且其中原料的浓度为：0.01-0.1mg/μL。
在本发明的一个或多个实施方式中，第一溶液的溶质选自K2HPO4、Na2HPO4。优选的，第一溶液为水溶液或者DMSO溶液。
在本发明的一个或多个实施方式中，FITC溶液中溶剂选自：DMSO、DMF、DME。
在本发明的一个或多个实施方式中，FITC溶液中FITC的浓度为：0.010-0.05mg/μL。
在本发明的一个或多个实施方式中，反应的条件为15-35℃避光条件下搅拌。
在本发明的一个或多个实施方式中，反应的反应时间为1-4h。
在本发明的一个或多个实施方式中，搅拌的速度为100-1000rpm。
在本发明的一个或多个实施方式中，试剂盒，包括如前述的PSMA荧光分子探针。
与现有技术相比，根据本发明实施方式的PSMA荧光分子探针、制备方法及试剂盒，优化了探针的分子结构，具有溶解性好，荧光穿透性强的特点，具有良好的应用性，同时采用优化选择的合成方案具有更高的合成产率和效率，改善产品的成本性能和推广应用性能。
附图说明
图1是根据本发明一实施方式的PSMA荧光分子探针的质谱图；
图2是根据本发明又一实施方式的PSMA荧光分子探针的质谱图；
图3是根据本发明一实施方式的PSMA荧光分子探针(化合物2)的结合力对照图，其中PC3是PSMA阴性的细胞，22RV1是PSMA阳性的细胞；
图4是根据本发明一实施方式的PSMA荧光分子探针(化合物2)在22RV1和PC3细胞染色的荧光成像，其中PC3是PSMA阴性的细胞，22RV1是PSMA阳性的细胞；
图5是根据本发明一实施方式的PSMA荧光分子探针(化合物2)在肿瘤中的荧光成像，其中PC3是PSMA阴性的细胞，22RV1是PSMA阳性的细胞；
图6是根据本发明一实施方式的PSMA荧光分子探针(化合物2)在肿瘤中的荧光成像，其中PC3是PSMA阴性的细胞，22RV1是PSMA阳性的细胞；
图7是根据本发明一实施方式的PSMA荧光分子探针(化合物2)在肿瘤和不同脏器中的荧光成像。
具体实施方式
下面结合附图，对本发明的具体实施方式进行详细描述，但应当理解本发明的保护范围并不受具体实施方式的限制。
除非另有其它明确表示，否则在整个说明书和权利要求书中，术语“包括”或其变换如“包含”或“包括有”等等将被理解为包括所陈述的元件或组成部分，而并未排除其它元件或其它组成部分。
实施例1-1
本实施例中PSMA荧光分子探针(化合物1)为：
Figure PCTCN2022105197-appb-000006
其一种合成路线为：
Figure PCTCN2022105197-appb-000007
Figure PCTCN2022105197-appb-000008
本实施例的合成方案为：向化合物1的水溶液(浓度：0.01mg/μL)50μL中加入0.01M Na2HPO4(150μL，pH 8.4)得到混合溶液。FITC(0.25mg)溶于10μL DMSO中，再加入到前述混合溶液中，在20℃避光条件下，200rpm搅拌2小时，通过高效液相色谱仪(Agilent 588915-902，HC-C18(2)4.6×150mm,5μm，0-5分钟：5％乙腈，5-45分钟：5-95％甲醇，流速：每分钟1毫升)纯化(产物纯度为90％，收率为85％)其化学结构由Waters的LC-MS进行表征，图谱如图1所示(M/2+1)。
流式结合力测试：
细胞：22Rv1、PC3细胞
实验设备：流式细胞仪
方法：
1)将细胞接种到T75瓶中。形成单层后使用胰酶消化，将细胞转入离心管(1×106个/管)，离心。
2)用添加化合物1不同浓度的新鲜培养液代替培养液，在37℃下孵育30min后使用PBS洗涤3次。用1％SDS(十二烷基硫酸钠)在ddH2O(1.0mL)中裂解细胞，用流式细胞仪分析细胞结合荧光。使用GraphPad Prism 6绘制细胞结合荧光百分比与浓度的关系图，化合物1选择性结合PSMA高表达细胞22RV1，计算结合亲和力Kd＝61.31nM，化合物1不 与PC3结合，体现了探针具有良好的靶向性能。
细胞荧光结合检测：
细胞：22Rv1、PC3细胞
实验设备：荧光显微镜
方法：
1)将细胞接种到T75瓶中。形成单层后使用胰酶消化，将细胞转入离心管(1×106个/管)，离心。
2)用添加化合物1不同浓度的新鲜培养液代替培养液，在37℃下孵育30min后使用PBS洗涤3次。用1％SDS(十二烷基硫酸钠)在ddH2O(1.0mL)中裂解细胞，用流式细胞仪分析细胞结合荧光。结果表明化合物1与PSMA高表达细胞22RV1有良好的结合性，并且具有良好的荧光穿透性，响应清晰。
以化合物1探针为例的前列腺癌PSMA靶向荧光成像实验
实验对象：22Rv1细胞或HEK293T-PSMA(武汉普诺赛)皮下荷瘤小鼠
实验设备：IVIS活体成像仪【IVIS Lumina LT】
1)动物模型构建：22Rv1或HEK293T-PSMA细胞培养于T75培养瓶中，收集细胞5×107重悬于1ml的PBS中(含有50％高浓度的基质胶BD 356234。
2)于裸鼠【动物来源：军事医学科学院实验动物中心(北京)，饲养设施(南开大学实验动物中心)】腋下进行种植，每只鼠皮下100μL缓慢注射一个皮丘
3)将裸鼠放回笼中继续饲养，待肿瘤体积达到300-500mm3时开始进行实验
4)尾静脉注射探针，探针使用含有5％DMSO的PBS溶液溶解(先用DMSO助溶)，配置浓度为500μM的溶液，尾静脉注射，每只鼠250μL。
5)于不同的时间点(1，1.5，3，6和9h)进行IVIS活体荧光成像，成像参数为激发750nm，发射为800nm。结果表明化合物1对PSMA高表达，灵敏度高。
实施例1-2
本实施例的合成方案为：向化合物1的水溶液(浓度：0.05mg/μL)50μL中加入pH 8的Na2HPO4(150μL)得到混合溶液。FITC(0.1mg)溶于10μL DMSO中，再加入到前述混合溶液中，在15℃避光条件下，1000rpm搅拌3小时，通过高效液相色谱仪(Agilent588915-902，HC-C18(2)4.6×150mm,5μm，0-5分钟：5％乙腈，5-45分钟：5-95％甲醇，流速：每分钟1毫升)纯化(产物纯度为93％，收率为84％)其化学结构由Waters的LC-MS进行表征，图谱如图1所示(M/2+1)。
实施例1-3
本实施例的合成方案为：向化合物1的水溶液(浓度：0.1mg/μL)50μL中加入pH 9的K2HPO4(150μL)得到混合溶液。FITC(0.5mg)溶于10μL DME中，再加入到前述混合溶液中，在35℃避光条件下，800rpm搅拌1小时，通过高效液相色谱仪(Agilent588915-902，HC-C18(2)4.6×150mm,5μm，0-5分钟：5％乙腈，5-45分钟：5-95％甲醇，流速：每分钟1毫升)纯化(产物纯度为91％，收率为86％)其化学结构由Waters的LC-MS进行表征，图谱如图1所示(M/2+1)。
实施例1-4
本实施例的合成方案为：向化合物1的水溶液(浓度：0.08mg/μL)50μL中加入pH8.6的K2HPO4(150μL)得到混合溶液。FITC(0.25mg)溶于10μL DMF中，再加入到前述混合溶液中，在30℃避光条件下，100rpm搅拌4小时，通过高效液相色谱仪(Agilent588915-902，HC-C18(2)4.6×150mm,5μm，0-5分钟：5％乙腈，5-45分钟：5-95％甲醇，流速：每分钟1毫升)纯化(产物纯度为87％，收率为80％)其化学结构由Waters的LC-MS进行表征，图谱如图1所示(M/2+1)。
对比例1
本对比例的合成方案为：向化合物1的水溶液(浓度：0.08mg/μL)50μL中加入FITC溶液(0.25mgFITC溶于10μL DMF中)得到混合溶液。再将pH8.6的K2HPO4(150μL)加入到前述混合溶液中，在30℃避光条件下，100rpm搅拌4小时，通过高效液相色谱仪(Agilent 588915-902，HC-C18(2)4.6×150mm,5μm，0-5分钟：5％乙腈，5-45分钟：5-95％甲醇，流速：每分钟1毫升)纯化(产物纯度为80％，收率为62％)其化学结构由Waters的LC-MS进行表征，图谱如图1所示(M/2+1)。
对比例2
本对比例的合成方案为：将化合物1的水溶液(浓度：0.08mg/μL)50μL、pH8.6的K2HPO4(150μL)以及FITC溶液(0.25mgFITC溶于10μL DMF中)共混后，在30℃避光条件下，100rpm搅拌4小时，通过高效液相色谱仪(Agilent 588915-902，HC-C18(2)4.6×150mm,5μm，0-5分钟：5％乙腈，5-45分钟：5-95％甲醇，流速：每分钟1毫升)纯化(产物纯度为73％，收率为55％)其化学结构由Waters的LC-MS进行表征，图谱如图1所示(M/2+1)。
实施例2-1
本实施例中PSMA荧光分子探针(化合物2)为：
Figure PCTCN2022105197-appb-000009
其一种合成路线为：
Figure PCTCN2022105197-appb-000010
Figure PCTCN2022105197-appb-000011
其一种具体的合成方案为：
向化合物3的水溶液(浓度：0.01mg/μL)50μL中加入0.01M Na2HPO4(150μL，pH8.4)。FITC(0.25mg)溶于10μL DMSO中，加入到向化合物3的水溶液中，在25℃避光条件下，600rpm搅拌2小时，通过高效液相色谱仪(Agilent 588915-902，HC-C18(2)4.6 x 150mm,5μm，0-5分钟：5％乙腈，5-45分钟：5-95％甲醇，流速：每分钟1毫升)纯化(产物纯度为92％，收率为78％)。其化学结构由Waters的LC-MS进行表征，质谱如图2所示。
流式结合力测试：
细胞：22Rv1、PC3细胞
实验设备：流式细胞仪
方法：
1)将细胞接种到T75瓶中。形成单层后使用胰酶消化，将细胞转入离心管(1×106个/管)，离心。
2)用添加化合物2不同浓度的新鲜培养液代替培养液，在37℃下孵育30min后使用PBS洗涤3次。用1％SDS(十二烷基硫酸钠)在ddH2O(1.0mL)中裂解细胞，用流式细胞仪分析细胞结合荧光。使用GraphPad Prism 6绘制细胞结合荧光百分比与浓度的关系图，化合物2选择性结合PSMA高表达细胞22RV1，计算结合亲和力Kd＝62.21nM，化合物2不与PC3结合，如图3所示。
细胞荧光结合检测：
细胞：22Rv1、PC3细胞
实验设备：荧光显微镜
方法：
1)将细胞接种到T75瓶中。形成单层后使用胰酶消化，将细胞转入离心管(1×106个/管)，离心。
2)用添加化合物2不同浓度的新鲜培养液代替培养液，在37℃下孵育30min后使用PBS洗涤3次。用1％SDS(十二烷基硫酸钠)在ddH2O(1.0mL)中裂解细胞，用流式细胞仪分析细胞结合荧光，荧光显微镜拍照结果如图4所示。
以化合物2探针为例的前列腺癌PSMA靶向荧光成像实验
实验对象：22Rv1细胞或HEK293T-PSMA(武汉普诺赛)皮下荷瘤小鼠
实验设备：IVIS活体成像仪【IVIS Lumina LT】
1)动物模型构建：22Rv1或HEK293T-PSMA细胞培养于T75培养瓶中，收集细胞5×107重悬于1ml的PBS中(含有50％高浓度的基质胶BD 356234。
2)于裸鼠【动物来源：军事医学科学院实验动物中心(北京)，饲养设施(南开大学实验动物中心)】腋下进行种植，每只鼠皮下100μL缓慢注射一个皮丘
3)将裸鼠放回笼中继续饲养，待肿瘤体积达到300-500mm3时开始进行实验
4)尾静脉注射探针，探针使用含有5％DMSO的PBS溶液溶解(先用DMSO助溶)，配置浓度为500μM的溶液，尾静脉注射，每只鼠250μL。
5)于不同的时间点(1，1.5，3，6和9h)进行IVIS活体荧光成像，成像参数为激发750nm，发射为800nm。成像结果如图5、6所示，解剖的脏器荧光显示如图7所示。
实施例2-2
本实施例的合成方案为：向化合物3的水溶液(浓度：0.05mg/μL)50μL中加入pH 8的Na2HPO4(150μL)得到混合溶液。FITC(0.1mg)溶于10μL DMSO中，再加入到前述混合溶液中，在15℃避光条件下，1000rpm搅拌3小时，通过高效液相色谱仪(Agilent588915-902，HC-C18(2)4.6×150mm,5μm，0-5分钟：5％乙腈，5-45分钟：5-95％甲醇，流速：每分钟1毫升)纯化(产物纯度为91％，收率为83％)其化学结构由Waters的LC-MS进行表征，图谱如图2所示(M/2+1)。
实施例2-3
本实施例的合成方案为：向化合物3的水溶液(浓度：0.1mg/μL)50μL中加入pH 9的K2HPO4(150μL)得到混合溶液。FITC(0.5mg)溶于10μL DME中，再加入到前述混合溶液中，在35℃避光条件下，800rpm搅拌1小时，通过高效液相色谱仪(Agilent  588915-902，HC-C18(2)4.6×150mm,5μm，0-5分钟：5％乙腈，5-45分钟：5-95％甲醇，流速：每分钟1毫升)纯化(产物纯度为90％，收率为84％)其化学结构由Waters的LC-MS进行表征，图谱如图2所示(M/2+1)。
实施例2-4
本实施例的合成方案为：向化合物3的水溶液(浓度：0.08mg/μL)50μL中加入pH8.6的K2HPO4(150μL)得到混合溶液。FITC(0.25mg)溶于10μL DMF中，再加入到前述混合溶液中，在30℃避光条件下，100rpm搅拌4小时，通过高效液相色谱仪(Agilent 588915-902，HC-C18(2)4.6×150mm,5μm，0-5分钟：5％乙腈，5-45分钟：5-95％甲醇，流速：每分钟1毫升)纯化(产物纯度为93％，收率为82％)其化学结构由Waters的LC-MS进行表征，图谱如图2所示(M/2+1)。
对比例3
本对比例的合成方案为：向化合物3的水溶液(浓度：0.08mg/μL)50μL中加入FITC溶液(0.25mgFITC溶于10μL DMF中)得到混合溶液。再将pH8.6的K2HPO4(150μL)加入到前述混合溶液中，在30℃避光条件下，100rpm搅拌4小时，通过高效液相色谱仪(Agilent 588915-902，HC-C18(2)4.6×150mm,5μm，0-5分钟：5％乙腈，5-45分钟：5-95％甲醇，流速：每分钟1毫升)纯化(产物纯度为88％，收率为65％)其化学结构由Waters的LC-MS进行表征，图谱如图2所示(M/2+1)。
对比例4
本对比例的合成方案为：将化合物3的水溶液(浓度：0.08mg/μL)50μL、pH8.6的K2HPO4(150μL)以及FITC溶液(0.25mgFITC溶于10μL DMF中)共混后，在30℃避光条件下，100rpm搅拌4小时，通过高效液相色谱仪(Agilent 588915-902，HC-C18(2)4.6×150mm,5μm，0-5分钟：5％乙腈，5-45分钟：5-95％甲醇，流速：每分钟1毫升)纯化(产物纯度为91％，收率为53％)其化学结构由Waters的LC-MS进行表征，图谱如图2所示(M/2+1)。
前述对本发明的具体示例性实施方案的描述是为了说明和例证的目的。这些描述并非想将本发明限定为所公开的精确形式，并且很显然，根据上述教导，可以进行很多改变和变化。对示例性实施例进行选择和描述的目的在于解释本发明的特定原理及其实际应用，从而使得本领域的技术人员能够实现并利用本发明的各种不同的示例性实施方案以及各种不同的选择和改变。本发明的范围意在由权利要求书及其等同形式所限定。

Claims (10)

  1. 一种PSMA荧光分子探针，通式为
    Figure PCTCN2022105197-appb-100001
    其中R 2为对甲基苯丁酰基或-CO(CH 2) 16COOH，所述荧光分子探针选自：
    Figure PCTCN2022105197-appb-100002
    Figure PCTCN2022105197-appb-100003
  2. 如权利要求1所述的PSMA荧光分子探针的制备方法，包括如下步骤：
    准备含有原料的原料液、第一溶液以及FITC溶液，所述第一溶液为pH8-9的磷酸氢盐溶液，所述原料适应性地选自：
    Figure PCTCN2022105197-appb-100004
    Figure PCTCN2022105197-appb-100005
    所述第一溶液加到所述原料液后，再加入所述FITC溶液，反应、分离、纯化即可。
  3. 如权利要求2所述的PSMA荧光分子探针的制备方法，其特征在于，所述原料液为水溶液，且其中原料的浓度为：0.01-0.1mg/μL。
  4. 如权利要求2所述的PSMA荧光分子探针的制备方法，其特征在于，所述第一溶液的溶质选自K 2HPO 4、Na 2HPO 4。
  5. 如权利要求2所述的PSMA荧光分子探针的制备方法，其特征在于，所述FITC溶液中溶剂选自：DMSO、DMF、DME。
  6. 如权利要求5所述的PSMA荧光分子探针的制备方法，其特征在于，所述FITC溶液中FITC的浓度为：0.010-0.05mg/μL。
  7. 如权利要求2所述的PSMA荧光分子探针的制备方法，其特征在于，所述反应的条件为15-35℃避光条件下搅拌。
  8. 如权利要求7所述的PSMA荧光分子探针的制备方法，其特征在于，所述反应的反应时间为1-4h。
  9. 如权利要求7所述的PSMA荧光分子探针的制备方法，其特征在于，所述搅拌的速度为100-1000rpm。
  10. 试剂盒，包括如权利要求1所述的PSMA荧光分子探针。
PCT/CN2022/105197 2022-07-01 2022-07-12 Psma荧光分子探针、制备方法及试剂盒 WO2024000648A1 (zh)

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