CN109641924B - 作为检测前列腺特异性膜抗原的过表达的放射性药物的99mtc-edda/hynic-ipsma - Google Patents
作为检测前列腺特异性膜抗原的过表达的放射性药物的99mtc-edda/hynic-ipsma Download PDFInfo
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- CN109641924B CN109641924B CN201780049494.4A CN201780049494A CN109641924B CN 109641924 B CN109641924 B CN 109641924B CN 201780049494 A CN201780049494 A CN 201780049494A CN 109641924 B CN109641924 B CN 109641924B
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Abstract
本发明涉及一种新的放射性药物，其抑制前列腺特异性膜抗原(iPSMA)，其含有肼基烟酰胺(HYNIC)作为在增加分子的亲脂性以结合PSMA的疏水性位点中的关键化学基团，结合HYNIC作为放射性金属99mTc的螯合剂的常规用途，其中乙二胺四乙酸(EDDA)用于完成放射性金属的配位层。新的放射性药物99mTc‑EDDA/HYNIC‑iPSMA以体内高亲和力和灵敏度使用核医学中的SPECT分子成像技术检测前列腺癌细胞中过表达的PSMA蛋白。本发明的目的是提供用于SPECT的新的特异性放射性药物(用于分子靶标的放射性药物)，其对于检测具有PSMA过表达的肿瘤具有高灵敏度。
Description
技术领域
本发明涉及一种新的放射性药物，其是前列腺特异性膜抗原(iPSMA) 的抑制剂，其含有肼基烟酰胺(HYNIC)作为化学基团，其在增加分子的亲脂性以偶合PSMA的疏水性位点方面是关键的，结合HYNIC作为放射性金属99mTc的螯合剂的常规用途，其中乙二胺二乙酸(EDDA)用于完成放射性金属的配位层(coordinationsphere)。新的99mTc-EDDA/HYNIC-iPSMA放射性药物以体内高亲和力通过核医学中的 SPECT分子成像技术检测前列腺癌细胞中过表达的蛋白质PSMA。
背景技术
前列腺癌(PCa)是全球男性中第二大最常见的癌症[JemalA,etal.Cancerstatistics,2010.CA CancerJClin.2010,60:277-300]。在患有局限性 PCa的患者中，五年存活率接近100％；然而，在转移患者中，五年存活率为31％[WeiQ,etal.Globalanalysisofdifferentiallyexpressedgenesin androgen-independentprostatecancer.ProstateCancerProstaticDis.2007,10: 167-174]。几乎所有转移患者最初都对抗雄激素治疗反应良好。然而，PCa 患者死亡的主要原因是进展到雄激素非依赖性状态。
谷氨酸羧肽酶II，也称为前列腺特异性膜抗原(PSMA)，在前列腺的上皮细胞中表达，并且在95％的晚期前列腺癌中高度过表达。PSMA的表达水平与PCa的雄激素非依赖性、转移和进展直接相关[SantoniM.,etal. Targetingprostate-specificmembraneantigenforpersonalizedtherapiesin prostate cancer:morphologic and molecularbackgrounds and future promises. J Biol Regul Homeost Agents.2014,28:555-563]。因此，PSMA是通过使用特异放射性药物成像和放射治疗转移性前列腺癌的用于检测的合适分子靶标。
PSMA基因由占约60kb的基因组DNA的19个外显子组成。该基因编码II型跨膜蛋白，其具有短的细胞质片段(19个氨基酸)、疏水性跨膜结构域(24个氨基酸)和大的细胞外结构域(707个氨基酸)。PSMA在酶的活性中心含有Zn，因此已提出序列Glu-NH-CO-NH-Lys(β-萘基丙氨酸)＝Glu-脲-Lys(NaI)作为其活性的有效抑制剂[Benesová,M.,et al.Preclinical evaluation of a tailor-made DOTA-conjugated PSMA inhibitor withoptimized linker moiety for imaging and endoradiotherapy of prostate cancer.JNucl Med,56,2015:914-920]。在特定的化学相互作用中，Glu-脲-Lys片段的3个羧基与PSMA活性中心的肽侧链以静电方式相互作用，脲的氧与锌配位，NaI中的芳香族结构相互作用以与酶的疏水活性位点偶合。在最近的临床研究中，Lu-177标记的两种不同iPSMA衍生物的应用显示PCa患者中70-80％的前列腺特异性抗原(PSA)水平的显著降低，没有显示出严重的副作用，显著提高患者的生存率[Ahmadzadehfar H.,et al.Early side-effects andfirst results of radioligand therapy with 177Lu-DKFZ-617 PSMA of castrate-resistant metastatic prostate cancer:a two-centre study. EJNMMI Res.2015,5:36doi:10.1186/s13550-015-0114-2；Kratochwil C,et al.[177Lu]Lutetium-labelledPSMA ligand-induced remission in a patient with metastatic prostatecancer.Eur J Nucl Med Mol Imaging,42,2015:987-988； Baum,Richard P.,etal.Lutetium-177PSMA radioligand therapy of metastatic castration-resistantprostate cancer:safety and efficacy.J Nucl Med,2016: DOI:doi:10.2967/jnumed.115.168443；Kratochwil,C,et al.PSMA-targeted radionuclide therapy ofmetastatic castration-resistant prostate cancer with Lu-177labeled PSMA-617.JNucl Med,2016: doi:10.2967/jnumed.115.171397；Rahbar,K et al.Response andtolerability of a single dose of 177Lu-PSMA-617in patients with metastaticcastration-resistant prostate cancer:a multicenter retrospective analysis.JNucl Med,2016:doi:10.2967/jnumed.116.173757]。蛋白PSMA是多功能的，因为其可以作为内化受体，作为吸收营养素的酶，或作为参与上皮细胞和细胞迁移中的信号转导的肽酶[Rajasekaran A.et al.Is prostate-specific membrane antigen a multifunctionalprotein？American Journal of Physiology -Cell Physiology,2005,288:C975-C981]。因此，PSMA抑制剂放射性药物也可用于不同于PCa的另一种类型的肿瘤，例如转移性乳腺癌、骨肉瘤、神经胶质瘤和分化的甲状腺癌等[la Fougère,et al.In vivo visualizationof prostate-specific membrane antigen in glioblastoma.Eur J Nucl Med and MolImaging,2015,42:170-171；Verburg FA,et al.First evidence of PSMA expression indifferentiated thyroid cancer using[68Ga]PSMA-HBED-CC PET/CT.Eur J Nucl Medand Mol imaging,2015,42:1622-1623；Zeng C et al. Prostate-specific membraneantigen:a new potential prognostic marker of osteosarcoma.Medical Oncology,2012,29:2234-2239；Sathekge M et al. 68Ga-PSMA imaging of metastatic breastcancer.(2015).Eur J Nucl Med and Mol imaging,2015,42:1482-1483]。
然而，在任何放射治疗之前，必须通过核磁成像评估肿瘤或其转移灶中放射性药物的捕获，以确认治疗是否会对患者有用，以及用于确定为施加用于肿瘤消融的辐射剂量而需要施用的活性，即实施个性化医疗。因此，有必要使用PSMA抑制性诊断放射性药物，目的是通过正电子发射断层扫描(PET)或通过单光子发射断层扫描(SPECT)获得分子图像。在这两种技术中，PET提供更高的空间分辨率和更高的灵敏度，因此大多数商业PSMA抑制性诊断放射性药物是基于68Ga开发的，68Ga是PET的放射性核素[Eder M et al.Novelpreclinical and radiopharmaceutical aspects of [68Ga]Ga-PSMA-HBED-CC:a newPET tracer for imaging of prostate cancer. Pharmaceuticals,2014,7:779-796；Eder M et al.68Ga-complex lipophilicity and the targeting property of a urea-based PSMA inhibitor for PET imaging. Bioconjugate Chem,2012,23:688-697；Weineisen et al.68Ga-and 177Lu-labeled PSMA I&T:optimization of a PSMA-targeted theranostic concept and first proof-of-concept human studies."J NuclMed,2015,56: 1169-1176；Afshar-Oromieh,A.,et al.Comparison of PET/CT and PET/MRI hybrid systems using a 68Ga-labelled PSMA ligand for the diagnosis ofrecurrent prostate cancer:initial experience.Eur J Nucl Med and MolecularImaging 41.5(2014):887-897]。
然而，在国家和国际层面上，因为没有必要在医院内或附近使用回旋加速器，所以通过SPECT的研究因成本较低以及设备和放射性核素的可用性较高而占核医学总量的70％以上。对于SPECT图像，最常用的放射性核素是99mTc，并且没有出版物来专门报道使用99mTc标记的PSMA抑制剂进行的完整临床研究，对此仅研究到临床前研究[Kularatne A.,et al.Design,synthesis,and preclinical evaluation of prostate-specific membraneantigen targeted 99mTc-radioimaging agents.Mol Pharmaceutics,2009,6: 790-800；Lu,G et al.Synthesis and SAR of 99mTc/Re-labeled small molecule prostatespecific membrane antigen inhibitors with novel polar chelates. Bioorganic&Medicinal Chemistry Letters,2013,23:1557-1563；Hillier S.M., et al.99mTc-labeled small-molecule inhibitors of prostate-specific membrane antigen formolecular imaging of prostate cancer.J Nucl Med,2013,54: 1369-1376]。仅发表了使用99mTc的诊断图像，作为患者中使用177Lu的放射治疗研究的一部分[Kratochwil,C,etal.PSMA-targeted radionuclide therapy of metastatic castration-resistantprostate cancer with Lu-177labeled PSMA-617.J Nucl Med,2016:doi:10.2967/jnumed.115.171397]。
为了能够与PET放射性核素的高灵敏度相等，有必要从用99mTc标记的亲和力和可行性的角度开发更具竞争力的分子，以便通过SPECT技术并以高灵敏度检测过表达PSMA的肿瘤病变。
具体实施方式
出于专利的目的，提出了一种新的放射性药物，其是前列腺特异性膜抗原(iPSMA)的抑制剂，其含有肼基烟酰胺(HYNIC)作为在增加分子的亲脂性以偶合PSMA的疏水性位点方面是关键的化学基团，结合HYNIC 作为放射性金属99mTc的螯合剂的常规用途，其中乙二胺二乙酸(EDDA) 用于完成放射性金属的配位层。新的99mTc-EDDA/HYNIC-iPSMA放射性药物以体内高亲和力通过核医学中的SPECT分子成像技术检测前列腺癌细胞中过表达的PSMA蛋白。图1示意性地显示了本申请的放射性药物的结构(99mTc-EDDA/HYNIC-iPSMA)。
基于作为PSMA抑制剂的各种衍生物的化学研究，其证明了结合或亲和力性质对放射性药物的亲脂性的明显依赖性[Kularatne A.,et al.Design, synthesis,andpreclinical evaluation of prostate-specific membrane antigen targeted 99mTc-radioimaging agents.Mol Pharmaceutics,2009,6:790-800]，设计并合成了衍生物HYNIC-iPSMA，其中通过肼基烟酰胺的芳香杂环的存在增加了分子的亲脂性，这继而对螯合99mTc是有用的。对于PSMA的各种抑制剂，下表1由使用定量结构-性质关系(QSPR)模型的算法按理论计算的分布系数值给出与本申请的放射性药物的比较结果以基于片段(CLogP)进行预测，其中较高的值表明该化合物更亲脂。
此外，在本申请的放射性药物的结构中，HYNIC还起到生物识别位点与放射性金属之间的间隔物的作用，而在其他放射性药物中，HYNIC 专门用作用于由99mTc进行标记的双功能试剂[Decristoforo C et al. 99mTc-EDDA/HYNIC-TOC:a new 99mTc-labelledradiopharmaceutical for imaging somatostatin receptor-positive tumours；firstclinical results and intra-patient comparison with 111In-labelled octreotidederivatives,2000,J Nucl Med 27；1318-25；Ferro-Flores G et al.Preparation andEvaluation of 99mTc EDDA/HYNIC-[Lys3]-Bombesin for imaging of GRP Receptor-Positive Tumours.Nucl Med Comm,2006,27:371-376；González-Vázquez A et al.Dosimetry and Biokinetics of 99mTc-EDDA/HYNIC-Tyr3-Octreotide Prepared fromLyophilized Kits.Appl Rad Isot,2006,64:792-79；Ortiz-Arzate Z et al. Kitpreparation and biokinetics in women of 99mTc-EDDA/HYNIC-E-[c(RGDfK)]2forbreast cancer imaging,Nucl Med Commun,2014,35:423-32；Medina-García V et al.AFreeze-Dried Kit Formulation for the Preparation of Lys27(99mTc-EDDA/HYNIC)-Exendin(9-39)/99mTc-EDDA/HYNIC-Tyr3-Octreo tide to Detect Benign and MalignantInsulinomas.Nucl Med Biol,2015,42: 911-916]。
制备本发明的放射性药物的方法
为了合成该分子，首先使用谷氨酸的二叔丁基酯，其在三乙胺(TEA) 存在下与羰基二咪唑(CDI)反应以形成酰基咪唑衍生物，其用三氟甲磺酸甲酯(MeOTf)活化以与(S)-叔丁基-2-氨基-6-(苄氧基羰基胺)己酸酯 (Cbz-Lys-Ot-Bu)反应，随后通过氢解脱保护Cbz，从而获得Glu-脲-Lys 衍生物，其在固相(MBHA树脂)中与氨基酸Fmoc-β-萘基丙氨酸(HBTU/HOBt)反应，然后与6-Boc-肼基吡啶-3-羧酸(Boc-HYNIC)反应，在二异丙基乙胺(DiPEA)和二甲基甲酰胺(DMF)存在下。
表1.临床研究中证明的具有肿瘤细胞捕获的前列腺特异性膜抗原的抑制剂
最后，将化合物用TFA脱保护，通过HPLC纯化并冻干。最终产物是Glu-NH-CO-NH-Lys(β-萘基丙氨酸)-HYNIC(HYNIC-iPSMA)，其具有预期的质谱(图2)。
冻干的白色固体的反相HPLC分析显示出化合物的化学纯度为 98.25％。
将HYNIC-iPSMA(37.5μg)配制成含有10mg EDDA，20mg三(羟甲基)甲基甘氨酸(tricine)，20μg氯化亚锡和50mg甘露醇的冻干剂型。该制剂用1mL 0.2M磷酸盐缓冲溶液(pH 7)和1mL高锝酸钠溶液 (99mTcO4Na)(从99Mo/99mTc的发生器原位获得)重构后，产生本申请的99mTc-EDDA/HYNIC-iPSMA(图1)，其具有通过反相HPLC测定的大于 98％的放射化学纯度，具有相应的放射色谱图(图3)。
标记后24小时，放射性药物保持稳定，放射化学纯度大于95％。人血清中稳定性的体外试验显示与血清蛋白的结合为8.3±2.1％和高放射化学稳定性(>90％)。通过在PSMA蛋白呈阳性的癌细胞(LNCaP)中的能力研究测定的HYNIC-iPSMA的亲和力显示IC50为2.9±0.7nM。
当在balb-C实验室小鼠中以40mg/kg的剂量施用时，该化合物没有显示出毒性或副作用。99mTc-EDDA/HYNIC-iPSMA在具有诱导LNCaP肿瘤的无胸腺小鼠中的生物分布测试显示，在肿瘤中的捕获为每克组织施用活性的8.7±1.3％(％ID/g)，主要是通过肾脏途径消除。在健康志愿者中的生物动力学和剂量测定试验表明，从血液中的快速清除，具有较大的捕获和肾排泄，较低的肝脏捕获以及在甲状旁腺、唾液腺和泪腺中的高捕获，平均有效剂量为4±2mSv/施用的740MBq。图4显示了在健康志愿者中获得的放射性药物99mTc-EDDA/HYNIC-iPSMA的SPECT图像。图5显示了在患有前列腺癌的患者中获得的放射性药物99mTc-EDDA/HYNIC-iPSMA 的SPECT图像，证实了放射性药物体内检测在前列腺癌细胞中过表达的PSMA的能力。最后，图6显示施用68Ga-PSMA-617(PET)和99mTc-EDDA/HYNIC-iPSMA(SPECT)的同一患有晚期转移性前列腺癌的患者的PET和SPECT图像，其表明两种放射性药物都以灵敏度检测到肿瘤以及前列腺癌的转移，与识别PSMA的过表达有关。该图像证实并且是主要证据，由于结合的HYNIC分子的亲脂性导致其亲和力增加，因此在检测过表达PSMA的肿瘤病变中，99mTc-EDDA/HYNIC-iPSMA能够等于 PET放射性核素的高成像灵敏度。
总之，获得具有以下特征的99mTc-EDDA/HYNIC-iPSMA：
·放射化学纯度大于95％
·放射性药物通过核医学中的单光子发射断层扫描(SPECT)在体内特异性地检测过表达前列腺特异性膜抗原的肿瘤的能力。
·除了基于99mTc的本申请的放射性药物对Glu-NH-CO-NH-序列的分子识别外，由于肼基烟酰胺(HYNIC)分子的存在赋予的亲脂性增加，这使得其能够有效地与酶PSMA的疏水活性位点偶合以通过SPECT成像检测，因此其还能够显著结合并以高灵敏度检测肿瘤和前列腺癌转移。
Claims (8)
1.一种化学式为99mTc-EDDA/HYNIC-iPSMA的放射性药物，所述放射性药物为以下结构：
2.一种放射性药物组合物，其特征在于，所述放射性药物组合物包含权利要求1所述的放射性药物。
3.权利要求1所述的放射性药物在制备放射性诊断剂中的用途。
4.一种用于放射性标记的组合物，包含：
和乙二胺二乙酸(EDDA)。
5.一种放射性标记的化合物，由权利要求4所述的用于放射性标记的组合物和放射性核素制备。
6.根据权利要求5所述的放射性标记的化合物，其中，所述放射性核素是用于放射性成像的放射性核素。
7.一种冻干剂型，包含HYNIC-iPSMA/EDDA。
8.一种冻干剂型，包含HYNIC-iPSMA/EDDA以及三(羟甲基)甲基甘氨酸、氯化亚锡和甘露醇。
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| CN111253465A (zh) * | 2020-03-03 | 2020-06-09 | 复旦大学附属肿瘤医院 | 一种psma结合剂及其用途 |
| JP2023522983A (ja) * | 2020-04-24 | 2023-06-01 | ラジオメディックス インコーポレイテッド | 前立腺がんの診断および処置のための組成物、キットおよび方法 |
| MX2021005089A (es) * | 2021-04-30 | 2022-11-01 | Instituto Nac De Investigaciones Nucleares | Radiofarmacos basados en el acido ((r)-1-((6-hidrazinilnicotinoil) d-alanil)pirrolidin-2-il)boronico (hynic-ifap) para la deteccion de la sobreexpresion de la proteina de activacion de fibrolastos. |
| WO2022253785A2 (en) | 2021-05-31 | 2022-12-08 | Universität Heidelberg | Improved prostate-specific membrane antigen targeting radiopharmaceuticals and uses thereof |
| WO2023030509A1 (zh) * | 2021-09-03 | 2023-03-09 | 晶核生物医药科技(南京)有限公司 | 一种肽脲素衍生物、含其的药物组合物及其应用 |
| CN114569744A (zh) * | 2022-03-08 | 2022-06-03 | 安徽淮仁堂药业股份有限公司 | 一种锝前列腺标特异性膜抗原显像剂试剂盒及其制备方法和应用 |
| CN115260155B (zh) * | 2022-08-08 | 2023-11-10 | 北京师范大学 | 一种含三唑环和肼基尼古酰胺基的谷氨酸-脲衍生物及其应用 |
| CN117434270B (zh) * | 2023-09-11 | 2024-05-07 | 江苏省人民医院（南京医科大学第一附属医院） | 一种可携带放射性信号的蛋白质支架及其抗体检测中的应用 |
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| CN104244991A (zh) * | 2012-04-10 | 2014-12-24 | 蓝瑟斯医学影像公司 | 放射性药物合成方法 |
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| EP3486249B1 (en) | 2021-11-10 |
| CN109641924A (zh) | 2019-04-16 |
| BR112018076593A2 (pt) | 2019-04-16 |
| ZA201807828B (en) | 2021-03-31 |
| EP3486249A1 (en) | 2019-05-22 |
| DK3486249T3 (da) | 2022-02-07 |
| MX2016008466A (es) | 2017-12-25 |
| US20210187132A1 (en) | 2021-06-24 |
| WO2017222362A1 (es) | 2017-12-28 |
| CA3059545C (en) | 2021-07-27 |
| US10918745B2 (en) | 2021-02-16 |
| EA201892668A1 (ru) | 2019-10-31 |
| ES2906332T3 (es) | 2022-04-18 |
| CA3059545A1 (en) | 2017-12-28 |
| US11547767B2 (en) | 2023-01-10 |
| EP4083049A3 (en) | 2022-12-21 |
| US20190343970A1 (en) | 2019-11-14 |
| MA45687A (fr) | 2021-03-31 |
| PT3486249T (pt) | 2022-02-02 |
| EP4083049A2 (en) | 2022-11-02 |
| PL3486249T3 (pl) | 2022-05-23 |
| BR112018076593B1 (pt) | 2022-05-24 |
| EP3486249A4 (en) | 2020-03-11 |
| HUE057891T2 (hu) | 2022-06-28 |
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