PMSA-617 | 1702967-37-0

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: PMSA-617
• 英文别名: PSMA-617；Vipivotide tetraxetan；(2S)-2-[[(1S)-1-carboxy-5-[[(2S)-3-naphthalen-2-yl-2-[[4-[[[2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetyl]amino]methyl]cyclohexanecarbonyl]amino]propanoyl]amino]pentyl]carbamoylamino]pentanedioic acid
• CAS: 1702967-37-0
• 化学式: C₄₉H₇₁N₉O₁₆
• 分子量: 1042.15
• InChiKey: JBHPLHATEXGMQR-VLOIPPKDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -8.2
• 重原子数：
  74
• 可旋转键数：
  27
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  365
• 氢给体数：
  11
• 氢受体数：
  20

反应信息

• 作为反应物：
  描述：

  lutetium(III) chloride 、 PMSA-617 以 aq. acetate buffer 为溶剂， 反应 0.25h， 生成 2-[4-[2-[[4-[[(2S)-1-[[(5S)-5-carboxy-5-[[(1S)-1,3-dicarboxypropyl]carbamoylamino]pentyl]amino]-3-naphthalen-2-yl-1-oxopropan-2-yl]carbamoyl]cyclohexyl]methylamino]-2-oxoethyl]-7,10-bis(carboxylatomethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetate;lutetium(3+)
  参考文献：
  名称：

  [EN] NOVEL RADIOMETAL-BINDING COMPOUNDS FOR DIAGNOSIS OR TREATMENT OF PROSTATE SPECIFIC MEMBRANE ANTIGEN-EXPRESSING CANCER
  [FR] NOUVEAUX COMPOSÉS DE LIAISON DE RADIOMÉTAUX POUR LE DIAGNOSTIC OU LE TRAITEMENT DU CANCER EXPRIMANT UN ANTIGÈNE MEMBRANAIRE SPÉCIFIQUE DE LA PROSTATE

  摘要：

  该应用涉及到Formula (I-a)或Formula (I-b)的化合物，或其盐或溶剂化合物。R1为-(CH2)5CH3或包含2-4个融合苯环。R2为I、Br、F、Cl、H、OH、OCH3、NH2、NO2或CH3。R3为肽键的甘氨酸、天冬酰胺或谷氨酸，或通过Cdelta连接的谷氨酸肽键。L为-CH2NH-、-(CH2)2NH-、-(CH2)3NH-或-(CH2)4NH-。R4为可选择地与放射金属结合的放射金属螯合剂。变量'n'为1-3。这些化合物可能用于成像前列腺特异性膜抗原（PSMA）表达组织或治疗PSMA表达疾病（例如癌症）。

  公开号：

  WO2019075583A1
• 作为产物：
  描述：

  Fmoc-Lys(ivDde)-Wang resin 、 α-tert-butyl-N-BOC-glutamate 、 FMOC-TRANEXAMIC ACID 、 1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸三叔丁酯 在 肼 、 三氟乙酸 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以25%的产率得到PMSA-617
  参考文献：
  名称：

  [EN] NOVEL RADIOMETAL-BINDING COMPOUNDS FOR DIAGNOSIS OR TREATMENT OF PROSTATE SPECIFIC MEMBRANE ANTIGEN-EXPRESSING CANCER
  [FR] NOUVEAUX COMPOSÉS DE LIAISON DE RADIOMÉTAUX POUR LE DIAGNOSTIC OU LE TRAITEMENT DU CANCER EXPRIMANT UN ANTIGÈNE MEMBRANAIRE SPÉCIFIQUE DE LA PROSTATE

  摘要：

  该应用涉及到Formula (I-a)或Formula (I-b)的化合物，或其盐或溶剂化合物。R1为-(CH2)5CH3或包含2-4个融合苯环。R2为I、Br、F、Cl、H、OH、OCH3、NH2、NO2或CH3。R3为肽键的甘氨酸、天冬酰胺或谷氨酸，或通过Cdelta连接的谷氨酸肽键。L为-CH2NH-、-(CH2)2NH-、-(CH2)3NH-或-(CH2)4NH-。R4为可选择地与放射金属结合的放射金属螯合剂。变量'n'为1-3。这些化合物可能用于成像前列腺特异性膜抗原（PSMA）表达组织或治疗PSMA表达疾病（例如癌症）。

  公开号：

  WO2019075583A1

文献信息

• 177Lu-labeled PSMA targeting therapeutic with optimized linker for treatment of disseminated prostate cancer; evaluation of biodistribution and dosimetry
  作者：Ayman Abouzayed、Kamila Seitova、Fanny Lundmark、Vitalina Bodenko、Maryam Oroujeni、Vladimir Tolmachev、Ulrika Rosenström、Anna Orlova

  DOI：10.3389/fonc.2023.1221103

  日期：——

  Prostate specific membrane antigen (PSMA), highly expressed in metastatic castration-resistant prostate cancer (mCRPC), is an established therapeutic target. Theranostic PSMA-targeting agents are widely used in patient management and has shown improved outcomes for mCRPC patients. Earlier, we optimized a urea-based probe for radionuclide visualization of PSMA-expression in vivo using computer modeling. With the purpose to develop a targeting agent equally suitable for radionuclide imaging and therapy, the agent containing DOTA chelator was designed (BQ7876). The aim of the study was to test the hypothesis that ¹⁷⁷Lu-labeled BQ7876 possesses target binding and biodistribution properties potentially enabling its use for radiotherapy.

  BQ7876 was synthesized and labeled with Lu-177. Specificity and affinity of [¹⁷⁷Lu]Lu-BQ7876 to PSMA-expressing PC3-pip cells was evaluated and its processing after binding to cells was studied. Animal studies in mice were performed to assess its biodistribution in vivo, target specificity and dosimetry. [¹⁷⁷Lu]Lu-PSMA-617 was simultaneously evaluated for comparison.

  BQ7876 was labeled with Lu-177 with radiochemical yield >99%. Its binding to PSMA was specific in vitro and in vivo when tested in antigen saturation conditions as well as in PSMA-negative PC-3 tumors. The binding of [¹⁷⁷Lu]Lu-BQ7876 to living cells was characterized by rapid association, while the dissociation included a rapid and a slow phase with affinities K_D1 = 3.8 nM and K_D2 = 25 nM. The half-maximal inhibitory concentration for ^natLu-BQ7876 was 59 nM that is equal to 61 nM for ^natLu-PSMA-617. Cellular processing of [¹⁷⁷Lu]Lu-BQ7876 was accompanied by slow internalization. [¹⁷⁷Lu]Lu-BQ7876 was cleared from blood and normal tissues rapidly. Initial elevated uptake in kidneys decreased rapidly, and by 3 h post injection, the renal uptake (13 ± 3%ID/g) did not differ significantly from tumor uptake (9 ± 3%ID/g). Tumor uptake was stable between 1 and 3 h followed by a slow decline. The highest absorbed dose was in kidneys, followed by organs and tissues in abdomen.

  Biodistribution studies in mice demonstrated that targeting properties of [¹⁷⁷Lu]Lu-BQ7876 are not inferior to properties of [¹⁷⁷Lu]Lu-PSMA-617, but do not offer any decisive advantages.

  导言前列腺特异性膜抗原（PSMA）在转移性去势抵抗性前列腺癌（mCRPC）中高度表达，是一种公认的治疗靶点。靶向 PSMA 的放射治疗药物已广泛应用于患者管理，并显示出对 mCRPC 患者的治疗效果有所改善。早些时候，我们利用计算机建模优化了一种基于尿素的探针，用于体内PSMA表达的放射性核素显像。为了开发一种同样适用于放射性核素成像和治疗的靶向制剂，我们设计了含有 DOTA 螯合剂的制剂（BQ7876）。本研究的目的是检验 177Lu 标记的 BQ7876 是否具有靶向结合和生物分布特性，从而有可能将其用于放射治疗。方法合成并用Lu-177标记BQ7876。评估了[177Lu]Lu-BQ7876对表达PSMA的PC3-pip细胞的特异性和亲和性，并研究了它与细胞结合后的处理过程。对小鼠进行了动物实验，以评估其体内生物分布、靶向特异性和剂量。[结果BQ7876用Lu-177标记，放射化学收率为>99%。在体外和体内抗原饱和状态下以及在PSMA阴性的PC-3肿瘤中测试时，它与PSMA的结合是特异性的。[177Lu]Lu-BQ7876与活细胞结合的特点是快速结合，而解离则包括快速和缓慢两个阶段，亲和力KD1 = 3.8 nM和KD2 = 25 nM。natLu-BQ7876 的半最大抑制浓度为 59 nM，相当于 natLu-PSMA-617 的 61 nM。[177Lu]Lu-BQ7876的细胞处理过程伴随着缓慢的内化。[177Lu]Lu-BQ7876能迅速从血液和正常组织中清除。肾脏最初升高的摄取量迅速下降，注射后3小时，肾脏摄取量（13 ± 3%ID/g）与肿瘤摄取量（9 ± 3%ID/g）没有显著差异。肿瘤摄取量在 1 至 3 小时内保持稳定，随后缓慢下降。在小鼠体内进行的生物分布研究表明，[177Lu]Lu-BQ7876的靶向特性并不逊色于[177Lu]Lu-PSMA-617，但并不具有决定性的优势。
• Labeled inhibitors of prostate specific membrane antigen (PSMA), their use as imaging agents and pharmaceutical agents for the treatment of prostate cancer
  申请人：DEUTSCHES KREBSFORSCHUNGSZENTRUM

  公开号：US10398791B2

  公开（公告）日：2019-09-03

  The present invention generally relates to the field of radiopharmaceuticals and their use in nuclear medicine as tracers, imaging agents and for the treatment of various disease states of prostate cancer. Thus, the present invention concerns compounds that are represented by the general Formulae (Ia) or (Ib).

  本发明一般涉及放射性药物领域及其在核医学中作为示踪剂、成像剂和治疗前列腺癌各种疾病状态的用途。因此，本发明涉及通式 (Ia) 或 (Ib) 所代表的化合物。
• METHODS OF TREATING CANCER
  申请人：ENDOCYTE, INC.

  公开号：US20210161911A1

  公开（公告）日：2021-06-03

  The invention described herein pertains to drug delivery conjugates for targeted therapy. The invention described herein relates to methods of treating PSMA expressing cancers with a compound of the formula 1. The invention described herein also relates to methods of treating PSMA-expressing cancers with a compound of the formula 1 inpatients where stable disease results after treatment with the compound of the formula 1.
• SHIELDING AGENTS AND THEIR USE
  申请人：ENDOCYTE, INC.

  公开号：US20210323985A1

  公开（公告）日：2021-10-21

  The present disclosure relates to compounds useful as shielding agents for PSMA therapies. The present disclosure relates to methods of treating PSMA expressing cancers with one or more radiotherapeutics agents in combination with one or more shielding agents. The present disclosure relates to methods of imaging using one or more imaging agents containing a radionuclide in combination with one or more shielding agents. The present disclosure also relates to methods of making shielding agents.
• PROSTATE-SPECIFIC MEMBRANE ANTIGEN (PSMA) INHIBITORS AS DIAGNOSTIC AND RADIONUCLIDE THERAPEUTIC AGENTS
  申请人：FIVE ELEVEN PHARMA INC.

  公开号：US20220125959A1

  公开（公告）日：2022-04-28

  The present disclosure relates to compounds according to Formula I. These compounds display very good binding affinities to the PSMA binding sites. They comprise a radioactive isotope or a chelating moiety that can be labeled with a radioactive metal such as [ 68 Ga]or [ 177 Lu]. The present disclosure also relates to pharmaceutical compositions comprising a pharmaceutical acceptable carrier and a compound of Formula I or a complex thereof, or a pharmaceutically acceptable salt thereof.