lutetium-177 chloride | 16434-14-3

• 分子结构分类: 无机化合物 - 混合金属/非金属化合物 - 镧系盐
• 英文名称: lutetium-177 chloride
• 英文别名: ¹⁷⁷LuCl₃；Lutetium chloride Lu-177；lutetium-177(3+);trichloride
• CAS: 16434-14-3
• 化学式: Cl₃Lu
• 分子量: 283.359
• InChiKey: AEDROEGYZIARPU-SUNKFXMWSA-K

计算性质

• 辛醇/水分配系数(LogP)：
  2.07
• 重原子数：
  4
• 可旋转键数：
  0
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  0
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  lutetium-177 chloride 、 (2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-[[(2S)-3-[1-[2-[[(2S)-5-carbamimidamido-2-[[(2S)-2-(3-carboxypropanoylamino)-4-methylpentanoyl]amino]pentanoyl]amino]ethyl]triazol-4-yl]-2-[[2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetyl]amino]propanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]hexanoyl]pyrrolidine-2-carbonyl]-methylamino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]-3-(4-hydroxy-2,6-dimethylphenyl)propanoyl]amino]-3,3-dimethylbutanoyl]amino]-4-methylpentanoic acid 在 sodium acetate 、 CuSO₄ 作用下， 以 水 为溶剂， 反应 0.33h， 以93.4%的产率得到
  参考文献：
  名称：

  Enhanced tumor retention of NTSR1-targeted agents by employing a hydrophilic cysteine cathepsin inhibitor

  摘要：

  We explored the approach of using an analog of E-64, a well-known and hydrophilic cysteine cathepsin (CC) inhibitor, as a potent cysteine cathepsin-trapping agent (CCTA) to improve the tumor retention of low-molecular-weight, receptor-targeted radiopharmaceuticals. The synthesized hydrophilic CCTA-incorporated, NTSR1-targeted agents demonstrated a substantial increase in cellular retention upon uptake into the NTRS1-positive HT-29 human colon cancer cell line. Similarly, biodistribution studies using HT-29 xenograft mice revealed a significant and substantial increase in tumor retention for the CCTA-incorporated, NTSR1-targeted agent. The intracellular trapping mechanism of the CCTA-incorporated agents by macromolecular adduct formation was confirmed using multiple in vitro and in vivo techniques. Furthermore, utilization of the more hydrophilic CCTA greatly increased the hydrophilicity of the resulting NTSR1-targeted constructs leading to substantial decreases in most non-target tissues in contrast to our previously reported dipeptidyl acyloxymethyl ketone (AOMK) constructs. This work further confirms that the CCTA trapping approach can make significant improvements in the clinical potential of NTSR1-and other receptor-targeted radiopharmaceuticals. (C) 2019 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2019.05.068

文献信息

• Investigation of the Biological Impact of Charge Distribution on a NTR1-Targeted Peptide
  作者：Yinnong Jia、Wenting Zhang、Wei Fan、Susan Brusnahan、Jered Garrison

  DOI：10.1021/acs.bioconjchem.6b00418

  日期：2016.11.16

  The neurotensin receptor 1 (NTR1) has been shown to be a promising target, due to its increased level of expression relative to normal tissue, for pancreatic and colon cancers. This has prompted the development of a variety of NTR1-targeted radiopharmaceuticals, based on the neurotensin (NT) peptide, for diagnostic and radiotherapeutic applications. A major obstacle for the clinical translation of NTR1-targeted radiotherapeutics would likely be nephrotoxicity due to the high levels of kidney retention. It is well-known that for many peptide-based agents, renal uptake is influenced by the overall molecular charge. Herein, we investigated the effect of charge distribution on receptor binding and kidney retention. Using the [(N-α-Me)Arg8,Dmt11,Tle12]NT(6–13) targeting vector, three peptides (177Lu–K2, 177Lu–K4, and 177Lu–K6), with the Lys moved closer (K6) or further away (K2) from the pharmacophore, were synthesized. In vitro competitive binding, internalization and efflux, and confocal microscopy studies were conducted using the NTR1-positive HT-29, human colon cancer cell line. The 177/natLu–K6 demonstrated the highest binding affinity (21.8 ± 1.2 nM) and the highest level of internalization (4.06% ± 0.20% of the total added amount). In vivo biodistribution, autoradiography, and metabolic studies of 177Lu-radiolabeled K2, K4, and K6 were examined using CF-1 mice. 177Lu–K4 and 177Lu–K6 gave the highest levels of in vivo uptake in NTR1-positive tissues, whereas 177Lu–K2 yielded nearly 2-fold higher renal uptake relative to the other radioconjugates. In conclusion, the position of the Lys (positively charged amino acid) influences the receptor binding, internalization, in vivo NTR1-targeting efficacy, and kidney retention profile of the radioconjugates. In addition, we have found that hydrophobicity likely play a role in the unique biodistribution profiles of these agents.

  神经降压素受体1 (NTR1)因其相对于正常组织在胰腺癌和结肠癌中的表达水平增高，被认为是一个有前景的治疗靶点。这促使基于神经降压素(NT)肽的NTR1靶向放射性药物的研发，用于诊断和放射治疗应用。NTR1靶向放射治疗的临床转化主要障碍可能是由于高水平的肾脏滞留导致的肾毒性。众所周知，对于许多肽类制剂，肾脏摄取受分子整体电荷的影响。在此，我们研究了电荷分布对受体结合和肾脏滞留的影响。使用[(N-α-Me)Arg8,Dmt11,Tle12]NT(6–13) 靶向载体，合成了三种肽(177Lu–K2, 177Lu–K4, 和 177Lu–K6)，其中赖氨酸(Lys)分别靠近(K6)或远离(K2)药效团。采用NTR1阳性的人结肠癌HT-29细胞系进行了体外竞争性结合、内化和流出以及共聚焦显微镜研究。177/natLu–K6显示出最高的结合亲和力(21.8 ± 1.2 nM)和最高水平的内化(4.06% ± 0.20%的总加入量)。通过CF-1小鼠检查177Lu放射性标记的K2、K4和K6的体内生物分布、放射自显影和代谢研究。177Lu–K4和177Lu–K6在NTR1阳性组织中显示出最高的体内摄取水平，而177Lu–K2的肾摄取相对其他放射性偶联物高出近2倍。总之，Lys(带正电荷的氨基酸)的位置影响放射性偶联物的受体结合、内化、体内NTR1靶向效能和肾脏滞留特征。此外，我们发现疏水性可能在这些制剂的独特生物分布特征中起作用。
• Enhanced tumor retention of NTSR1-targeted agents by employing a hydrophilic cysteine cathepsin inhibitor
  作者：Wei Fan、Wenting Zhang、Sameer Alshehri、Trey R. Neeley、Jered C. Garrison

  DOI：10.1016/j.ejmech.2019.05.068

  日期：2019.9

  We explored the approach of using an analog of E-64, a well-known and hydrophilic cysteine cathepsin (CC) inhibitor, as a potent cysteine cathepsin-trapping agent (CCTA) to improve the tumor retention of low-molecular-weight, receptor-targeted radiopharmaceuticals. The synthesized hydrophilic CCTA-incorporated, NTSR1-targeted agents demonstrated a substantial increase in cellular retention upon uptake into the NTRS1-positive HT-29 human colon cancer cell line. Similarly, biodistribution studies using HT-29 xenograft mice revealed a significant and substantial increase in tumor retention for the CCTA-incorporated, NTSR1-targeted agent. The intracellular trapping mechanism of the CCTA-incorporated agents by macromolecular adduct formation was confirmed using multiple in vitro and in vivo techniques. Furthermore, utilization of the more hydrophilic CCTA greatly increased the hydrophilicity of the resulting NTSR1-targeted constructs leading to substantial decreases in most non-target tissues in contrast to our previously reported dipeptidyl acyloxymethyl ketone (AOMK) constructs. This work further confirms that the CCTA trapping approach can make significant improvements in the clinical potential of NTSR1-and other receptor-targeted radiopharmaceuticals. (C) 2019 Elsevier Masson SAS. All rights reserved.