(2S,3R)-2-[[(4R,7S,10S,13R,16S,19R)-10-(4-aminobutyl)-7-[(1R)-1-hydroxyethyl]-16-[(4-hydroxyphenyl)methyl]-13-(1H-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-19-[[(2R)-3-phenyl-2-[[2-[4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetyl]amino]propanoyl]amino]-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carbonyl]amino]-3-hydroxybutanoate;hydron;lutetium-177(3+) | 437608-50-9

• 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: (2S,3R)-2-[[(4R,7S,10S,13R,16S,19R)-10-(4-aminobutyl)-7-[(1R)-1-hydroxyethyl]-16-[(4-hydroxyphenyl)methyl]-13-(1H-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-19-[[(2R)-3-phenyl-2-[[2-[4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetyl]amino]propanoyl]amino]-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carbonyl]amino]-3-hydroxybutanoate;hydron;lutetium-177(3+)
• CAS: 437608-50-9
• 化学式: C65H87LuN14O19S2
• 分子量: 1609.5
• InChiKey: MXDPZUIOZWKRAA-PRDSJKGBSA-K

计算性质

• 辛醇/水分配系数(LogP)：
  -7.38
• 重原子数：
  101
• 可旋转键数：
  19
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.51
• 拓扑面积：
  557
• 氢给体数：
  14
• 氢受体数：
  26

ADMET

代谢

177Lu-DOTATATE不经历肝脏代谢。

Lutetium Lu 177 dotatate does not undergo hepatic metabolism.

来源:DrugBank

毒理性

• 毒性总结

177Lu-DOTATATE是一种放射性同位素，被认为具有致癌性和致突变性。尚未进行有关177Lu-DOTATATE的致癌性和致突变性研究。没有进行过生育力研究。在大鼠重复剂量毒性研究中，当Lu 175 doTATAte剂量≥5 mg/kg时，发生了胰腺腺泡细胞凋亡。在狗的重复剂量毒理学研究中，当剂量≥500 mg/kg时，也发生了胰腺腺泡细胞萎缩。

While carcinogenicity and mutagenicity studies have not been conducted with lutetium 177 dotatate, radioisotope is considered a carcinogen and mutagen. No fertility studies have been performed. In repeat dose toxicity studies of rats, pancreatic acinar apoptosis occurred at lutetium Lu 175 dotatate doses ≥ 5 mg/kg. Pancreatic acinar cell atrophy also occurred in repeat dose toxicology studies in dogs at doses ≥ 500 mg/kg.

来源:DrugBank

毒理性

• 蛋白质结合

非放射性形式的镥[177Lu]奥曲肽与人体血浆蛋白的结合率为43%。

The non-radioactive form of lutetium dotatate is 43% bound to human plasma proteins.

来源:DrugBank

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：镥177标记的.dotatate是一种放射性标记的生长抑素类似物，用于治疗生长抑素受体阳性的胃肠胰腺神经内分泌肿瘤。目前没有关于在母乳喂养期间使用镥177标记的.dotatate的信息。制造商建议在镥177标记的.dotatate治疗期间及最后一次给药后2.5个月内停止母乳喂养，这通常意味着永久停止对当前婴儿的母乳喂养。 担心乳汁中放射性水平的母亲可以要求在医院核医学科进行检测。当放射性水平达到安全水平时，她可以恢复母乳喂养。已经发布了一种测量乳汁放射性并确定母亲可以安全恢复母乳喂养的时间的方法。 ◉ 对哺乳婴儿的影响：截至修订日期，没有找到相关已发布信息。 ◉ 对泌乳和母乳的影响：截至修订日期，没有找到相关已发布信息。

◉ Summary of Use during Lactation:Lutetium Lu 177 dotatate is a radiolabeled somatostatin analog indicated for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. No information is available on the use of lutetium Lu 177 dotatate during breastfeeding. The manufacturer recommends that breastfeeding be discontinued during lutetium Lu 177 dotatate therapy and for 2.5 months following the last dose, which would usually mean permanently discontinuing breastfeeding of the current infant. Mothers concerned about the level of radioactivity in their milk could ask to have it tested at a nuclear medicine facility at their hospital. When the radioactivity is at a safe level she may resume breastfeeding. A method for measuring milk radioactivity and determining the time when a mother can safely resume breastfeeding has been published. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

吸收、分配和排泄

• 吸收

在推荐的静脉注射剂量下，镥177标记的.dotatate的平均血药暴露（AUC）为41 ng·h/mL（变异系数，CV，36%）。平均最大血浆浓度（Cmax）为10 ng/mL（CV 50%），在镥177标记的.dotatate静脉输注结束时观察到。

At the recommended intravenous dose, the mean blood exposure (AUC) of lutetium Lu 177 dotatate was 41 ng.h/mL (coefficient of variation, or CV, 36 %). The mean maximum plasma concentration (Cmax) was 10 ng/mL (CV 50%) and was observed at the end of the intravenous infusion of lutetium Lu 177 dotatate.

来源:DrugBank

吸收、分配和排泄

• 消除途径

177Lu-Dotatate主要经肾脏排泄，在静脉给药后的5小时内累计排泄44%，24小时内累计排泄58%，48小时内累计排泄65%。预计在给药后的14天内，超过99%的总给药剂量将被消除，尽管肾排泄过程可能会延长。

Lutetium Lu 177 dotatate predominantly undergoes renal excretion with cumulative excretion of 44% within 5 hours, 58% within 24 hours, and 65% within 48 hours following intravenous administration. Greater than 99% of total administered dose is expected to be eliminated within 14 days after administration although prolonged renal elimination is expected.

来源:DrugBank

吸收、分配和排泄

• 分布容积

平均分布容积为460升（变异系数为54%）。在给药后4小时内，观察到肾脏、肿瘤病变、肝脏、脾脏，以及部分患者的垂体和甲状腺有分布。在动物生物分布研究中，由于SSTR2的高表达，观察到胰腺对放射性标记肽的高摄取。与177镥标记的奥曲肽共同给药的氨基酸可能会减少药物分布到肾脏的程度。

The mean volume of distribution is 460 L (CV 54%). Within 4 hours of administration, distribution in kidneys, tumor lesions, liver, spleen, and, in some patients, pituitary gland and thyroid was observed. High uptake of the radiolabeled peptide in the pancreas in animal biodistribution studies was observed due to high expression of SSTR2. Co-administration of amino acids with lutetium Lu 177 dotatate may decrease the extent of drug distribution to the kidneys.

来源:DrugBank

吸收、分配和排泄

• 清除

平均清除率（CL）为4.5 L/h（变异系数31%）。与氨基酸联合给药时，lutetium Lu 177 dotatate的平均β相血清除率增加了36%。

The mean clearance (CL) is 4.5 L/h (CV 31%). Co-administration of amino acids with lutetium Lu 177 dotatate increased the mean beta-phase blood clearance of lutetium Lu 177 dotatate by 36%.

来源:DrugBank

文献信息

• ⁶⁸Ga/¹⁷⁷Lu-labeled DOTA-TATE shows similar imaging and biodistribution in neuroendocrine tumor model
  作者：Fei Liu、Hua Zhu、Jiangyuan Yu、Xuedi Han、Qinghua Xie、Teli Liu、Chuanqin Xia、Nan Li、Zhi Yang

  DOI：10.1177/1010428317705519

  日期：2017.6

  Somatostatin receptors are overexpressed in neuroendocrine tumors, whose endogenous ligands are somatostatin. DOTA-TATE is an analogue of somatostatin, which shows high binding affinity to somatostatin receptors. We aim to evaluate the Ga-68/Lu-177-labeling DOTA-TATE kit in neuroendocrine tumor model for molecular imaging and to try human-positron emission tomography/computed tomography imaging of Ga-68-DOTA-TATE in neuroendocrine tumor patients. DOTA-TATE kits were formulated and radiolabeled with Ga-68/Lu-177 for Ga-68/Lu-177-DOTA-TATE (M-DOTA-TATE). In vitro and in vivo stability of Lu-177-DOTA-TATE were performed. Nude mice bearing human tumors were injected with Ga-68-DOTA-TATE or Lu-177-DOTA-TATE for micro-positron emission tomography and micro-single-photon emission computed tomography/computed tomography imaging separately, and clinical positron emission tomography/computed tomography images of Ga-68-DOTA-TATE were obtained at 1 h post-intravenous injection from patients with neuroendocrine tumors. Micro-positron emission tomography and micro-single-photon emission computed tomography/computed tomography imaging of Ga-68-DOTA-TATE and Lu-177-DOTA-TATE both showed clear tumor uptake which could be blocked by excess DOTA-TATE. In addition, Ga-68-DOTA-TATE-positron emission tomography/computed tomography imaging in neuroendocrine tumor patients could show primary and metastatic lesions. Ga-68-DOTA-TATE and Lu-177-DOTA-TATE could accumulate in tumors in animal models, paving the way for better clinical peptide receptor radionuclide therapy for neuroendocrine tumor patients in Asian population.
• WO2022/43754
  申请人：——

  公开号：——

  公开（公告）日：——