N,N',N'',N'''-tetrakis(tert-butyloxycarbonyl)-6-carboxy-1,4,8,11-tetraazaundecane | 402828-00-6

• 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: N,N',N'',N'''-tetrakis(tert-butyloxycarbonyl)-6-carboxy-1,4,8,11-tetraazaundecane
• 英文别名: N,N',N'',N'''-tetrakis-(t-butoxycarbonyl)-6-(carboxy)-1,4,8,11-tetraazaundecane；3-[(2-methylpropan-2-yl)oxycarbonyl-[2-[(2-methylpropan-2-yl)oxycarbonylamino]ethyl]amino]-2-[[(2-methylpropan-2-yl)oxycarbonyl-[2-[(2-methylpropan-2-yl)oxycarbonylamino]ethyl]amino]methyl]propanoic acid
• CAS: 402828-00-6
• 化学式: C₂₈H₅₂N₄O₁₀
• 分子量: 604.742
• InChiKey: IHELDPZEJVVYCI-UHFFFAOYSA-N

物化性质

• 熔点：
  153-154 °C
• 沸点：
  703.4±60.0 °C(Predicted)
• 密度：
  1.136±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  42
• 可旋转键数：
  19
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.82
• 拓扑面积：
  173
• 氢给体数：
  3
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  N,N',N'',N'''-tetrakis(tert-butyloxycarbonyl)-6-carboxy-1,4,8,11-tetraazaundecane 、 神经介素C肽 在 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 N-甲基吡咯烷酮 为溶剂， 反应 0.75h， 生成 N,N′,N″,N‴-tetrakis-(tert-butoxycarbonyl)-6-(carboxy)-1,4,8,11-tetraazaundecane
  参考文献：
  名称：

  [^99mTc]Demomedin C, a Radioligand Based on Human Gastrin Releasing Peptide(18-27): Synthesis and Preclinical Evaluation in Gastrin Releasing Peptide Receptor-Expressing Models

  摘要：

  The synthesis and preclinical evaluation of [Tc-99m]Demomedin C in GRPR-expressing models are reported. Demomedin C resulted by coupling a Boc-protected N-4-chelator to neuromedin C (human GRP(18-27)), which, after Tc-99m-labeling, afforded [Tc-99m]Demomedin C. Demomedin C showed high affinity and selectivity for the GRPR during receptor autoradiography on human cancer samples (IC50 in nM: GRPR, 1.4 +/- 0.2; NMBR, 106 +/- 18; and BB3R, >1000). It triggered GRPR internalization in HEK-GRPR cells and Ca2+ release in PC-3 cells (EC50 = 1.3 nM). [Tc-99m]Demomedin C rapidly and specifically internalized at 37 degrees C in PC-3 cells and was stable in mouse plasma. [Tc-99m]Demomedin C efficiently and specifically localized in human PC-3 implants in mice (9.84 +/- 0.81%ID/g at 1 h pi; 6.36 +/- 0.8596ID/g at 4 h pi, and 0.41 +/- 0.07%ID/g at 4 h pi block). Thus, human GRP-based radioligands, such as [Tc-99m]Demomedin C, can successfully target GRPR-expressing human tumors in vivo while displaying attractive biological features-e.g. higher GRPR-selectivity-vs their frog-homologues.

  DOI：

  10.1021/jm300741f
• 作为产物：
  描述：

  N-叔丁氧羰基-1,2-乙二胺 以 四氢呋喃 、 水 、 丙酮 为溶剂， 反应 19.0h， 生成 N,N',N'',N'''-tetrakis(tert-butyloxycarbonyl)-6-carboxy-1,4,8,11-tetraazaundecane
  参考文献：
  名称：

  [EN] CXCR4-LIGANDS FOR DIAGNOSTIC AND THERAPEUTIC USE AND PRECURSORS THEREOF
  [FR] LIGANDS CXCR4 DESTINÉ À UNE UTILISATION DIAGNOSTIQUE ET THÉRAPEUTIQUE ET LEURS PRÉCURSEURS

  摘要：

  The invention provides a CXCR4 receptor ligand compound of formula (I) or a salt thereof: formula (I) wherein: a is 0 or 1; b is 0 or 1; c is 0 or 1, and d is 0 or 1, with the proviso that at least one of c and d is 1; e is an integer of 1 to 4; RCPis a binding motif which allows the compound to bind to the CXCR4 receptor; RL1is H or alkyl; RL2is substituted alkyl, which substituted alkyl is substituted with at least one group selected from -NH2and -NH-C(=X)-NH2with X being selected from NH and O; RL3is -CH2-NH2or -CH2-(1H-imidazol-4-yl); RL4is -NH2; X1is a coupling group; RSis a divalent spacer group; and RAis a functional group comprising a moiety with diagnostic or therapeutic utility. The compounds of the invention are suitable for use in the treatment, prevention, and/or diagnosis of a disease or disorder which can be treated or prevented by blocking the CXCR4 receptor, or which is associated with an increased or aberrant expression of the CXCR4 receptor.

  公开号：

  WO2022171869A1

文献信息

• Tetraamine-Derived Bifunctional Chelators for Technetium-99m Labelling: Synthesis, Bioconjugation and Evaluation as Targeted SPECT Imaging Probes for GRP-Receptor-Positive Tumours
  作者：Keelara Abiraj、Rosalba Mansi、Maria-Luisa Tamma、Flavio Forrer、Renzo Cescato、Jean Claude Reubi、Kayhan G. Akyel、Helmut R. Maecke

  DOI：10.1002/chem.200902011

  日期：2010.2.15

  groups at the 6‐position for the conjugation of biomolecules and subsequent labelling with 99mTc is described herein. The chelator 01 was used as a starting material for the facile synthesis of chelators functionalised with OH (02), N3 (04) and O‐succinyl ester (05) groups. A straightforward and easy synthesis of carboxyl‐functionalised tetraamine‐based chelator 06 was achieved by using inexpensive and commercially

  由于其最佳的核性质，易于获得的价格，低成本和良好的剂量学，99m Tc仍然是医学成像应用的理想放射性同位素。基于四胺骨架的双功能螯合剂表现出与Tc（V）O 2的容易络合，形成具有高体内稳定性和显着亲水性的单阳离子物质，这导致了良好的药代动力学。一系列1,4,8,11-四氮杂十一烷衍生物（的合成01 - 06）含有不同官能团的生物分子，并用随后的标记的缀合的6位99米Tc的本文中所描述。螯合剂01用作合成容易被OH（02），N 3（04）和O-琥珀酸酯（05）基团官能化的螯合剂的原料。通过使用便宜的和可商购的原料，可以轻松，简单地合成羧基官能化的四胺基螯合剂06。将06与强力的蛙皮素-拮抗剂肽缀合并随后用99m Tc进行标记，可得到放射性示踪剂99m Tc-N4-BB-ANT，在37 GBqμmol -1的比活度下，放射性标记收率> 97％。IC 50值为（3.7±1.3）n获得了M，这证实
• N4 Chelator Conjugates
  申请人：Storey Anthony Eamonn

  公开号：US20080131368A1

  公开（公告）日：2008-06-05

  The present invention provides tetra-amine chelator conjugates with biological targeting moieties, linked via a linker group and technetium complexes thereof as radiopharmaceuticals. The linker group is such that the chelator is mono-functionalised at the bridgehead position and provides both flexibility and a lack or aryl groups, to minimise lipophilicity and steric hulk. Protected versions of the chelators are provided which permit conjugation with a wide range of targeting molecules without interfering reactions with the amine nitrogens of the tetra-amine chelator. Syntheses of the functionalised chelators are described, together with bifunctional chelate precursors. Radiopharmaceutical compositions comprising the technetium metal complexes of the invention are described, together with non-radioactive kits for the preparation of such radiopharmaceuticals.

  本发明提供了四胺螯合物共轭体，其具有生物靶向基团，通过连接基团和银的技术复合物作为放射性药物。连接基团使得螯合物在桥头位置上单功能化，并提供了灵活性和缺乏芳基团，以最小化亲脂性和立体障碍。本发明提供了保护型螯合物，允许与广泛的靶向分子结合，而不会干扰四胺螯合物的胺氮原子的反应。本发明还描述了功能化螯合物的合成，以及双功能螯合前体。本发明还描述了包括本发明技术复合物的放射性药物组合物，以及用于制备这种放射性药物的非放射性试剂盒。
• [EN] COMPOUNDS COMPRISING A FIBROBLAST ACTIVATION PROTEIN LIGAND AND USE THEREOF<br/>[FR] COMPOSÉS COMPRENANT UN LIGAND DE PROTÉINE D'ACTIVATION DES FIBROBLASTES ET LEUR UTILISATION
  申请人：3B PHARMACEUTICALS GMBH

  公开号：WO2022148843A1

  公开（公告）日：2022-07-14

  The present invention is related to a compound comprising a cyclic peptide of formula (I) and an N-terminal modification group A attached to Xaa1, wherein each and any one of Xaa1, Xaa2, Xaa3, Xaa4, Xaa5, Xaa6 and Xaa7 is a residue of an amino acid, and Yc is a structure of formula (X).

  本发明涉及一种化合物，该化合物包括公式（I）的环肽和附加在Xaa1上的N-末端修饰基团A，其中Xaa1、Xaa2、Xaa3、Xaa4、Xaa5、Xaa6和Xaa7中的任何一个都是氨基酸残基，而Yc是公式（X）的结构。
• Optimization of the Pharmacokinetic Profile of [99mTc]Tc-N4-Bombesin Derivatives by Modification of the Pharmacophoric Gln-Trp Sequence
  作者：Thomas Günther、Matthias Konrad、León Stopper、Jan-Philip Kunert、Sebastian Fischer、Roswitha Beck、Angela Casini、Hans-Jürgen Wester

  DOI：10.3390/ph15091133

  日期：——

  Current radiolabeled gastrin-releasing peptide receptor (GRPR) ligands usually suffer from high accumulation in GRPR-positive organs (pancreas, stomach), limiting tumor-to-background contrast in the abdomen. In novel N4-bombesin derivatives this was addressed by substitutions at the Gln7-Trp8 site within the MJ9 peptide (H-Pip5-phe6-Gln7-Trp8-Ala9-Val10-Gly11-His12-Sta13-Leu14-NH2) either by homoserine (Hse7), β-(3-benzothienyl) alanine (Bta8) or α-methyl tryptophan (α-Me-Trp8), with the aim of optimizing pharmacokinetics. We prepared and characterized the peptide conjugates 6-carboxy-1,4,8,11-tetraazaundecane (N4)-asp-MJ9, N4-asp-[Bta8]MJ9, N4-[Hse7]MJ9 and N4-[α-Me-Trp8]MJ9, and evaluated these compounds in vitro (GRPR affinity via IC50,inverse; internalization; lipophilicity via logD7.4) and in vivo (biodistribution and μSPECT/CT studies at 1 h post injection (p.i.) in PC-3 tumor-bearing CB17-SCID mice). 99mTc-labeling resulted in radiochemical yields (RCYs) > 95%. All 99mTc-labeled MJ9 analogues showed comparable or higher GRPR affinity than the external reference [99mTc]Tc-Demobesin 4. Receptor-bound fractions were noticeably higher than that of the reference. Despite a slightly enhanced lipophilicity, all novel MJ9 derivatives revealed improved in vivo pharmacokinetics compared to the reference. The Bta8-modified ligand revealed the most favorable tumor-to-abdomen contrast at 1 h p.i. Substitutions at the Gln7-Trp8 site within GRPR ligands hold great potential to modify pharmacokinetics for improved imaging.

  目前放射性标记的胃泌素释放肽受体（GRPR）配体通常在GRPR阳性器官（胰腺、胃）中积累高，限制了腹部肿瘤与背景的对比度。在新型N4-泵肽衍生物中，通过在MJ9肽（H-Pip5-phe6-Gln7-Trp8-Ala9-Val10-Gly11-His12-Sta13-Leu14-NH2）中Gln7-Trp8位点上用同型丝氨酸（Hse7）、β-（3-苯并噻吩）丙氨酸（Bta8）或α-甲基色氨酸（α-Me-Trp8）进行替换，旨在优化药代动力学。我们制备并表征了肽偶联物6-羧基-1,4,8,11-四氮杂十二烷（N4）-asp-MJ9、N4-asp-［Bta8］MJ9、N4-［Hse7］MJ9和N4-［α-Me-Trp8］MJ9，并在体外（通过IC50、内化和通过logD7.4的亲脂性）和体内（在PC-3肿瘤携带的CB17-SCID小鼠中注射后1小时的生物分布和μSPECT/CT研究）评估了这些化合物。99mTc标记的放射化学收率（RCY）> 95％。所有99mTc标记的MJ9类似物显示出与外部参考[99mTc]Tc-Demobesin 4相当或更高的GRPR亲和力。受体结合分数明显高于参考。尽管亲脂性稍有增强，所有新型MJ9衍生物与参考相比在体内药代动力学方面均有所改善。Bta8修饰的配体在注射后1小时显示出最有利的肿瘤与腹部对比度。在GRPR配体的Gln7-Trp8位点进行替换具有改善药代动力学以进行更好的成像的巨大潜力。
• [^99mTc]Demomedin C, a Radioligand Based on Human Gastrin Releasing Peptide(18-27): Synthesis and Preclinical Evaluation in Gastrin Releasing Peptide Receptor-Expressing Models
  作者：Berthold A. Nock、Renzo Cescato、Eleni Ketani、Beatrice Waser、Jean Claude Reubi、Theodosia Maina

  DOI：10.1021/jm300741f

  日期：2012.10.11

  The synthesis and preclinical evaluation of [Tc-99m]Demomedin C in GRPR-expressing models are reported. Demomedin C resulted by coupling a Boc-protected N-4-chelator to neuromedin C (human GRP(18-27)), which, after Tc-99m-labeling, afforded [Tc-99m]Demomedin C. Demomedin C showed high affinity and selectivity for the GRPR during receptor autoradiography on human cancer samples (IC50 in nM: GRPR, 1.4 +/- 0.2; NMBR, 106 +/- 18; and BB3R, >1000). It triggered GRPR internalization in HEK-GRPR cells and Ca2+ release in PC-3 cells (EC50 = 1.3 nM). [Tc-99m]Demomedin C rapidly and specifically internalized at 37 degrees C in PC-3 cells and was stable in mouse plasma. [Tc-99m]Demomedin C efficiently and specifically localized in human PC-3 implants in mice (9.84 +/- 0.81%ID/g at 1 h pi; 6.36 +/- 0.8596ID/g at 4 h pi, and 0.41 +/- 0.07%ID/g at 4 h pi block). Thus, human GRP-based radioligands, such as [Tc-99m]Demomedin C, can successfully target GRPR-expressing human tumors in vivo while displaying attractive biological features-e.g. higher GRPR-selectivity-vs their frog-homologues.