NOTA-PEG₂-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH₂ | 1446005-10-2

• 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: NOTA-PEG₂-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH₂
• 英文别名: 2-[4-[2-[2-[2-[2-[[(2R)-1-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-1-[[(3S,4S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-3-hydroxy-6-methyl-1-oxoheptan-4-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-2-oxoethoxy]ethoxy]ethylamino]-2-oxoethyl]-7-(carboxymethyl)-1,4,7-triazonan-1-yl]acetic acid
• CAS: 1446005-10-2
• 化学式: C₇₃H₁₁₀N₁₈O₁₉
• 分子量: 1543.79
• InChiKey: MZMIUKVXOOFRJV-MXOQNATHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -5.1
• 重原子数：
  110
• 可旋转键数：
  48
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  545
• 氢给体数：
  17
• 氢受体数：
  23

反应信息

• 作为反应物：
  描述：

  [⁶⁴Cu]-copper acetate 、 NOTA-PEG₂-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH₂ 以 aq. acetate buffer 为溶剂， 反应 0.17h， 生成
  参考文献：
  名称：

  Impact of dianionic and dicationic linkers on tumor uptake and biodistribution of [⁶⁴Cu]Cu/NOTA peptide-based gastrin-releasing peptide receptors antagonists

  摘要：

  在本研究中，我们首次探讨了2-氨基乙基-哌嗪-1-羧酸（APCA）和氨基己二酸-1-酸（AHDA）对[64Cu]放射性标记胃泌素释放肽受体（GRPR）拮抗剂的肿瘤摄取和消除动力学的影响。合成了三种含有RM26序列的GRPR拮抗剂，并通过不同的连接器（LK）与NOTA结合：聚乙二醇（PEG-中性）、APCA（双阳离子）或AHDA（双阴离子）。将NOTA-LK-RM26肽用64Cu标记，以评估其药代动力学和正电子发射断层显像（PET）成像特性，使用PC3肿瘤带瘤的无胸腺裸小鼠进行研究。三个包含PEG、双阳离子和双阴离子链接的natCu/NOTA-LK-RM26肽的抑制常数（Ki）分别为0.98 ± 0.48 nM、0.95 ± 0.21 nM和17.97 ± 2.79 nM。[64Cu] NOTA-LK-RM26结合物的标记产率超过95%，特异活性为67到77 TBq/mmol。这三种放射肽在体内稳定，并在胰腺中显示GRPR特异性摄取，同时观察到[64Cu]-NOTA-AHDA-RM26肽的快速洗脱。成像研究的结果显示[64Cu]-NOTA-APCA-和AHDA-RM26在PC3肿瘤中的特异性摄取，肾脏排除相似，肝脏快速洗脱。考虑到它们良好的成像特性，[64Cu]-NOTA-LK-RM26含有APCA和AHDA连接的肽是有希望的候选者，用于GRPR靶向的PET成像前列腺癌。

  DOI：

  10.1002/jlcr.3491

文献信息

• Synthesis and Characterization of a High-Affinity NOTA-Conjugated Bombesin Antagonist for GRPR-Targeted Tumor Imaging
  作者：Zohreh Varasteh、Irina Velikyan、Gunnar Lindeberg、Jens Sörensen、Mats Larhed、Mattias Sandström、Ram Kumar Selvaraju、Jennie Malmberg、Vladimir Tolmachev、Anna Orlova

  DOI：10.1021/bc300659k

  日期：2013.7.17

  The gastrin-releasing peptide receptor (GRPR/BB2) is a molecular target for the visualization of prostate cancer. This work focused on the development of high-affinity, hydrophilic, antagonistic, bombesin-based imaging agents for PET and SPECT. The bombesin antagonist analog D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 ([D-Phe(6),Sta(13),Leu(14)]-bombesin[6-14]) was synthesized and conjugated to 1,4,7-triazacyclononane-N,N',N ''-triacetic acid (NOTA) via a diethylene glycol (PEG(2)) linker. The resulting conjugate, NOTA-PEG(2)-[D-Phe(6),Sta(13),Leu(14)]bombesin[6-14] (NOTA-P2-RM26), was labeled with Ga-68 (T-1/2 = 68 min, positron emitter) and In-111 (T-1/2 = 2.8 days, gamma emitter). The labeling stability, specificity, inhibition efficiency (IC50), and dissociation constant (K-D) of both labeled compounds as well as their cellular retention and internalization were investigated. The pharmacokinetics of the dual isotope) (In-111/Ga-68)-labeled peptide in both normal NMRI mice and PC-3 tumor-bearing Balb/c nu/nu mice was also studied. NOTA-P2-RM26 was labeled with In-111 and Ga-68 at a radiochemical yield of >98%. Both conjugates were shown to have high specificity and binding affinity for GRPR. The K-D value was determined to be 23 +/- 13 pM for the In-111-labeled compound in a saturation binding experiment. In addition, In-nat- and Ga-nat-NOTA-P2-RM26 showed low nanomolar binding inhibition concentrations (IC50 = 1.24 +/- 0.29 nM and 0.91 +/- 0.19 nM, respectively) in a competitive binding assay. The internalization rate of the radiolabeled conjugates was slow. The radiometal-labeled tracers demonstrated rapid blood clearance via the kidney and GRPR-specific uptake in the pancreas in normal mice. Tumor targeting and biodistribution studies in mice bearing PC-3 xenografts displayed high and specific uptake in tumors (8.1 +/- 0.4%ID/g for Ga-68 and 5.7 +/- 0.3%ID/g for In-111) and high tumor-to-background ratios (tumor/blood: 12 +/- 1 for Ga-68 and 10 +/- 1 for In-111) after only 1 h pi of 45 pmol of peptide. The xenografts were visualized by gamma and microPET cameras shortly after injection. In conclusion, the antagonistic bombesin analog NOTA-PEG(2)-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 (NOTA-P2-RM26) is a promisindg candidate for prostate cancer imaging using PET and SPECT/CT.