99mTc-Labeled Dimeric Octreotide Peptide: A Radiotracer with High Tumor Uptake for Single-Photon Emission Computed Tomography Imaging of Somatostatin Receptor Subtype 2-Positive Tumors
99mTc-Labeled Dimeric Octreotide Peptide: A Radiotracer with High Tumor Uptake for Single-Photon Emission Computed Tomography Imaging of Somatostatin Receptor Subtype 2-Positive Tumors
复制标题
(99m)Tc 标记的二聚奥曲肽肽：一种具有高肿瘤摄取率的放射性示踪剂，用于生长抑素受体亚型 2 阳性肿瘤的单光子发射计算机断层扫描成像。
DOI：
10.1021/mp400040z
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发表时间：
2013-08-01
影响因子：
4.9
通讯作者：
Wang, Fan
中科院分区：
文献类型：
--
作者：
Dong, Chengyan;Zhao, Huiyun;Wang, Fan
放射性标记的多价配体的开发越来越受到关注，因为它们的肿瘤摄取比相应的单体更高。本报告介绍了[Tyr（3）]奥曲肽二聚体缀合物HYNIC-E（[Tyr（3）]奥曲肽）2 {HYNIC-TOC 2，HYNIC = 6-[2-（2-磺酸基苯甲醛）亚肼基]烟碱基}的合成及其在AR 42 J肿瘤模型中的生物学评价。在AR 42 J大鼠胰腺癌细胞中，使用（125）I-[Tyr（3）]奥曲肽作为放射性示踪剂，测定HYNIC-TOC 2与生长抑素受体亚型2（SSTR 2）的结合亲和力。以N，N ′-乙二胺-N，N ′-二乙酸（EDDA）和三羟甲基甘氨酸（Tricine）为共配体，制备了（99 m）Tc-HYNIC-TOC_2。在荷AR 42 J肿瘤的裸鼠中进行生物分布和γ显像。（99 m）Tc-HYNIC-TOC 2标记率>95%，稳定性良好。与HYNIC-TOC（IC_（50）= 3.74 ± 0.82 nM）相比，HYNIC-TOC_2显示出显著增加的SSTR 2结合亲和力（IC_（50）= 0.74 ± 0.19 nM），并且（99 m）Tc-HYNIC-TOC_2显示出显著增加的肿瘤摄取[注射（p.i.）和12.05 ± 2.92%ID/g对5.87 ± 1.96%ID/g 4 h p.i.]。尽管（99 m）Tc-HYNIC-TOC 2在肾中的蓄积水平显著增加（94.40 ± 6.51%ID/g vs 32.27 ± 4.51%ID/g，1 h p.i.），在注射（99 m）Tc-HYNIC-TOC_2（30.99 ± 5.05%ID/g，1h p.i.）而肿瘤摄取仅轻微降低。与生物分布数据一致，体内平面γ成像显示肿瘤清晰可见，而背景信号弱得多，除了肾脏和膀胱。设计并评价了一种新的放射性示踪剂（99 m）Tc-HYNIC-TOC_2，该示踪剂具有较高的结合亲和力和良好的稳定性。（99 m）Tc-HYNIC-TOC 2的较高肿瘤摄取表明（90）Y/（177）Lu标记的TOC 2可能在SSTR 2阳性肿瘤的放射治疗中具有优势。这些数据值得将（99 m）Tc-HYNIC-TOC 2转化为临床环境。
There is growing interest in the development of radiolabeled multivalent ligands because of their higher tumor uptake versus that of the corresponding monomer. This report presents the synthesis of a [Tyr(3)]octreotide dimer conjugate, HYNIC-E([Tyr(3)]octreotide)2 {HYNIC-TOC2, HYNIC = 6-[2-(2-sulfonatobenzaldehyde)hydrazono]nicotinyl}, and its biological evaluation in the AR42J tumor model. The binding affinity of HYNIC-TOC2 for somatostatin receptor subtype 2 (SSTR2) was determined in AR42J rat pancreatic cancer cells, using (125)I-[Tyr(3)]octreotide as the radiotracer. (99m)Tc-HYNIC-TOC2 was prepared by using tricine and EDDA as coligands (EDDA = ethylenediamine-N,N'-diacetic acid). Biodistribution and γ imaging were performed in nude mice bearing AR42J tumors. (99m)Tc-HYNIC-TOC2 was obtained in >95% labeling yield with favorable stability. Compared with those of HYNIC-TOC (IC50 = 3.74 ± 0.82 nM), HYNIC-TOC2 showed significantly increased SSTR2 binding affinity (IC50 = 0.74 ± 0.19 nM), and (99m)Tc-HYNIC-TOC2 showed significantly increased tumor uptake [13.31 ± 3.14%ID/g vs 5.32 ± 0.94%ID/g 1 h postinjection (p.i.) and 12.05 ± 2.92%ID/g vs 5.87 ± 1.96%ID/g 4 h p.i.]. Although the level of accumulation of (99m)Tc-HYNIC-TOC2 in kidneys was significantly increased (94.40 ± 6.51%ID/g vs 32.27 ± 4.51%ID/g 1 h p.i.), this high uptake was inhibited by the injection of l-lysine before the administration of (99m)Tc-HYNIC-TOC2 (30.99 ± 5.05%ID/g 1 h p.i.) while tumor uptake decreased only slightly. Consistent with biodistribution data, in vivo planar γ imaging showed that the tumors were clearly visualized, while the background signal was much weaker except for that of the kidneys and bladder. The new radiotracer (99m)Tc-HYNIC-TOC2 with a higher binding affinity and good stability was designed and evaluated. The higher tumor uptake of (99m)Tc-HYNIC-TOC2 suggests that (90)Y/(177)Lu-labeled TOC2 might have an advantage for the radiotherapy of SSTR2-positive tumors. These data merit the translation of (99m)Tc-HYNIC-TOC2 to a clinical setting.