Medical Isotopes Research Center, Peking University , Beijing 100191, China.
Mol Pharm. 2013 Aug 5;10(8):2925-33. doi: 10.1021/mp400040z. Epub 2013 Jun 28.
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.
人们对放射性标记的多价配体的开发越来越感兴趣，因为与相应的单体相比，它们具有更高的肿瘤摄取率。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-TOC2，HYNIC = 6-[2-(2-磺酰基苯甲醛)腙基]烟酰基）的合成及其在 AR42J 肿瘤模型中的生物学评价。使用 (125)I-[Tyr(3)]奥曲肽作为示踪剂，在 AR42J 大鼠胰腺癌细胞中测定了 HYNIC-TOC2 对生长抑素受体亚型 2（SSTR2）的结合亲和力。(99m)Tc-HYNIC-TOC2 是通过使用三羧酸和 EDDA 作为共配体（EDDA = 乙二胺-N,N'-二乙酸）制备的。在携带 AR42J 肿瘤的裸鼠中进行了生物分布和γ成像。(99m)Tc-HYNIC-TOC2 的标记产率超过 95%，稳定性良好。与 HYNIC-TOC（IC50 = 3.74 ± 0.82 nM）相比，HYNIC-TOC2 表现出明显增加的 SSTR2 结合亲和力（IC50 = 0.74 ± 0.19 nM），并且 (99m)Tc-HYNIC-TOC2 表现出明显增加的肿瘤摄取率[13.31 ± 3.14%ID/g 与 5.32 ± 0.94%ID/g 1 h 后注射（p.i.）和 12.05 ± 2.92%ID/g 与 5.87 ± 1.96%ID/g 4 h p.i.]。尽管 (99m)Tc-HYNIC-TOC2 在肾脏中的积累水平显著增加（94.40 ± 6.51%ID/g 与 32.27 ± 4.51%ID/g 1 h p.i.），但通过在给予 (99m)Tc-HYNIC-TOC2 之前注射 l-赖氨酸，这种高摄取被抑制（99m)Tc-HYNIC-TOC2 的 1 h p.i.），而肿瘤摄取仅略有下降。与生物分布数据一致，体内平面γ成像显示肿瘤清晰可见，而背景信号除肾脏和膀胱外，明显较弱。设计并评价了具有更高结合亲和力和良好稳定性的新型放射性示踪剂 (99m)Tc-HYNIC-TOC2。(99m)Tc-HYNIC-TOC2 的较高肿瘤摄取率表明，(90)Y/(177)Lu 标记的 TOC2 可能在治疗 SSTR2 阳性肿瘤的放射治疗方面具有优势。这些数据证明了 (99m)Tc-HYNIC-TOC2 向临床应用的转化。
