Development of a Tc-99m labeled sigma-2 receptor-specific ligand as a potential breast tumor imaging agent
Development of a Tc-99m labeled sigma-2 receptor-specific ligand as a potential breast tumor imaging agent
复制标题
DOI：
10.1016/s0969-8051(01)00234-7
复制
发表时间：
2001-08-01
影响因子：
3.1
通讯作者：
Kung, HF
中科院分区：
文献类型：
--
作者：
Choi, SR;Yang, B;Kung, HF
一种新型体内显像剂，Tc-99m 标记为 [(N-[2-((3'-N'-丙基-[3,3.1]aza-bicyclononan-3 α-yl)(2"-甲氧基-5-甲基-苯基氨基甲酸酯)(2-巯基乙基)氨基)乙酰基]-2-氨基乙硫醇]锝(V) 氧化物)，[Tc-99m]2，显示出与 sigma-2 的特异性结合体外结合试验表明，铼（[Tc-99m]2 的替代物 Re-2）对 sigma-2 受体表现出优异的结合亲和力和选择性（对于 sigma-1 和 sigma-2 受体，K-i 分别为 2,723 和 22 nM）。在酸、还原剂（葡萄糖庚酸亚锡）和[Tc-99m]高锝酸钠的存在下，成功制备了亲脂性外消旋混合物，收率10%至50%，放射化学纯度>98%。使用等度溶剂（正己烷/异丙醇；3:1； v/v)。在相同的 HPLC 条件下，峰 A 和峰 B 似乎与替代物 Re-2 的异构体共洗脱。在荷瘤小鼠（小鼠乳腺癌细胞系 66，已知过度表达 sigma-2 受体）中进行的生物分布研究表明，肿瘤中的外消旋 [Tc-99m]2 摄取为 2.11，静脉内注射后 1、4 和 8 小时分别为 1.30 和 1.11% 剂量/克，表明肿瘤细胞中的吸收和保留良好。通过共注射“冷”(+)喷他辛或氟哌啶醇 (1 mg/Kg)，肿瘤吸收被显着但不完全地阻断（约 25-30% 阻断）。 (>60%)，HPLC 分析显示它是原始化合物，外消旋 [Tc-99m]2 (>98% 纯度)。在静脉内注射 4 小时后，在同一荷瘤小鼠中测定了纯化的峰 A 和峰 B 的分布。两种异构体的肿瘤摄取相似，但峰 B 中的异构体的血液和外周组织含量高于峰 A 中的异构体。很明显，峰 A 中的异构体显示出明显更好的结果。与峰 A 相比，峰 B 中异构体的甲状腺摄取值更高也证实了体内代谢率较高。 总之，Tc-99m 标记的 σ 受体成像剂 [Tc-99m]2 已证明使用 Tc-99m 标记的试剂对肿瘤细胞中的 σ 受体表达进行成像的可行性。报道了用于 Sigma 受体位点成像的 Tc-99m 标记试剂 (C) 2001 Elsevier Science Inc. 保留所有权利。
A novel in vivo imaging agent, Tc-99m labeled [(N-[2-((3'-N'-propyl-[3,3.1]aza-bicyclononan-3 alpha -yl)(2"-methoxy-5-methyl-phenylcarbamate)(2-mercaptoethyl)amino)acetyl]-2-aminoethanethiolato] technetium(V) oxide), [Tc-99m]2, displaying specific binding towards sigma-2 receptors was prepared and characterized. In vitro binding assays showed that the rhenium, surrogate of [Tc-99m]2, Re-2, displayed excellent binding affinity and selectivity towards sigma-2 receptors (K-i = 2,723 and 22 nM for sigma-1 and sigma-2 receptor, respectively). Preparation of [Tc-99m]2 was achieved by heating the S-protected starting material, 1, in the presence of acid, reducing agent (stannous glucoheptonate) and sodium [Tc-99m]pertechnetate. The lipophilic racemic mixture was successfully prepared in 10 to 50% yield and the radiochemical purity was >98%. Separation of the isomers, peak A and peak B, was successfully achieved by using a chiralpak AD column eluted with an isocratic solvent (n-hexane/isopropanol; 3: 1; v/v). The peak A and peak B appear to co-elute with the isomers of the surrogate, Re-2, under the same HPLC condition. Biodistribution studies in tumor bearing mice (mouse mammary adenocarcinoma, cell line 66, which is known to over-express sigma-2 receptors) showed that the racemic [Tc-99m]2 localized in the tumor. Uptake in the tumor was 2.11, 1.30 and 1.11 %dose/gram at 1, 4 and 8 hr post iv injection. respectively, suggesting good uptake and retention in the tumor cells. The tumor uptake was significantly, but incompletely, blocked (about 25-30% blockage) by co-injection of "cold" (+)pentazocine or haloperidol (1 mg/Kg). A majority of the radioactivity localized in the tumor tissue was extractable (>60%), and the HPLC analysis showed that it is the original compound, racemic [Tc-99m]2 (>98% pure). The distribution of the purified peak A and peak B was determined in the same tumor bearing mice at 4 hr post iv injection. The tumor uptake was similar for both isomers, but the blood and peripheral tissue content for the isomer in peak B was higher than that for the isomer in peak A. It is evident that the isomer in peak A displayed significantly better tumor/blood and tumor/muscle ratios. The higher rate of in vivo metabolism was also confirmed by the higher thyroid uptake values for the isomer in peak B as compared to peak A. in summary, a Tc-99m-labeled sigma receptor imaging agent. [Tc-99m]2, has demonstrated the feasibility of using a Tc-99m-labeled agent for imaging sigma receptor expression in tumor cells. This is the first time a subtype-selective Tc-99m-labeled agent for imaging sigma receptor sites is reported. (C) 2001 Elsevier Science Inc. All rights reserved.