Development and evaluation of a novel radioiodinated vesamicol analog as a sigma receptor imaging agent.
Development and evaluation of a novel radioiodinated vesamicol analog as a sigma receptor imaging agent.
复制标题
DOI：
10.1186/2191-219x-2-54
复制
发表时间：
2012-09-28
期刊：
影响因子：
3.2
通讯作者：
Odani A
中科院分区：
文献类型：
--
作者：
Ogawa K;Kanbara H;Shiba K;Kitamura Y;Kozaka T;Kiwada T;Odani A
Sigma受体在人类肿瘤中高度表达，应该成为开发肿瘤显像剂的合适靶点。此前，我们合成了对Sigma受体具有高亲和力的维沙米考类似物(+)-2-[4-(4-iodophenyl)piperidino]cyclohexanol((+)-PIV)，并制备了放射性碘化(+)-PIV。结果表明，在生物分布实验中，(+)-[125I]PIV具有较高的肿瘤摄取能力。然而，正常组织，如肝脏，放射性积聚很高。我们推测(+)-PIV在肝脏中的部分蓄积可能是由于其高亲脂性所致，并制备和评价了亲水性更强的放射性标记维沙米考类似物(+)-4-[1-(2-hydroxycyclohexyl)piperidine-4-yl]-2-iodophenol((+)-IV-OH)。以(+)-[125I]IV-OH为原料，采用氯胺T法制备了(+)-[125I]IV-OH。测定了(+)-[125I]IV-OH的分配系数。通过静脉注射(+)-[125I]IV-OH和(+)-[131I]PIV混合液在DU-145荷瘤小鼠体内进行生物分布实验。通过静脉注射(+)-[125I]IV-OH和过量的配体对DU-145荷瘤小鼠进行阻断研究。(+)-[125I]IV-OH的亲水性远高于(+)-[125I]PIV。在生物分布实验中，(+)-[125I]IV-OH和(+)-[131I]PIV在注射后10min在肿瘤组织中有较高的摄取。虽然(+)-[131I]PIV倾向于在大多数组织中保留，但(+)-[125I]IV-OH在大多数组织中被清除。在肝脏中，(+)-[125I]IV-OH的放射性水平在所有时间点均显著低于(+)-[131I]PIV。在阻断研究中，联合注射过量的Sigma配体导致注射(+)-[125I]IV-OH后肿瘤/血液摄取比率显著降低。结果表明，放射性碘标记的(+)-IV-OH具有作为Sigma受体显像剂的潜力。
Sigma receptors are highly expressed in human tumors and should be appropriate targets for developing tumor imaging agents. Previously, we synthesized a vesamicol analog, (+)-2-[4-(4-iodophenyl)piperidino]cyclohexanol ((+)-pIV), with a high affinity for sigma receptors and prepared radioiodinated (+)-pIV. As a result, (+)-[125I]pIV showed high tumor uptake in biodistribution experiments. However, the accumulation of radioactivity in normal tissues, such as the liver, was high. We supposed that some parts of the accumulation of (+)-pIV in the liver should be because of its high lipophilicity, and prepared and evaluated a more hydrophilic radiolabeled vesamicol analog, (+)-4-[1-(2-hydroxycyclohexyl)piperidine-4-yl]-2-iodophenol ((+)-IV-OH). (+)-[125I]IV-OH was prepared by the chloramine T method from the precursor. The partition coefficient of (+)-[125I]IV-OH was measured. Biodistribution experiments were performed by intravenous administration of a mixed solution of (+)-[125I]IV-OH and (+)-[131I]pIV into DU-145 tumor-bearing mice. Blocking studies were performed by intravenous injection of (+)-[125I]IV-OH mixed with an excess amount of ligand into DU-145 tumor-bearing mice. The hydrophilicity of (+)-[125I]IV-OH was much higher than that of (+)-[125I]pIV. In biodistribution experiments, (+)-[125I]IV-OH and (+)-[131I]pIV showed high uptake in tumor tissues at 10-min post-injection. Although (+)-[131I]pIV tended to be retained in most tissues, (+)-[125I]IV-OH was cleared from most tissues. In the liver, the radioactivity level of (+)-[125I]IV-OH was significantly lower at all time points compared to those of (+)-[131I]pIV. In the blocking studies, co-injection of an excess amount of sigma ligands resulted in significant decreases of tumor/blood uptake ratios after injection of (+)-[125I]IV-OH. The results indicate that radioiodinated (+)-IV-OH holds a potential as a sigma receptor imaging agent.