Development of a radioiodinated lipophilic cation as a new SPECT radiopharmaceutical for cancer diagnosis.

开发放射性碘化亲脂性阳离子作为用于癌症诊断的新型 SPECT 放射性药物。

• 批准号: 13470478
• 负责人: SAJI Hideo
• 金额: $ 9.09万
• 依托单位: Kyoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470478/
• 关键词: mitochondria; membrane potentia; lipophilic cation; Rhodacyanine derivative; Radioiodine; tumor; radiopharmaceutical; ログシアニン誘導体; 脂溶性カオチン

The role of mitochondria in cancer cell phenotypes has been related with changes in cellular redox balance, cell cycle progression, protons gradients thus, large differences in mitochondrial membrane potential between carcinoma cells and normal cells occurs. Exploitation of this mitochondrial membrane potential difference has lead to the selection of a lipophilic cationic compound as a tumor-imaging agent by expecting the selective accumulation in negatively charged mitochondria in tumor cells due to the electrochemical proton gradient. In this study, we synthesized a radioiodinated rhodacyanine dye, MKT 077 derivative (IBMKT), a n electron-delocalized lipophilic cation, and evaluated its potential for cancer diagnosis.[^<125>I]IBMKT was synthesized by a halogen-exchange reaction with the total radiochemical yield of 50% after HPLC purification. The radiochemical purity of the product was greater than 95%, and the produced [^<125>I]IBMKT was stable for at least one month after labeling. The selective accumulation into tumor cells was investigated by determining the uptake of IBMKT by six cancer cell lines. In incubation with tumor cells, [^<125>I]IBMKT was accumulated by tumor cells to a much, greater than by normal cells it accumulated 2-to 7-fold by tumor cells, as compared with that by normal cells. Furthermore, the mitochondrial membrane potential of these tumor cells was determined using radiolabeled, Rb and compared with the accumulation of [^<125>I]IBMKT by the cells. Consequently, the accumulation of [^<125>I]IBMKT by the tumor cells correlated well with the mitochondrial membrane potential of these cells. In addition, biodistribution studies in tumor-bearing mice showed higher accumulation of [^<125>I]IBMKT in tumor than those in the blood and muscle. These results indicate that this newly designed radioiodinated IBMKT seemed to hold potential for the SPECT study of tumor imaging.

线粒体在癌细胞表型中的作用与细胞氧化还原平衡、细胞周期进程、质子梯度的变化有关，因此，癌细胞和正常细胞之间的线粒体膜电位存在很大差异。这种线粒体膜电位差的开发导致选择亲脂性阳离子化合物作为肿瘤成像剂，通过预期由于电化学质子梯度在肿瘤细胞中带负电荷的线粒体中的选择性积累。在这项研究中，我们合成了一种放射性碘标记的罗丹菁染料，MKT 077衍生物（IBMKT），一种n电子离域亲脂性阳离子，并评估其用于癌症诊断的潜力。通过<125>卤素交换反应合成了[^ I]IBMKT，HPLC纯化后总放射化学产率为50%。产物的放射化学纯度大于95%，并且所产生的[^<125>I]IBMKT在标记后至少稳定一个月。通过测定六种癌细胞系对IBMKT的摄取来研究向肿瘤细胞中的选择性积累。在与肿瘤细胞一起孵育时，[^<125>I]IBMKT在肿瘤细胞中的蓄积量比在正常细胞中的蓄积量大得多，与正常细胞相比，肿瘤细胞中的蓄积量是正常细胞的2- 7倍。此外，使用放射性标记的Rb测定这些肿瘤细胞的线粒体膜电位，并与细胞的[^<125>I]IBMKT积累进行比较。因此，肿瘤细胞积累的[^<125>I]IBMKT与这些细胞的线粒体膜电位密切相关。此外，荷瘤小鼠的生物分布研究表明，[^<125>I]IBMKT在肿瘤中的蓄积高于血液和肌肉中的蓄积。这些结果表明，这种新设计的放射性碘标记的IBMKT似乎持有肿瘤显像的SPECT研究的潜力。

项目成果

Yasuhiro Magata, et al.: "Development of multi purpose synthetic system."J.Labelled Compd.Radiopharm.. 44(1). 1047-1049 (2001)

Yasuhiro Magata 等人：“多用途合成系统的开发”。J.Labelled Compd.Radiopharm.. 44(1)。

Hideo Saji: "A new norepinephrine transporter imaging agent for cardiac sympathetic nervous function imaging : radioiodinated(R)-N-methyl-3-(2-iodophenyl)-3-phenylpropanamine"Nucl.Med.Biol.. 30・4. 679-706 (2003)

佐治英雄：“用于心脏交感神经功能成像的新型去甲肾上腺素转运蛋白显像剂：放射性碘化(R)-N-甲基-3-(2-碘苯基)-3-苯基丙胺”Nucl.Med.Biol.. 30・4。 -706 (2003)

Yasuhiko Iida: "Development of a radioiodinated π electron-delocalized lipophilic cation as a new SPECT radiopharmaceutical for cancer diagnosis"J.Nucl.Med.. 44・5. 304-304 (2003)

饭田泰彦：“开发放射性碘化π电子离域亲脂性阳离子作为癌症诊断的新型SPECT放射性药物”J.Nucl.Med.. 44・5（2003）。

Hideo Saji: "In vivo imaging of brain dopaminergic neurotransmission system in small animals with high-resolution single photon emission computed tomography"Anal. Sci.. 19・1. 67-71 (2003)

Hideo Saji：“利用高分辨率单光子发射计算机断层扫描对小动物脑多巴胺能神经传递系统进行体内成像”，Sci.19・1（2003）。

Takayuki Morimoto: "Drug design of a tumor imaging agent based on mitochondrial membrane potential"Jpn.J.Nucl.Med.. 39(3). 409-409 (2002)

Takayuki Morimoto：“基于线粒体膜电位的肿瘤显像剂的药物设计”Jpn.J.Nucl.Med. 39(3)。