Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Trombay, Mumbai-400 085, India.
Nucl Med Biol. 2013 Feb;40(2):197-205. doi: 10.1016/j.nucmedbio.2012.11.001. Epub 2012 Dec 4.
The introduction of (68)Ga-based positron emission tomography (PET) to clinical practice using (68)Ge/(68)Ga generator represents a developmental milestone in the field of molecular imaging. Herein, we report a systematic study on (68)Ga complexes with different bifunctional chelators (BFCs) and the effect of metal ion impurities on the radiochemical yields in order to identify the most suitable BFC to be used for the development of (68)Ga-based target specific radiopharmaceuticals.
Radiolabeling of four commonly used BFCs namely p-isothiocyanato benzyl derivatives of diethylenetriaminepentacetic acid (DTPA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) and 3,6,9,15-tetraazabicyclo [9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (PCTA) with (68)Ga was studied with respect to optimal radiolabeling conditions, effect of metal ion impurities on radiochemical yield, in vitro stability and in vivo clearance properties in biological system.
Out of the four BFCs studied, p-isothiocyanato benzyl-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA-NCS) could be radiolabeled instantly with (68)Ga at room temperature with >98% yield, even in presence of up to 10 ppm of other metal ion impurities (such as Zn, Cu, Fe, Al, Sn and Ti ions). The (68)Ga-complex of NOTA-NCS demonstrated high in vitro stability even in the presence of 1000 times molar excess of metal ions (such as Fe, Cu, Zn and Ca ions). In contrast, other (68)Ga-labeled BFCs (DTPA-NCS, DOTA-NCS and PCTA-NCS) showed reduced radiochemical yields when incubated with the above concentration of metal ions. The biodistribution studies in Swiss mice revealed that (68)Ga-NOTA-NCS cleared rapidly through the kidneys with minimum retention in any major organ.
The simple and rapid approach for preparation of (68)Ga-radiopharmaceuticals using NOTA based bifunctional chelators would render (68)Ga-radiopharmaceutical chemistry more convenient with minimum interference from other metal ion impurities; and increase the scope of making (68)Ga based agents for PET imaging.
使用（68）Ge/（68）Ga 发生器将基于（68）Ga 的正电子发射断层扫描（PET）引入临床实践代表了分子成像领域的一个发展里程碑。在此，我们报告了一项关于不同双功能螯合剂（BFC）的（68）Ga 配合物的系统研究，以及金属离子杂质对放射化学产率的影响，以确定最适合用于开发基于（68）Ga 的靶向放射性药物的 BFC。
研究了四种常用 BFC 的放射性标记，即二亚乙基三胺五乙酸（DTPA）的对异硫氰酸根苯甲基衍生物、1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸（DOTA）、1,4,7-三氮杂环壬烷-1,4,7-三乙酸（NOTA）和 3,6,9,15-四氮杂双环[9.3.1]十五烷-1（15）、11、13-三烯-3,6,9-三乙酸（PCTA）与（68）Ga 的最佳放射性标记条件、金属离子杂质对放射化学产率的影响、体外稳定性和体内清除特性进行了研究。
在所研究的四种 BFC 中，对异硫氰酸根苯甲基-1,4,7-三氮杂环壬烷-1,4,7-三乙酸（NOTA-NCS）可在室温下立即与（68）Ga 进行放射性标记，产率超过 98%，即使存在高达 10 ppm 的其他金属离子杂质（如 Zn、Cu、Fe、Al、Sn 和 Ti 离子）也是如此。NOTA-NCS 的（68）Ga 配合物即使在存在 1000 倍摩尔过量的金属离子（如 Fe、Cu、Zn 和 Ca 离子）时，也表现出高的体外稳定性。相比之下，其他（68）Ga 标记的 BFC（DTPA-NCS、DOTA-NCS 和 PCTA-NCS）在与上述浓度的金属离子孵育时，放射化学产率降低。在瑞士小鼠中的生物分布研究表明，（68）Ga-NOTA-NCS 通过肾脏迅速清除，在任何主要器官中均有最小的保留。
使用基于 NOTA 的双功能螯合剂制备（68）Ga 放射性药物的简单快速方法将使（68）Ga 放射性药物化学更加方便，并且受其他金属离子杂质的干扰最小;并增加了用于 PET 成像的基于（68）Ga 的制剂的范围。
