Ferreira Cara L, Lamsa Eric, Woods Michael, Duan Yin, Fernando Pasan, Bensimon Corinne, Kordos Myra, Guenther Katharina, Jurek Paul, Kiefer Garry E
MDS Nordion, 4004 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 2A3, Ottawa Heart Institute, Ottawa, Ontario, Canada, MDS Nordion, Kanata, Ontario, Canada, and Macrocyclics, Dallas, Texas.
Bioconjug Chem. 2010 Mar 17;21(3):531-6. doi: 10.1021/bc900443a. Epub 2010 Feb 22.
Ga radioisotopes, including the generator-produced positron-emitting isotope (68)Ga (t1/2 = 68 min), are of increasing interest for the development of new radiopharmaceuticals. Bifunctional chelates (BFCs) that can be efficiently radiolabeled with Ga to yield complexes with good in vivo stability are needed. To this end, we undertook a systematic comparison of four BFCs containing different chelating moieties: two novel BFCs, p-NO2-Bn-Oxo (1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid) and p-NO2-Bn-PCTA (3,6,9,15-tetraazabicyclo [9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid), and two more commonly used BFCs, p-NO2-Bn-DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and p-NO2-Bn-NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid). Each BFC was compared with respect to radiolabeling conditions, radiochemical yield, stability, and in vivo clearance properties. p-NO2-Bn-PCTA, p-NO2-Bn-Oxo, and p-NO2-Bn-NOTA were all more efficiently radiolabeled with Ga compared to p-NO2-Bn-DOTA. p-NO2-Bn-DOTA required longer reaction time, higher concentrations of BFC, or heating to obtain equivalent radiochemical yields. Better stability was observed for p-NO2-Bn-NOTA and p-NO2-Bn-PCTA compared to p-NO2-Bn-DOTA and p-NO2-Bn-Oxo, especially with respect to transmetalation to transferrin. Ga-radiolabled p-NO2-Bn-Oxo was found to be kinetically labile and therefore unstable in vivo. Ga-radiolabeled p-NO2-Bn-NOTA and p-NO2-Bn-PCTA were relatively inert, while Ga-radiolabeled p-NO2-Bn-DOTA had intermediate stability, losing >20% of Ga in less than one hour when incubated with apo-transferrin. Similar stability differences were seen when incubating at pH 2. In vivo PET imaging and biodistribution studies in mice showed that (68)Ga-radiolabeled p-NO2-Bn-PCTA, p-NO2-Bn-NOTA, and p-NO2-Bn-DOTA all cleared through the kidneys. While there was no statistical difference in the biodistribution results of (68)Ga-radiolabeled p-NO2-Bn-PCTA and p-NO2-Bn-DOTA, (68)Ga-radiolabeled p-NO2-Bn-NOTA cleared more rapidly from blood and muscle tissue but retained at up to 5 times higher activity in the kidneys.
包括由发生器产生的正电子发射同位素（68）Ga（半衰期 = 68分钟）在内的镓放射性同位素，在新型放射性药物的研发中越来越受到关注。需要能够用镓高效放射性标记以产生具有良好体内稳定性的配合物的双功能螯合剂（BFC）。为此，我们对四种含有不同螯合部分的BFC进行了系统比较：两种新型BFC，对硝基苄基 - 氧杂环十二烷三乙酸（1-氧杂-4,7,10-三氮杂环十二烷-4,7,10-三乙酸）和对硝基苄基 - 多胺多羧基大环配体（3,6,9,15-四氮杂双环[9.3.1]十五碳-1（15）,11,13-三烯-3,6,9-三乙酸），以及另外两种常用的BFC，对硝基苄基 - 二乙三胺五乙酸（1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸）和对硝基苄基 - 氮杂环壬烷三乙酸（1,4,7-三氮杂环壬烷-1,4,7-三乙酸）。对每种BFC在放射性标记条件、放射化学产率、稳定性和体内清除特性方面进行了比较。与对硝基苄基 - 二乙三胺五乙酸相比，对硝基苄基 - 多胺多羧基大环配体、对硝基苄基 - 氧杂环十二烷三乙酸和对硝基苄基 - 氮杂环壬烷三乙酸都能用镓更有效地进行放射性标记。对硝基苄基 - 二乙三胺五乙酸需要更长的反应时间、更高浓度的BFC或加热才能获得相当的放射化学产率。与对硝基苄基 - 二乙三胺五乙酸和对硝基苄基 - 氧杂环十二烷三乙酸相比，对硝基苄基 - 氮杂环壬烷三乙酸和对硝基苄基 - 多胺多羧基大环配体表现出更好的稳定性，尤其是在向转铁蛋白的金属转移方面。发现镓放射性标记的对硝基苄基 - 氧杂环十二烷三乙酸在动力学上不稳定，因此在体内不稳定。镓放射性标记的对硝基苄基 - 氮杂环壬烷三乙酸和对硝基苄基 - 多胺多羧基大环配体相对惰性，而镓放射性标记的对硝基苄基 - 二乙三胺五乙酸具有中等稳定性，与脱铁转铁蛋白孵育时在不到一小时内失去超过20%的镓。在pH 2下孵育时也观察到类似的稳定性差异。在小鼠体内进行的正电子发射断层扫描（PET）成像和生物分布研究表明，（68）Ga放射性标记的对硝基苄基 - 多胺多羧基大环配体、对硝基苄基 - 氮杂环壬烷三乙酸和对硝基苄基 -二乙三胺五乙酸都通过肾脏清除。虽然（68）Ga放射性标记的对硝基苄基 - 多胺多羧基大环配体和对硝基苄基 - 二乙三胺五乙酸的生物分布结果没有统计学差异，但（68）Ga放射性标记的对硝基苄基 - 氮杂环壬烷三乙酸从血液和肌肉组织中清除得更快，但在肾脏中保留的活性高达5倍。
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