Evaluation of Bifunctional Chelates for the Development of Gallium-Based Radiopharmaceuticals

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• 作者：Cara L. Ferreira ; Eric Lamsa ; Michael Woods ; Yin Duan ; Pasan Fernando ; Corinne Bensimon ; Myra Kordos ; Katharina Guenther ; Paul Jurek ; Garry E. Kiefer
• 刊名：Bioconjugate Chemistry
• 出版年：2010
• 出版时间：March 17, 2010
• 年：2010
• 卷：21
• 期：3
• 页码：531-536
• 全文大小：217K
• 年卷期：v.21,no.3(March 17, 2010)
• ISSN：1520-4812

文摘

Ga radioisotopes, including the generator-produced positron-emitting isotope ⁶⁸Ga (t_1/2 = 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 ⁶⁸Ga-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 ⁶⁸Ga-radiolabeled p-NO₂-Bn-PCTA and p-NO₂-Bn-DOTA, ⁶⁸Ga-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.