Detailed evaluation on the effect of metal ion impurities on complexation of generator eluted 68Ga with different bifunctional chelators

Introduction: The introduction of 68Ga-based positron emission tomography (PET) to clinical practice using 68Ge/68Ga generator represents a developmental milestone in the field of molecular imaging. Herein, we report a systematic study on 68Ga 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 68Ga-based target specific radiopharmaceuticals. Methods: 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 68Ga 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. Results: 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 68Ga 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 68Ga-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 68Ga-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 68Ga-NOTA-NCS cleared rapidly through the kidneys with minimum retention in any major organ. Conclusions: The simple and rapid approach for preparation of 68Ga-radiopharmaceuticals using NOTA based bifunctional chelators would render 68Ga-radiopharmaceutical chemistry more convenient with minimum interference from other metal ion impurities; and increase the scope of making 68Ga based agents for PET imaging