Effect of metal impurities on the radiolabeling efficiency of DOTA with terbium-161 and lutetium-177: a comparative study

Objectives: During the past decade, the radiolanthanide 161Tb has emerged as a promising β–-emitter for radionuclide therapy. 161Tb is often compared to 177Lu due to its similar decay properties. An increased therapeutic effect is however expected due to the higher emissions of Auger/conversion electrons. Both isotopes are currently being produced in SCK CEN. During production, it is important to control the presence of metals in the radionuclide solution. For 177Lu, it has indeed been demonstrated that metallic contaminants have an impact on the radiolabeling efficiency [1], however, for 161Tb this has yet to be investigated. In this study, we will therefore evaluate the influence of metal contaminants on the radiolabeling efficiency of two DOTA derivatives with 161Tb and 177Lu. Methods: p-SCN-Bn-DOTA and maleimido-mono-amide-DOTA, two commonly used chelators, were chosen for this study. Radiolabeling was performed by reacting 20 MBq of 161Tb or 177Lu with the chelator (molar activity 70MBq/nmol) in 50 µl of 0.15 M sodium acetate buffer at pH 4.7, at 95 °C for 15 min. The radiolabeling reactions were carried out in the presence of several metals (Cu2+, Zn2+, Pb2+, Fe3+) and the target material and daughter isotopes of both radiolanthanides. For each metal, five different metal/radionuclide molar ratios, ranging from 0.1 to 20, were evaluated. All reactions were performed in triplicate and radiochemical yields (RCYs) were assessed by ITLC analysis using an acetonitrile/water mixture (1:3) as the mobile phase. Results: A first set of radiolabeling experiments was carried out with p-SCN-Bn-DOTA. In the case of 177Lu, transition metals showed no notable impact on the RCY for metal/177Lu molar ratios ≤5. When 20 molar equivalents of the metals were added, the RCYs dropped below 10% for Zn2+ and Pb2+, below 20% for Fe3+, and nearly to 0% for Cu2+. No competition of Hf4+ was observed, which is in accordance with earlier findings [2]. In case of 161Tb, a significant impact on the RCY was observed for all the metals at ≥5 molar equivalents, while Pb2+ already caused a decrease of the RCY at a Pb2+/161Tb equimolar ratio. Conclusions: This study again confirms the impact of metal contaminants on the radiolabeling efficiency of DOTA for both 161Tb and 177Lu. Initial data suggest that 161Tb is more sensitive to metal impurities than 177Lu. Therefore, monitoring metal impurities will be even more important for 161Tb than it already is for 177Lu. Additionally, in contrast to 177Lu, 161Tb has a daughter nuclide (161Dy) that is competing in the radiolabeling reaction of DOTA. This is an important consideration in light of determining the shelf-life of 161Tb. Further studies are ongoing to confirm these data with maleimido-mono-amide-DOTA. References: [1] Asti, M., Tegoni, M., Farioli, D. et al. Influence of cations on the complexation yield of DOTATATE with yttrium and lutetium: a perspective study for enhancing the 90Y and 177Lu labeling conditions. Nuc. Med. Biol. 2012, 39, 509–517. [2] Breeman, W. A. P., de Jong, M., Visser, T. J. et al. Optimising conditions for radiolabelling of DOTA-peptides with 90Y, 111In and 177Lu at high specific activities. Eur. J. Nucl. Med. Mol. Imaging 2003, 30, 917–920.