The effects of trace metal impurities on Ga-68-radiolabelling with a tris(3-hydroxy-1,6-dimethylpyridin-4-one) (THP) chelator

• Published in: RSC advances Vol. 9; no. 64; pp. 37214 - 37221
• Main Authors: Cusnir, Ruslan, Cakebread, Andrew, Cooper, Margaret S, Young, Jennifer D, Blower, Philip J, Ma, Michelle T
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 14.11.2019; The Royal Society of Chemistry
• Subjects: Aluminum; Chelates; Chemistry; Cyclotrons; Ferric ions; Gallium; Impurities; Ions; Iron; Metal ions; Positron emission; Purification; Radioactive tracers; Radiochemical analysis; Radioisotopes; Radiolabelling; Titanium; Tomography; Trace metals
• ISSN: 2046-2069; 2046-2069
• DOI: 10.1039/c9ra07723e

GMP-grade 68 Ge/ 68 Ga generators provide access to positron-emitting 68 Ga, enabling preparation of Positron Emission Tomography (PET) tracers and PET imaging at sites that do not have access to cyclotron-produced radionuclides. Radiotracers based on tris(3-hydroxy-1,6-dimethylpyridin-4-one) (THP) chelators enable simple one-step preparations of 68 Ga PET radiopharmaceuticals from pre-fabricated kits without pre-processing of generator eluate or post-purification. However, trace metal impurities eluted along with 68 Ga could compete for THP and reduce radiochemical yields (RCY). We have quantified trace metal impurities in 68 Ga eluate from an Eckert & Ziegler (E&Z) generator using ICP-MS. The metals Al, Fe, nat Ga, Pb, Ti and nat Zn were present in generator eluate in significantly higher concentrations than in the starting eluent solution. Concentrations of Fe and nat Ga in eluate were in the range of 0.01-0.1 μM, Al, Zn and Pb in the range of 0.1-1 μM, and Ti in the range of 0.9-1.5 μM. To assess the ability of THP to chelate 68 Ga in the presence of such metal ions, radiolabelling reactions were undertaken in which selected metal ions were added to make them equimolar with THP, or higher. Al 3+ , Fe 3+ , nat Ga 3+ and Ti 4+ reduced RCY at concentrations equimolar with THP and higher, but at lower concentrations they did not affect RCY. Pb 2+ , Zn 2+ , Ni 2+ and Cr 3+ had no effect on RCY (even under conditions in which each metal ion was present in 100-fold molar excess over THP). The multi-sample ICP-MS analysis reported here is (to date) the most comprehensive and robust quantification of metal impurities in the widely used E&Z 68 Ga generator. 68 Ga from an E&Z generator enables near-quantitative radiolabelling of THP at chelator concentrations as low as 5 μM (lower than other common gallium chelators) without pre-processing. The combination of Al 3+ , Fe 3+ , nat Ga 3+ and Ti 4+ in unprocessed 68 Ga eluate is likely to decrease RCY of 68 Ga radiolabelling if a lower amount of THP chelator is used, and future kit design should take this into account. To increase specific activities by using even lower THP concentrations, purification of 68 Ga from trace metal ions will likely be required. We have quantified trace metal impurities present in 68 Ga generator eluant from the widely used Eckert & Ziegler 68 Ga generator, and measured the effect of these metal impurities on 68 Ga radiolabelling of a THP chelator.