How is 68Ga Labeling of Macrocyclic Chelators Influenced by Metal Ion Contaminants in 68Ge/68Ga Generator Eluates?
Abstract
To assess the influence of Zn(2+), Cu(2+), Fe(3+), Al(3+), Ti(IV), and Sn(IV) on incorporation of (68)Ga(3+) into pendant-arm macrocyclic chelators, the (68)Ga labeling of 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra-acetic acid (DOTA), 1,4,7-triazacyclononane-1,4,7-tris[methyl(2-carboxyethyl) phosphinic acid]) (TRAP), and 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl) phosphinic acid]-4,7-bis-[methyl(2-hydroxymethyl)phosphinic acid] (NOPO), as well as their peptide conjugates, was investigated in the presence of varying concentrations of these metal ions. The (68)Ga labeling yield for carboxylate-type chelators NOTA and DOTA is decreased at lower metal ion contaminant concentrations compared with phosphinate-type chelators TRAP and NOPO.
The latter are able to rapidly exchange coordinated Zn(II) with (68)Ga(3+), as confirmed by mass spectrometry and (31)P NMR spectroscopy. (68)Ga labeling of Zn(II) complexes of TRAP and NOPO proceeds as efficient as labeling of neat NOTA; this applies also to the corresponding peptide conjugates of these chelators. This behavior results in substantially improved selectivity for Ga(3+) and, therefore, in more robust and reliable (68)Ga labeling procedures.
In addition, none of the investigated chelators binds (68)Ge, rendering post-labeling purification protocols, for example, solid-phase extraction, a reliable means of removal of (68)Ge contamination from (68)Ga radiopharmaceuticals.