De Novo Approaches to the Solid-Phase Separation of Titanium(IV) and Scandium(III): Translating Speciation Data to Selective On-Bead Chelation toward Applications in Nuclear Medicine.

The solution chemistry of the hydrolytic, early-transition-metal ions Ti 4+ and Sc 3+ represents a coordination chemistry challenge with important real-world implications, specifically in the context of 44 Ti/ 44 Sc and 45 Ti/ Nat Sc radiochemical separations. Unclear speciation of the solid and solution phases and tertiary mixtures of mineral acid, organic chelators, and solid supports are common confounds, necessitating tedious screening of multiple variables. Herein we describe how thermodynamic speciation data in solution informs the design of new solid-phase chelation approaches enabling separations of Ti 4+ and Sc 3+ . The ligands catechol (benzene-1,2-diol) and deferiprone [3-hydroxy-1,2-dimethyl-4(1 H )-pyridone] bind Ti 4+ at significantly more acidic conditions (2-4 pH units) than Sc 3+ . Four chelating resins were synthesized using either catechol or deferiprone with two different solid supports. Of these, deferiprone appended to carboxylic acid polymer-functionalized silica (CA-Def) resin exhibited excellent binding affinity for Ti 4+ across a wide range of HCl concentrations (1.0-0.001 M), whereas Sc 3+ was only retained in dilute acidic conditions (0.01-0.001 M HCl). CA-Def resin produced separation factors of >100 (Ti/Sc) in 0.1-0.4 M HCl, and the corresponding K d values (>1000) show strong retention of Ti 4+ . A model 44 Ti/ 44 Sc generator was produced, showing 65 ± 3% yield of 44 Sc in 200 μL of 0.2 M HCl with a significant 44 Ti breakthrough of 0.1%, precluding use in its current form. Attempts, however, removed nat Sc in loading fractions and a dilute (0.4 M HCl) wash and recovered 80% of the loaded 45 Ti activity in 400 μL of 6 M HCl. The previously validated 45 Ti chelator TREN-CAM was used for comparative proof-of-concept reactions with the CA-Def eluent (in HCl) and literature-reported hydroxamate-based resin eluents (in citric acid). CA-Def shows improved radiolabeling efficiency with an apparent molar activity (AMA) of 0.177 mCi nmol -1 , exceeding the established methods (0.026 mCi nmol -1 ) and improving the separation and recovery of 45 Ti for positron emission tomography imaging applications.