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

Angus J Koller; Lilian Wang; Molly Deluca; Owen Glaser; Mariae J Robis; Jason C Mixdorf; Margarita N Chernysheva; Ilia A Guzei; Eduardo Aluicio-Sarduy; Todd E Barnhart; Jonathan W Engle; Eszter Boros

doi:10.1021/acs.inorgchem.3c01493

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

Inorg Chem. 2023 Dec 18;62(50):20655-20665. doi: 10.1021/acs.inorgchem.3c01493. Epub 2023 Jul 31.

Authors

Affiliations

¹ Department of Chemistry, Stony Brook University, Stony Brook, New York 11794, United States.
² Department of Medical Physics, University of Wisconsin, 1111 Highland Avenue, Madison, Wisconsin 53705, United States.
³ Department of Chemistry, University of Wisconsin─Madison, 1101 University Avenue, Madison, Wisconsin 53706, United States.

PMID: 37523384
DOI: 10.1021/acs.inorgchem.3c01493

Abstract

The solution chemistry of the hydrolytic, early-transition-metal ions Ti⁴⁺ and Sc³⁺ represents a coordination chemistry challenge with important real-world implications, specifically in the context of ⁴⁴Ti/⁴⁴Sc and ⁴⁵Ti/^NatSc 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 Ti⁴⁺ and Sc³⁺. The ligands catechol (benzene-1,2-diol) and deferiprone [3-hydroxy-1,2-dimethyl-4(1H)-pyridone] bind Ti⁴⁺ at significantly more acidic conditions (2-4 pH units) than Sc³⁺. 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 Ti⁴⁺ across a wide range of HCl concentrations (1.0-0.001 M), whereas Sc³⁺ 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 Ti⁴⁺. A model ⁴⁴Ti/⁴⁴Sc generator was produced, showing 65 ± 3% yield of ⁴⁴Sc in 200 μL of 0.2 M HCl with a significant ⁴⁴Ti breakthrough of 0.1%, precluding use in its current form. Attempts, however, removed ^natSc in loading fractions and a dilute (0.4 M HCl) wash and recovered 80% of the loaded ⁴⁵Ti activity in 400 μL of 6 M HCl. The previously validated ⁴⁵Ti 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 ⁴⁵Ti for positron emission tomography imaging applications.