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 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 Kd 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.

[1]  S. Hurley,et al.  Cyclotron production of 43Sc and 44gSc from enriched 42CaO, 43CaO, and 44CaO targets , 2023, Frontiers in Chemistry.

[2]  Derek R. McLain,et al.  Evaluation of two extraction chromatography resins for scandium and titanium separation for medical isotope production , 2023, Journal of Radioanalytical and Nuclear Chemistry.

[3]  Jason S. Lewis,et al.  Sc-HOPO: A Potential Construct for Use in Radioscandium-Based Radiopharmaceuticals. , 2023, Inorganic chemistry.

[4]  C. Cutler,et al.  Evaluation of hydroxamate-based resins towards a more clinically viable 44Ti/44Sc radionuclide generator. , 2022, Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine.

[5]  Alexander Koller,et al.  A General Design Strategy Enabling the Synthesis of Hydrolysis-Resistant, Water-Stable Titanium(IV) Complexes. , 2022, Angewandte Chemie.

[6]  A. Larenkov,et al.  Separation of 44Sc from 44Ti in the Context of A Generator System for Radiopharmaceutical Purposes with the Example of [44Sc]Sc-PSMA-617 and [44Sc]Sc-PSMA-I&T Synthesis , 2021, Molecules.

[7]  Christopher J. Johnson,et al.  Homologous Structural, Chemical, and Biological Behavior of Sc and Lu Complexes of the Picaga Bifunctional Chelator: Toward Development of Matched Theranostic Pairs for Radiopharmaceutical Applications. , 2020, Bioconjugate chemistry.

[8]  E. Boros,et al.  Optimized methods for production and purification of Titanium-45. , 2020, Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine.

[9]  Korey P. Carter,et al.  Developing scandium and yttrium coordination chemistry to advance theranostic radiopharmaceuticals , 2020, Communications Chemistry.

[10]  B. A. Shiekh,et al.  Hierarchy of Commonly Used DFT Methods for Predicting the Thermochemistry of Rh-Mediated Chemical Transformations , 2019, ACS omega.

[11]  Jason S. Lewis,et al.  Preclinical optimization of antibody-based radiopharmaceuticals for cancer imaging and radionuclide therapy-Model, vector, and radionuclide selection. , 2018, Journal of labelled compounds & radiopharmaceuticals.

[12]  S. Braccini,et al.  Production and separation of 43Sc for radiopharmaceutical purposes , 2017, EJNMMI Radiopharmacy and Chemistry.

[13]  A. Ereditato,et al.  Measurement of 43Sc and 44Sc production cross-section with an 18MeV medical PET cyclotron. , 2017, Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine.

[14]  J. E. Rode,et al.  Benchmarking density functionals in conjunction with Grimme’s dispersion correction for noble gas dimers (Ne2, Ar2, Kr2, Xe2, Rn2) , 2017 .

[15]  Feng Chen,et al.  Intrinsic radiolabeling of Titanium-45 using mesoporous silica nanoparticles , 2017, Acta Pharmacologica Sinica.

[16]  F. M. Nortier,et al.  Separation of 44Ti from proton irradiated scandium by using solid-phase extraction chromatography and design of 44Ti/44Sc generator system. , 2016, Journal of chromatography. A.

[17]  T. Barnhart,et al.  Spot-welding solid targets for high current cyclotron irradiation. , 2016, Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine.

[18]  J. Engle,et al.  45Ti extraction using hydroxamate resin , 2012 .

[19]  C. A. Gnanathasan,et al.  Acute renal failure following oxalic acid poisoning: a case report , 2012, Journal of Occupational Medicine and Toxicology.

[20]  J. Engle,et al.  Cyclotron produced ⁴⁴gSc from natural calcium. , 2012, Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine.

[21]  F. Roesch,et al.  Scandium-44: benefits of a long-lived PET radionuclide available from the (44)Ti/(44)Sc generator system. , 2012, Current radiopharmaceuticals.

[22]  A. Pourmand,et al.  Distribution coefficients of 60 elements on TODGA resin: application to Ca, Lu, Hf, U and Th isotope geochemistry. , 2010, Talanta.

[23]  Jason S. Lewis,et al.  Standardized methods for the production of high specific-activity zirconium-89. , 2009, Nuclear medicine and biology.

[24]  C. Incarvito,et al.  Titanium(IV) citrate speciation and structure under environmentally and biologically relevant conditions. , 2005, Inorganic chemistry.

[25]  Shuang Liu,et al.  Synthesis, characterization, and structures of Mn(DMHP)3 x 12H2O and Mn(DMHP)2Cl x 0.5H2O. , 2005, Inorganic chemistry.

[26]  M. Welch,et al.  Production, processing and small animal PET imaging of titanium-45. , 2005, Nuclear medicine and biology.

[27]  J. McNeill,et al.  Insulin-enhancing vanadium(III) complexes. , 2001, Inorganic chemistry.

[28]  R. Hider,et al.  Synthesis, physicochemical properties, and evaluation of N-substituted-2-alkyl-3-hydroxy-4(1H)-pyridinones. , 1998, Journal of medicinal chemistry.

[29]  F. Langevelde,et al.  Production of highly pure no-carrier added 89Zr for the labelling of antibodies with a positron emitter , 1994 .

[30]  C. Orvig,et al.  Neutral water-soluble indium complexes of 3-hydroxy-4-pyrones and 3-hydroxy-4-pyridinones , 1988 .

[31]  C. Orvig,et al.  Aluminum and gallium compounds of 3-hydroxy-4-pyridinones: synthesis, characterization, and crystallography of biologically active complexes with unusual hydrogen bonding , 1988 .

[32]  C. Orvig,et al.  Exoclathrate Al(C7H8NO2)3.cntdot.12H2O. A facial geometry imposed by extensive hydrogen bonding with the ice I structure , 1987 .

[33]  P. Comba,et al.  The titanyl question revisited , 1987 .

[34]  B. Borgias,et al.  Synthetic, structural, and physical studies of titanium complexes of catechol and 3,5-di-tert-butylcatechol , 1984 .

[35]  E. Seidl,et al.  Die Radionuklidgeneratoren ,113Sn/113m In, 68Ge/68Ga und 44Ti/44Sc , 1973 .

[36]  F. Rösch,et al.  A 44Ti/44Sc radionuclide generator for potential application of 44Sc-based PET-radiopharmaceuticals , 2010 .

[37]  B. Jachimska,et al.  Characterization of rheological properties of colloidal zirconia , 2007 .

[38]  G. V. D. Velde The oxalato complexes of titanium(IV)—I : Mononuclear Ti(OH)2(C2O4)22− in solution , 1977 .