Evaluation of hydroxamate-based resins towards a more clinically viable 44Ti/44Sc radionuclide generator

Gajecki, Leah; Marino, Celine M.; Cutler, Cathy S.; Sanders, Vanessa

doi:10.1016/j.apradiso.2022.110588

Cited by 9 publications

(10 citation statements)

References 34 publications

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“…Sc-43 43 Ca(p,n) 43 Scandium-47 can be produced via multiple routes and its manufacturing has been extensively explored, particularly in recent years. Notably, its production in high yields and isotopic purity for use in pharmaceuticals has long posed a major challenge to researchers [29,72]. Production methods that have been thoroughly investigated include the use of cyclotrons with fast or thermal neutrons, use of protons, alpha rays, and, more recently, photonuclear reactions [77].…”

Section: Isotope Nuclear Reaction Target Structure Referencesmentioning

confidence: 99%

“…This process could be avoided if: (i) the eluate is free of competing chelators, (ii) the eluate is not too acidic, or (iii) the volume-to-activity ratio is low enough to maintain the total volumes of the radiolabeling reaction. A generator presented recently by Gajecki et al, used to isolate Sc-44 from the eluent, has met all the above-mentioned criteria [ 72 ]. This allowed the eluted Sc-44 to be used directly from the generator without post-elution treatment or loss of activity.…”

Section: Properties and Effects Of Scandium In The Context Of Nuclear...mentioning

confidence: 99%

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Towards Clinical Development of Scandium Radioisotope Complexes for Use in Nuclear Medicine: Encouraging Prospects with the Chelator 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic Acid (DOTA) and Its Analogues

Ioannidis,

Lefkaritis,

Georgiades

et al. 2024

IJMS

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Scandium (Sc) isotopes have recently attracted significant attention in the search for new radionuclides with potential uses in personalized medicine, especially in the treatment of specific cancer patient categories. In particular, Sc-43 and Sc-44, as positron emitters with a satisfactory half-life (3.9 and 4.0 h, respectively), are ideal for cancer diagnosis via Positron Emission Tomography (PET). On the other hand, Sc-47, as an emitter of beta particles and low gamma radiation, may be used as a therapeutic radionuclide, which also allows Single-Photon Emission Computed Tomography (SPECT) imaging. As these scandium isotopes follow the same biological pathway and chemical reactivity, they appear to fit perfectly into the “theranostic pair” concept. A step-by-step description, initiating from the moment of scandium isotope production and leading up to their preclinical and clinical trial applications, is presented. Recent developments related to the nuclear reactions selected and employed to produce the radionuclides Sc-43, Sc-44, and Sc-47, the chemical processing of these isotopes and the main target recovery methods are also included. Furthermore, the radiolabeling of the leading chelator, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), and its structural analogues with scandium is also discussed and the advantages and disadvantages of scandium complexation are evaluated. Finally, a review of the preclinical studies and clinical trials involving scandium, as well as future challenges for its clinical uses and applications, are presented.

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Section: Isotope Nuclear Reaction Target Structure Referencesmentioning

confidence: 99%

Section: Properties and Effects Of Scandium In The Context Of Nuclear...mentioning

confidence: 99%

Towards Clinical Development of Scandium Radioisotope Complexes for Use in Nuclear Medicine: Encouraging Prospects with the Chelator 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic Acid (DOTA) and Its Analogues

Ioannidis,

Lefkaritis,

Georgiades

et al. 2024

IJMS

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“…Simple chelating moieties on solid supports are attractive for the de novo resin designs. Hydroxamate-type chelating resins have been employed as solid supports for 44 Ti/ 44 Sc generators 11,22 and for the purification of 45 Ti from the nat Sc target material. 12 However, the largest disadvantage of this system is the difficulty in removing coordinated Ti 4+ ions.…”

Section: ■ Introductionmentioning

confidence: 99%

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

Koller,

Wang,

Deluca

et al. 2023

Inorg. Chem.

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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.

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“…For sites without accelerators, a generator of 44g Sc’s long-lived parent 44 Ti (t 1/2 = 60.0 year) ( National Nuclear Data Center, Brookhaven National, 2022 ) has been developed ( Gajecki and Marino., 2023 ; under review; Schumann et al, 2007 ; Loktionova, et al, 2010 ; Filosofov, et al, 2010 ; Pruszyński and Loktionova, 2010 ; Radchenko, et al, 2016 ; Radchenko, et al, 2017 ; Rane, et al, 2015 ; Kerdjoudj, et al, 2016 ; Müller, et al, 2018 ; Roesch, 2012 ) 1 . 44 Ti’s long half-life, the potential for high efficiency elutions (>97%) ( Filosofov, et al, 2010 ), and the lack of 44m Sc make this system appealing.…”

Section: Introductionmentioning

confidence: 99%

“…Several published generator designs use AG 1-X8 anion exchange resins which result in large elution volumes and 44 Ti breakthrough requiring reverse elution modes ( Filosofov, et al, 2010 ; Pruszyński and Loktionova, 2010 ; Roesch, 2012 ; Kerdjoudj, et al, 2016 ). More recent designs use ZR hydroxamate resin which may increase generator lifetimes due to the increased number of elutions achieved before 44 Ti breakthrough is observed ( Gajecki and Marino, 2023 ). A 47 Ca/ 47 Sc generator system for the therapeutic radioisotope of scandium is also in development ( Mausner, et al, 1998 ; Rane, et al, 2015 ; Starovoitova, et al, 2015 ; Misiak, et al, 2017 ; Carzaniga et al, 2019 ; Pawlak, et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Cyclotron production of 43Sc and 44gSc from enriched 42CaO, 43CaO, and 44CaO targets

et al. 2023

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Introduction:43Sc and 44gSc are both positron-emitting radioisotopes of scandium with suitable half-lives and favorable positron energies for clinical positron emission tomography (PET) imaging. Irradiation of isotopically enriched calcium targets has higher cross sections compared to titanium targets and higher radionuclidic purity and cross sections than natural calcium targets for reaction routes possible on small cyclotrons capable of accelerating protons and deuterons.Methods: In this work, we investigate the following production routes via proton and deuteron bombardment on CaCO3 and CaO target materials: 42Ca(d,n)43Sc, 43Ca(p,n)43Sc, 43Ca(d,n)44gSc, 44Ca(p,n)44gSc, and 44Ca(p,2n)43Sc. Radiochemical isolation of the produced radioscandium was performed with extraction chromatography using branched DGA resin and apparent molar activity was measured with the chelator DOTA. The imaging performance of 43Sc and 44gSc was compared with 18F, 68Ga, and 64Cu on two clinical PET/CT scanners.Discussion: The results of this work demonstrate that proton and deuteron bombardment of isotopically enriched CaO targets produce high yield and high radionuclidic purity 43Sc and 44gSc. Laboratory capabilities, circumstances, and budgets are likely to dictate which reaction route and radioisotope of scandium is chosen.

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Evaluation of hydroxamate-based resins towards a more clinically viable 44Ti/44Sc radionuclide generator

Cited by 9 publications

References 34 publications

Towards Clinical Development of Scandium Radioisotope Complexes for Use in Nuclear Medicine: Encouraging Prospects with the Chelator 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic Acid (DOTA) and Its Analogues

Towards Clinical Development of Scandium Radioisotope Complexes for Use in Nuclear Medicine: Encouraging Prospects with the Chelator 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic Acid (DOTA) and Its Analogues

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

Cyclotron production of 43Sc and 44gSc from enriched 42CaO, 43CaO, and 44CaO targets

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