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

Abstract

Today, 44Sc is an attractive radionuclide for molecular imaging with PET. In this work, we evaluated a 44Ti/44Sc radionuclide generator based on TEVA resin as a source of 44Sc. The generator prototype (5 MBq) exhibits high 44Ti retention and stable yield of 44Sc (91 ± 6 %) in 1 mL of eluate (20 bed volumes, eluent—0.1 M oxalic acid/0.2 M HCl) during one year of monitoring (more than 120 elutions). The breakthrough of 44Ti did not exceed 1.5 × 10−5% (average value was 6.5 × 10−6%). Post-processing of the eluate for further use in radiopharmaceutical synthesis was proposed. The post-processing procedure using a combination of Presep® PolyChelate and TK221 resins made it possible to obtain 44Sc-radioconjugates with high labeling yield (≥95%) while using small precursor amounts (5 nmol). The proposed method takes no more than 15 min and provides ≥90% yield relative to the 44Sc activity eluted from the generator. The labeling efficiency was demonstrated on the example of [44Sc]Sc-PSMA-617 and [44Sc]Sc-PSMA-I&T synthesis. Some superiority of PSMA-I&T over PSMA-617 in terms of 44Sc labeling efficiency was demonstrated (likely due to presence of DOTAGA chelator in the precursor structure). It was also shown that microwave heating of the reaction mixture considerably shortened the reaction time and improved radiolabeling yield and reproducibility of [44Sc]Sc-PSMA-617 and [44Sc]Sc-PSMA-I&T synthesis.

Engineering a modular 44Ti/44Sc generator: eluate evaluation in preclinical models and estimation of human radiation dosimetry

“…Consistent with prior investigation [ 4 , 13 , 14 ], 44 Ti was efficiently loaded on the resin, and we observed that this material can re-distribute on the column following repeated 44 Sc elutions. This resulted in breakthrough of 44 Ti and has the potential to contaminate the radiopharmaceutical and work space for compounding.…”

“…In order to harness the potential for this isotope for theranostics, greater availability of the isotope and improved understanding of in vivo stability and pharmacodynamics is required [ 11 – 13 ]. In this work, we sought to produce and better understand how 44 Sc is excreted in vivo, and to what degree this will impact the radiation burden in research and clinical use.…”

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

“…As such, 44 Ti is of interest as the parent nuclide in the long-lived 44 Ti/ 44 Sc generator system. 44 Sc can be chemically separated to create an essentially perpetual source of 44 Sc. − For PET imaging, 45 Ti ( t 1/2 = 3.08 h, β + = 85%, and E ⟨β + ⟩ = 0.439 MeV) , offers higher inherent resolution and fewer concomitant γ emissions than any other short-lived radionuclide except 18 F . We and others have demonstrated the chelation and targeting of 45 Ti, revealing a potential path to its application in nuclear medicine .…”

Radiometallation and photo-triggered release of ready-to-inject radiopharmaceuticals from the solid phase

“…15–17 Specifically, bifunctional chelators, peptides and biomolecules utilized as disease-specific targeting vectors typically require a pH range of 4–8 to form stable complexes. 18–22…”

“…[15][16][17] Specically, bifunctional chelators, peptides and biomolecules utilized as disease-specic targeting vectors typically require a pH range of 4-8 to form stable complexes. [18][19][20][21][22] To enable the concerted separation and labeling with radiometals, we proposed the immobilization of a radiopharmaceutical synthesis precursor comprised of a chelator linked peptide appended to a water-compatible solid-support with a photo-labile amino acid. We drew inspiration from solidphase synthesis approaches of metal-based drugs and the clinical, solid-phase based radiosynthesis 131 I-MIBG, 23,24 and recently reported photochemical radiosynthesis strategies.…”