Liquid–liquid extraction in flow of the radioisotope titanium-45 for positron emission tomography applications

Pedersen, Kristina Søborg; Imbrogno, Joseph; Fonslet, Jesper; Lusardi, Marcella; Jensen, Klavs F.; Zhuravlev, Fedor

doi:10.1039/c8re00175h

Cited by 26 publications

(26 citation statements)

References 28 publications

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“…The LLE of 45 Ti proved to be a reliable way to recover and purify the radionuclide from 12 M HCl containing a significant amount of Sc. The extraction was found to be scalable and could be performed manually at low levels of activity, or via the syringe pump-driven membrane separator [15]. The latter could be remotely controlled and implemented as a part of an automated radiosynthesis module.…”

Section: Discussionmentioning

confidence: 99%

“…Hence, the thin scandium foil was preferred and the size of the foil was reduced from 1-0.7 cm 2 to 0.4 cm 2 , which decreased the yield of the 45 Ti production due to the increased risk of not hitting the foil with the entire proton beam profile. 45 Ti was separated from scandium by LLE with guaiacol/anisole 9/1 (v/v) either in batch or by using a Zaiput membrane separator, as described previously [15]. The extraction efficiency with different ratios between the aqueous and organic phases is shown in Table 1.…”

Section: Production Of 45 Ti and Synthesis Of [ 45 Ti]salan-ti-ca-psmamentioning

confidence: 99%

“…Higher recovery yields (93%) could be obtained on a HypoGel 1,3-diol resin in organic solvents, but the procedure required on-resin chelation chemistry. Recently, we reported the efficient LLE of 45 Ti from Sc-containing 12 M HCl using a guaiacol/anisole mixture [15]. The extraction is very fast and can be performed manually at low radioactivity levels.…”

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis, Computational, and Preclinical Evaluation of natTi/45Ti-Labeled Urea-Based Glutamate PSMA Ligand

et al. 2020

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Despite promising anti-cancer properties in vitro, all titanium-based pharmaceuticals have failed in vivo. Likewise, no target-specific positron emission tomography (PET) tracer based on the radionuclide 45Ti has been developed, notwithstanding its excellent PET imaging properties. In this contribution, we present liquid–liquid extraction (LLE) in flow-based recovery and the purification of 45Ti, computer-aided design, and the synthesis of a salan-natTi/45Ti-chelidamic acid (CA)-prostate-specific membrane antigen (PSMA) ligand containing the Glu-urea-Lys pharmacophore. The compound showed compromised serum stability, however, no visible PET signal from the PC3+ tumor was seen, while the ex vivo biodistribution measured the tumor accumulation at 1.1% ID/g. The in vivo instability was rationalized in terms of competitive citrate binding followed by Fe(III) transchelation. The strategy to improve the in vivo stability by implementing a unimolecular ligand design is presented.

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Section: Discussionmentioning

confidence: 99%

Section: Production Of 45 Ti and Synthesis Of [ 45 Ti]salan-ti-ca-psmamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis, Computational, and Preclinical Evaluation of natTi/45Ti-Labeled Urea-Based Glutamate PSMA Ligand

et al. 2020

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“…Furthermore, the aqueous and organic phases with partial miscibility tend to have low interfacial tension, which might cause a phase breakthrough during the membrane separation step. [15] The earlier work established that dialkyl ethers, and in particular Et 2 O and i Pr 2 O, efficiently and selectively extracted gallium from 5-7 M hydrochloric acid solutions in batch. [18,[22][23][24][25][26] In view of the dialkyl ethers being generally nontoxic, readily available, low boiling-point liquids with significant variation in hydrophobicity, we decided to evaluate this class of compounds for further development in LLE and membrane-based separation of Ga from Zn.…”

Section: System Designmentioning

confidence: 99%

“…We have recently described an efficient LLE in flow of radioisotope titanium-45 ( 45 Ti), where we used a static mixer and a membrane separator with integrated pressure control [14] to extract the 45 Ti radionuclide into the organic phase and separate it from the 12 M HCl feed containing scandium-45. [15] By implementing a similar technique here, one can envision a continuous production of 68 Ga on the cyclotron through the 68 Zn(p,n) 68 Ga nuclear reaction using a liquid target with a 68 Zn salt solution ( Figure 1). After irradiation, the aqueous target solution is combined with the organic extractant, and before entering a membrane separator, the aqueous and organic phases are thoroughly mixed via static mixers and a slug flow developing in the mixing tubing, further facilitating the liquid-liquid extraction.…”

Section: Introductionmentioning

confidence: 99%

Separation of Radiogallium from Zinc Using Membrane-Based Liquid-Liquid Extraction in Flow: Experimental and COSMO-RS Studies

Pedersen

Nielsen

Fonslet

et al. 2019

Solvent Extraction and Ion Exchange

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A switch from batch to continuous manufacturing of gallium-68 (68 Ga) and 68 Ga-labeled pharmaceuticals can be advantageous, as it recycles isotopically-enriched zinc-68 (68 Zn), removes pre-and post-irradiation target manipulations, and provides scalability via dose-on-demand production. Herein we report efficient extraction of radiogallium (66,67,68 Ga = *Ga) from ZnCl 2 /HCl solutions in batch and in flow using a membrane-based liquidliquid separator. From 5.6 M ZnCl 2 /3 M HCl, a 1/2 (v/v) diisopropyl ether (i Pr 2 O)/trifluorotoluene (TFT) solvent extracts 76.3 ± 1.9% of *Ga and 1.9 ± 1.6% of Zn in flow using a single pass through. From 1 M ZnCl 2 /6 M HCl, a 1/2 (v/v) n-butyl methyl ether (n-BuOMe)/TFT solvent extracts 95.7 ± 2.0% of *Ga and 0.005 ± 0.003% of Zn in flow. TFT plays a key role in controlling the interfacial tension between the aqueous and the organic phases, ensuring clean membrane-based separation. The process did not extract Cu, Mn, and Co but did extract Fe. Using HGaCl 4 and ZnCl 2 as the extractable species, the COSMO-RS theory predicts the solvation-driven extraction of Ga and Zn with a mean unsigned error of prediction of 4.0% and 3.4% respectively. KEYWORDS Gallium-68; gallium-67; liquid-liquid extraction in flow; COSMO-RS 68 Ge/ 68 Ga-generators further contribute to 68 Ga popularity in clinical and pre-clinical settings. [6] Meeting the growing demand for 68 Ga is a challenge, as it is mostly supplied by the gallium generators which suffer from high prices, long lead time, quality inconsistencies, and limited shelf life. [7] An alternative method of 68 Ga production is the irradiation of 68 Zn using a cyclotron. [8] Since many PET-centers have their own cyclotrons, this is potentially a convenient means of in-house production of 68 Ga-tracers. However, the cyclotron production of 68 Ga in solid targets from 68 Zn

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Thermochromatographic separation of 45Ti and subsequent radiosynthesis of [45Ti]salan

Giesen

Spahn

Neumaier

2020

J Radioanal Nucl Chem

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Due to its favorable decay properties, the non-standard radionuclide 45Ti is a promising PET isotope for tumor imaging. Additionally, titanium complexes are widely used as anti-tumor agents and 45Ti could be used to study their in vivo distribution and metabolic fate. However, although 45Ti can be obtained using the 45Sc(p,n)45Ti nuclear reaction its facile production is offset by the high oxophilicity and hydrolytic instability of Ti4+ ions in aqueous solutions, which complicate recovery from the irradiated Sc matrix. Most available 45Ti recovery procedures rely on ion exchange chromatography or solvent extraction techniques which are time-consuming, produce large final elution volumes, or, in case of solvent extraction, cannot easily be automated. Thus a more widespread application of 45Ti for PET imaging has been hampered. Here, we describe a novel, solvent-free approach for recovery of 45Ti that involves formation of [45Ti]TiCl4 by heating of an irradiated Sc target in a gas stream of chlorine, followed by thermochromatographic separation of the volatile radiometal chloride from co-produced scandium chloride and trapping of [45Ti]TiCl4 in a glass vial at − 78 °C. The recovery of 45Ti amounted to 76 ± 5% (n = 5) and the radionuclidic purity was determined to be > 99%. After trapping, the [45Ti]TiCl4 could be directly used for 45Ti-radiolabeling, as demonstrated by the successful radiosynthesis of [45Ti][Ti(2,4-salan)].

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Liquid–liquid extraction in flow of the radioisotope titanium-45 for positron emission tomography applications

Abstract: The continuous liquid–liquid extraction of the PET radioisotope 45Ti using a membrane-based separator allows for efficient 45Ti recovery and radiolabeling.

Cited by 26 publications

References 28 publications

Design, Synthesis, Computational, and Preclinical Evaluation of natTi/45Ti-Labeled Urea-Based Glutamate PSMA Ligand

Design, Synthesis, Computational, and Preclinical Evaluation of natTi/45Ti-Labeled Urea-Based Glutamate PSMA Ligand

Separation of Radiogallium from Zinc Using Membrane-Based Liquid-Liquid Extraction in Flow: Experimental and COSMO-RS Studies

Thermochromatographic separation of 45Ti and subsequent radiosynthesis of [45Ti]salan

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