Introduction

Cancer represents an important axis of research all around the world. The current treatments are based on the surgery, chemotherapy or the external irradiation. The vectorized radiotherapy, whose radioimmunotherapy (RIT) is

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an example, is a technique particularly innovative of treatments of cancer complementary to the existing therapies. It is based on the use of a specific vector (antibody or peptide) of the target cell to destroy, labelled by a ra- dioactive isotope. This radioisotope can be an alpha emitter, a beta emitter or an emitter of Auger electrons. The challenge consists in delivering the radioactive molecules on the cellular sites and finding a compromise between toxicity to healthy tissues and the anti-tumour effects. Among all the emit- ters under consideration in the field, scandium is a theranostic element for nuclear medicine, for imaging using Positron Emission Tomography (PET) with ⁴⁴Sc as well as for the radiotherapy with ⁴⁷Sc. ⁴⁷Sc is a β⁻ emitter which has close physical properties compared to ⁶⁷Cu or ¹⁷⁷Lu, which leads to a promising candidate for targeted radionuclide therapy. ⁴⁷Sc has already been investigated for its potential interest for β-RIT [1–3]. High specific activity ^44m,

44Sc radionuclides would provide an attractive radionuclide for labelling of various biomarkers for PET imaging to better diagnose cancers, enabling further consideration for ⁴⁷Sc as a matched pair theranostic radionuclide, making them highly relevant as potential theranostic radionuclides (a single molecule labelled with two different isotopes of the same chemical element). ⁴⁴Sc based imaging agent for dose planning of further ⁴⁷Sc-based therapy in a theranostic approach could be considered [4]. The main advantage of scandium is that it has both a positron emitter and a therapeutic radionuclide of the same element.

Additionally as scandium is a trivalent element, it should behave like any other trivalent lanthanides already used. Currently the radionuclide used for imaging is a different radionuclide such as ⁶⁸Ga or ¹¹¹In than the therapeutic such as ⁹⁰Y or ¹⁷⁷Lu. Is known they behave differently in vivo especially in the critical organs such as the bone and liver thus not truly reflecting the

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pharmacokinetics of the therapeutic. In this case the pharmacokinetics will be matched allowing for optimal dosimetry and increased efficacy. In the case of scandium isotope, ⁴³Sc (T_1/2=3.891 h) and ⁴⁴Sc (T_1/2=3.97 h) are β⁺ emitters that can be used for imaging in association to ⁴⁷Sc (T_1/2=80.4 h) for therapy. But their half-lives are too different to use beta emitters as ⁴⁷Sc tracers. To increase the half-life of β⁺ emitters, ^44mSc (T1/2=58.6 h), an isomeric state of ⁴⁴Sc via the in-vivo ^44mSc/⁴⁴Sc generator concept can be used. The ^44mSc/⁴⁴Sc pair can be used to perform studies with longer pharmacokinetics (long biological half- life), which is the case with antibodies as biological vectors (immuno-PET imaging). With regards to the existing ⁸⁹Zr radionuclide, even if it has a longer half-life, the main drawback remains in its coordination chemistry; ligands exist but are not completely satisfactory. Whereas Scandium with +III as the most common oxidation state, can be easily complexed by the most commonly utilized polyaminocarboxylate chelators. In addition, ^44mSc and ⁴⁷Sc have comparable half-lives allowing following the metabolic pathways over long period of time, which is an advantage compared to the ⁴⁴Ti/⁴⁴Sc generator.

44mSc decays by internal transition (98.8%) to the ground state (^44g Sc) with an associated small secondary emission (Auger emission 2.74%). The main photon emission (271 keV) will induce some recoil of the nuclei. Due to the large mass difference, this recoil energy is estimated to be only 0.89 eV. These two elements and the fact that the chemical nature of the parent nuclei and its daughter nuclei are identical suggest that the ^44mSc/⁴⁴Sc generator should be a good candidate for an in-vivo generator. Indeed, no change in oxidation state is expected like for ¹⁴⁰Nd/¹⁴⁰Pr, or large recoil leading to the release of the isotope from the molecule [5] or radiolysis effects coming by the secondary emission.

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Another application of ⁴⁴Sc is the development of a new nuclear medical imaging technique using the ability of the ⁴⁴Sc to emit in 99.9% of the cases a photon with energy of 1.15 MeV and a characteristic emission time of few picoseconds. When calculating radiation doses, the specific emission characteristics of ⁴⁴Sc make it a unique candidate promising for 3-coincidence imaging with potentially improved local resolution, from which the very first results obtained on a small-dimension prototype let foresee a very promising perspective [6].

Recently, the scandium chemistry has revealed a growing interest with an increasing number of papers available within ⁴⁴Ti/⁴⁴Sc generator form [7–9],

44Sc [10, 11], ^44mSc/⁴⁴Sc [12], ^natSc [13], ⁴⁶Sc [14, 15] or ⁴⁷Sc [3, 16, 17].

Many different ways have been investigated to produce ⁴⁴Sc and ^44mSc. They can be formed using radiative mechanism on ⁴⁵Sc, by spallation on ^natFe or

natCu. Scandium-44 can also be obtained through the decay of titanium-44 using the so-called ⁴⁴Ti/⁴⁴Sc generator but in this case no ^44mSc can be obtained. For further labelling, recovery of the ^44mSc/⁴⁴Sc from calcium needs to remove bulk alkaline earth and give the final product in a small volume.

Small amounts of residual calcium do not interfere with DOTA chelation [18]

but it could be important to minimize this quantity in case of in-vivo injections. Thus, the chemical processing aimed recovering scandium while minimizing cationic impurities (i.e. Ca, metals).

Many authors have previously developed processes to purify scandium from calcium [19–24]. Most of them used solvent extraction. Moreover Kalyanaraman and Khopkar [21] evidenced that scandium can be selectively extracted with mesityl oxide as its thiocyanate complex and then recovers

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in HCl solution. Nonetheless, calcium seemed to be a significant interferent for quantities higher than 25 mg. These authors evidenced that this quantity is sufficient to cause 2% error in the recovery of scandium. For higher quantities of calcium, the loss of scandium can be important. Vibhute and Khopkar [19] and Karve and Khopkar [20] purified scandium as citrate and ascorbato complex, respectively, using aliquat 336S as extractant. In this case, scandium was obtained in the final solution with some organic acid that could become competing agent as far as radiolabelling was concerned.

Radhakrishnan and Owens [22] proposed another route for scandium purification, by liquid-liquid extraction, using tri-n-butyl phosphate as solvent.

But in this study the authors evidenced that the selectivity coefficient of scandium as regard of calcium increased when nitric acid concentration increased while the distribution coefficient of scandium decreased. This meant that, despite the huge amount of calcium used, quantitative recovery of scandium was not easy. Moreover no data are available concerning the other metals which can be present at the end of irradiation. One such viable separation uses precipitation and filtration [25]. This approach takes advantage of the insolubility of Sc(OH)3 either as a precipitate or coprecipitate, and is similar to a technique developed for purifying yttrium from strontium [26].

Due to these difficulties, a chromatographic process for purification was thus studied. Rane and Bhatki [24] reported a method using cation exchange resin (DOWEX 50x8) to prepare ⁴⁵Ca from natural scandium with high resulting specific activity.

But this type of resin is not really specific with regards to metal transitions. So purification of scandium from metal transitions using

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DOWEX 50x8, seems difficult. But, the major used complexing agent for metals, DOTA, is not a specific ligand. Thus the presence of others metals requires higher quantities of DOTA for radiolabelling. In order to minimize the metallic impurities, D G A ® r e s i n which is specific to lanthanides and already used to purify scandium [16], w a s e m p l o y e d

This work aimed to produce and purify ^44mSc/⁴⁴Sc with high specific activities. Then the radiolabelling with DOTA was performed from scandium source in order to evaluate the specific activity with regards to all metallic impurities that could be present in the final source.

2. Materials and Methods