Oxidation of terbium(III) as a first step towards high purity terbium-161 for medical applications

Arman Meryem

Promoter

SCK•CEN Mentor

Geboes Bart
bart.geboes@sckcen.be
+32 14 33 82 08

SCK•CEN Co-mentor

Van Hecke Karen
karen.van.hecke@sckcen.be
+32 14 33 32 75

Expert group

Radiochemistry

PhD started

2018-10-01

Short project description

Four radioisotopes of the lanthanide element terbium (Tb) possess suitable decay characteristics for use in a clinical setting: 149Tb (T1/2 4.16 h, α-decay), 152Tb (T1/2 17.5 h, β+ -decay), 155Tb (T1/2 5.32 d, E.C.), and 161Tb (T1/2 6.89 d, β--decay) (Müller et al., 2012). These isotopes are complementary since 152Tb is useful for Positron Emission Therapy (PET) imaging, 155Tb can be used for Single-Photon Emission Computed Tomography (SPECT) diagnosis while 161Tb can be used for β--particle targeted radionuclide therapy and 149Tb for α-particle radionuclide therapy. Since Tb belongs to the group of the lanthanide elements, the proven procedures for the radiolabelling of targeting carrier molecules such as a monoclonal antibodies or peptides with the clinically already frequently used 177Lu can be used to prepare Tb-based radiopharmaceuticals. Moreover, because of the identical chemical characteristics of these four Tb radioisotopes, carrier molecules can be labelled with each of them by means of the same radiolabelling procedure, and, the resulting radiopharmaceuticals should have the same pharmacokinetics and bio-distribution which enables a synergistic therapy.

Currently, SCK•CEN can only produce one of these four interesting isotopes, i.e. 161Tb in the Belgian Reactor 2 (BR2). The BR2 reactor, which offers high neutron fluxes, is perfectly suited for the production of carrier-free 161Tb by irradiation of highly enriched 160Gd targets. 161Tb is produced by neutron capture of 160Gd according to the following reaction: 160Gd(n,γ)161Gd, followed by β- decay of the produced 161Gd (T1/2 3.66 min) to 161Tb. Since the intermediate 161Gd is short-lived, it will already have disappeared when the target is unloaded from the reactor. Part of the produced 161Tb will already have decayed to the stable isotope 161Dy. Therefore, in order to isolate and purify 161Tb from the dissolved irradiated 160Gd targets, a method must be developed to separate Tb from other lanthanide elements.

Due to the similarity in chemical properties (most stable oxidation state in aqueous solutions is the trivalent state, similar ionic radii), the separation of adjacent lanthanide elements is highly challenging. Lehenberger (Lehenberger et al., 2011) used a well-known cation exchange HPLC method with α-hydroxyisobutyric acid (α-HIBA) as eluent to isolate 161Tb from small (mg amounts) irradiated 160Gd targets. This is one of the most efficient separation methods known for the separation of adjacent lanthanides. There are however several downsides to this separation process: (i) the duration of this separation is rather long, (ii) a complete separation cannot be achieved when a small amount of 161Tb has to be isolated from a lanthanide matrix and as a result  one can only obtain part of the available 161Tb as a pure fraction and (iii) with increasing target size, the pure 161Tb fraction decreases due to severe peak broadening and increased tailing. Because of these important disadvantages, especially when larger targets have to be processed, a new and improved separation method needs to be developed.

In order to develop a highly efficient separation method, Tb(III) could be selectively oxidized to Tb(IV) in advance of the separation process, to obtain different chemical properties compared to the other lanthanides present in the dissolved irradiated 160Gd targets. Tb is, together with cerium (Ce) and praseodymium (Pr), one of the rare lanthanide elements that can exist in the tetravalent oxidation state. The stability of Tb(III) in relation to Tb(IV) is illustrated by the very high standard reduction potential of the Tb(IV)/Tb(III) couple (+3.1 V vs. SHE). In aqueous solutions Tb(IV) would be spontaneously reduced by water (Wiberg, 2007), (Hobart et al., 1980).

The envisaged consecutive separation method is column chromatography as this separation method can be easily automated, which is important for an industrial scale 161Tb production process. Supported Ionic Liquid Phases (SILPs), using Ionic Liquids (ILs) as the basis of the stationary phase, might offer improved performance compared to existing solid phase extraction chromatographic materials (Hawkins et al., 2017). This assumption is further supported by results obtained in an ongoing PhD project in which ILs are used to separate radiolanthanides to produce high purity 153Sm.

Objective

The main objective of this PhD proposal is the separation of 161Tb from a 160Gd matrix to produce a high purity isotope for medical applications. Therefore, an electrochemical oxidation methodology will be developed to oxidize Tb(III) to Tb(IV) in such a way that compatibility with a nuclear configuration (glove box or hot cell) is assured. In addition, the stability of Tb(IV) must be guaranteed for the subsequent column chromatography separation process. Finally, a proof of concept for the separation methodology will be developed.

The following global work packages (WPs) are defined:

  1. Development and optimization of an electrochemical oxidation method
  2. Development of the Tb(IV)/Gd(III) separation method as a proof of concept

WP1

An elegant methodology to apply sufficient oxidation strength without the use of strong oxidative agents is electrochemical oxidation. Due to the relatively small potential window of aqueous electrolytes, water would be oxidized at the anode at a potential lower than the Tb(III) oxidation. In complexing aqueous solutions the formal reduction potential of Ln(IV)/Ln(III) couples can vary considerably because it is a function of the ratio of the stability constants of the formed Ln(IV) and Ln(III) complexes. This way, the reduction potential could be shifted to a more favorable value. Propst (Propst, 1974) and Saprykin (Saprykin et al., 1976) reported the electrochemical oxidation of Tb(III) from aqueous solutions of potassium phosphotungstate and 2.5 mol/L potassium carbonate containing 0.5 mol/L potassium hydroxide, respectively. However, these methods resulted in insoluble Tb(IV) deposits.

An alternative method to Tb complexation would be to use an electrolyte medium with a broader potential window (e.g. organic solvents) where Tb(III) could be oxidized without interference of the electrolyte solution. Possible (inflammable) organic solvents with a strong oxidation resistance are propylene carbonate (3.4 V vs. SHE) or sulfolane (3.3 V vs. SHE) (Izutsu, 2009). The supporting electrolyte will be selected based on the conductivity and oxidation resistance. Frequently used candidates are quaternary ammonium salts such as tetrabutyl ammonium perchlorate (Bu4NClO4), lithiumperchlorate (LiClO4) or lithium tetrafluoroborate (LiBF4). To prevent interference of the reduction products formed at the cathode, a divided electrochemical cell will be used. This will benefit both the electrochemical oxidation step and the sequential column separation.

Su et al. (Su et al., 1995), (Su et al., 1996) prepared Tb(IV) stabilized with periodate by reduction with ozone. However, the oxidation yield was not quantitative and the stability of Tb in its tetravalent state during the liquid-liquid extraction experiments was also limited, which is disadvantageous for the separation of Tb from other lanthanides. To overcome these issues a dual strategy will be used here: (i) solvent and electrolyte will selected where no strong reducing agents are present and (ii) the electrochemical cell will be designed to reduce the dead time between the oxidation and separation steps.

WP2

To our knowledge the separation of tetravalent Tb from other lanthanides has only been reported by Su (Su et al., 1995), (Su et al., 1996). They have demonstrated the separation of Tb(IV) from Y(III), which was chosen as a representative of the Y group (Y and the heavier lanthanides) by means of solvent extraction with the Aliquat 336 ionic liquid. However, the separation between Tb(IV) and the lighter lanthanides, samarium (Sm) and europium (Eu), will be more difficult according to results of their distribution experiments (Su et al., 1996).

Supported ionic liquid phases (SILPs) will be prepared, by impregnation or covalently binding of a porous support (e.g. silica, polyvinyl divinyl benzene) with ionic liquids (ILs) that have been successfully used for the separation of lanthanides to produce high purity 153Sm (ongoing PhD project). In a first step, by means of batch adsorption experiments, the kinetics and optimal separation conditions for Tb(IV) and Gd(III) will be determined. In a second step, column experiments will be performed to optimize the column separation of Tb(IV) and Gd(III). The focus will lie on the selection of a suitable SILP and the possibility for future scale-up of the process.

Experimental techniques

Since the potential window of the electrolyte solution depends on a variety of parameters (solvent, supporting electrolyte, electrode material), an experimental determination of these parameters will be performed in WP1 for each system. A three-electrode setup will be used where the working electrode functions as anode. Cyclic voltammetry will reveal the potential window and redox potential of the Tb(III)/Tb(IV) couple. A rotating disc electrode (RDE) will be used in combination with linear sweep voltammetry (LSV) to isolate the influence of the oxidation kinetics from diffusional limitations. The oxidation step will be executed through a chronoamperometric or chronopotentiometric scheme.

To quantify the conversion efficiency between Tb(III) and Tb(IV), and to assess the stability of Tb(IV), a suitable analysis technique is indispensable. Jones et al. applied UV/VIS spectroscopy to determine Tb(III) (Jones and Vullev, 2002). If an insufficiently low molar absorption coefficient is measured for Tb(III) or Tb(IV), a magnetic susceptibility balance could be used for quantitative analysis. Both techniques will be used in WP1 and WP2.

For the development of the separation methodology, non-radioactive lanthanides will be used. Therefore, the quantification of Tb and Gd needed to evaluate the parameters of the separation process (e.g. distribution ratios and separation factors) will be performed with ICP-MS or ICP-OES.