Modelling and Spectroscopy
Detailed topic: Investigating the chemistry of radionuclides:
Involved people: Nicolas Galland ( Assistant Prof. ), Eric Renault ( Assistant Prof. ), Dumitru-Claudiu-Sergentu (PhD student), Cecilia Gomez Pech (PhD student)
Within this research area, our work mainly concerns the use in oncology of the 211 radioisotope of astatine ( 211At). The principle is to label, with this radionuclide, a biological vector that will target tumor cells and destroy them, thanks to the alpha particles emitted during the nucleus decay. However, the binding of biomolecules with 211At remains a challenge that requires a minimum of understanding of the At chemistry (many of the basic chemical studies were set aside due to the few amounts of available astatine). Working in close collaboration with the radiochemistry group at SUBATECH laboratory (UMR IN2P3 6457), we investigate the basic chemistry of astatine using quantum chemistry tools. We also build on our expertise through methodological developments (see Axis-1) in relativistic calculations and through the study of other radionuclides ( 44Sc, 210Po, etc.).
Chem. Eur. J. 2016, 22, 2964–2971
Axe-1 : Identifying the basic astatine species
Before studying the astatine reactivity, one need to identify the chemical forms of At in the experimental conditions. Our team is working on establishing the Pourbaix diagram in non-complexing aqueous medium (r.h.s. Figure). At differs from the other halogens by the existence, in addition to At– , of thermodynamically stable cationic forms, At+ and AtO+ , in oxidizing and acidic conditions. In addition, the AtO+ cation reacts with water to form the AtO(OH) species. The constant of the hydrolysis reaction is particularly high (~10-2 ) and is unique in the literature compared to other hydrolysis reactions of singly charged cations!
We are also interested in the solvation of AtO+ . The modeling results (Figure below) reveal a change in of spin state between the gas phase (triplet ground state, preventing any reaction with most of the chemical compounds) and the aqueous phase (singlet ground state): the solvation induces AtO+ reactivity! This unique behavior in the literature may explain the lack of reproducibility for some experiments with At. Astatine is produced within cyclotrons, and then it is either directly extracted within acidic aqueous solutions, or evaporated in gas phase followed by a condensation process in solution. The kinetic parameters ruling the conversion from At in the gas phase to the solvated singlet-spin AtO+ species being unknown, the astatine reactivity may behave differently according to the production protocol ("wet" extraction/gas phase distillation) ).
J. Chem. Theory Comput., 2014, 10, 4830-4841
Axe-2 : Characterizing the nature of At-bonds
Previous quantum chemical calculations have evidenced the influence of the relativistic effects, notably the spin-orbit coupling (SOC), on the astatine reactivity. This theme is focused on revealing both the nature and the SOC effects, on the chemical bonds involving At. Innovative theoretical tools locally developed, e.g. ELF and QTAIM topological analysis programs, have notably demonstrated that SOC is able to reverse the bond polarization and increases the ability of astatine to form charge-shift bonds. This character was notably found to stabilize bonds with sp3 carbon atoms. In the case of bonds formed with O and N, they are mainly ionic while the bonds with B seem rather covalent (r.h.s. Figure).
Axe-3 : Investigating the astatine reactivity
This theme is situated at the heart of the astatine project. The first studies, coupling radiochemistry experiments and relativistic quantum calculations, showed that the reactivity of both At+ and AtO+ cationic forms is especially sensitive to solvation. The latter are supposed to be involved in current 211 At-labeling protocols based on electrophilic substitutions. An apparent correlation has been evidenced between in vivo stability of 211 At-labeled agents and the At– R ( R = C, B) calculated bond enthalpies (Figure below). Furthermore, since astatine is positively charged in At–C bonds, while for stronger At–B bonds it bears a negative charge, this may lead to different stabilities with respect to oxidation conditions, or nucleophilic/electrophilic attacks within the body's tissues and cells. Given the importance of the At–C and At–B bonds for the labeling protocols under development, the revealed disparities should be considered for preventing in vivo deastatination.
T. Ayed et al., Eur. J. Med. Chem., 2016, 116, 156-164
Axe-4 : Other radionuclides
Among the radioisotopes employed for diagnostic and/or therapeutic purposes in nuclear medicine, we study the complexation of various radionuclides produced by the Arronax cyclotron. Scandium isotopes such as 47Sc and 44Sc, are interesting both for internal radiotherapy ( 47Sc) and for pre-therapeutic dosimetric study that may be achieved through PET ( Positron emission tomography ) images obtained with 44Sc. 64Cu is another good candidate for molecular imaging and PET dosimetry .