Exploration of the chemistry of At(III) in solution. Towards new labelling approaches in nuclear medicine? – EXCAT3

Astatine is an element whose radioactive isotopes have only short half-lives (the time taken for half of the atoms initially present to decay). This means that it cannot be obtained at a measurable scale and must be produced via bismuth-209 with an alpha-particle beam provided by a cyclotron. Within the project, At-211 is produced by the Arronax cyclotron, which must provide an astatine target every two weeks on average. Because of its short half-life (7.2 h), solutions of astatine can only be studied for two days. Moreover, this means working with an “invisible” radioisotope, as no spectroscopic technique can be applied to characterize the species formed due to the very small quantities involved (10-12 to 10-15 mol/L). This also explains the lack of data about this element. Thus, a key part of the project is focused on the implementation and validation of appropriate tools to study the behavior of astatine in solution. Its originality lies in the development of a dual approach that combines experimental studies, to observe astatine’s behavior at the macroscopic scale, with theoretical studies, which provide information at the molecular scale.

The method to produce astatine-211 at Arronax has been set up but needs further improvement in order to obtain sufficient activities for the clinical tests. Several tools have been tested/developed to study the reactivity of At. In particular, a method to “visualize” the nature of the bonds has been developed and adapted to the study of heavy elements such as astatine. These tools have been used to understand the reactivity of the species AtO+. Surprising results have been revealed; they indicate the formation of relatively strong covalent bonds between AtO+ and heteroatoms, such as S, whereas “coordination-type” bonds were expected. These tools have also been used to answer some questions raised by in vivo experiments carried out on mice, namely the role of the strength of the chemical bond At-X in in vivo stability as well as the value of boron cages in radiolabeling. Today, this project is part of the IRON Labex, led by the head of the nuclear medicine department of Nantes Hospital, and continues with the aim of using data from fundamental research to provide innovative molecules for radiolabeling.

The project «astatine«, supported by two ANR financial supports (ANR RM-ASTATE211, 2007-2009 - ANR EXCAT3, 2010-2014) adopts a long-term perspective with a support by the CNRS/IN2P3 (new axis « innovative radioisotopes for nuclear medicine « in the GDR MI2B, the creation of a position (CR2) in 2013 at Subatech to strengthen the approach by molecular modelling), the region Pays de la Loire (priority theme « nuclear medicine and ionizing radiations « selected) and investments for the future (Labex IRON and Equipex ArronaxPlus).
In summary :
1/ANR JCJC RM-ASTATE211 ( 2007-2009 ): Work on the Pourbaix Pourbaix of astatine and highlighting of the species AtO +, with a first development which connects the molecular modelling and the experimental work
2/project “blanc” ANR EXCAT3 ( 2010-2014 ): extension of the consortium (PhLAM, LCT), production of At-211 at Arronax, continuation of the development of tools, the study of the reactivity of the species AtO + and first links with the question of the radiolabelling. The project has been slowed down by the problems of production of At-211 at Arronax but will have been able to benefit from a consequent work in molecular modelling.
3/2015 corresponds to a «transition« year at two levels. It is a question of finalizing the experimental work proposed within the framework of the ANR EXCAT3 (five planned articles). 2015 will also be a strategic year with the proposal of a project appearing within the framework of Labex IRON and in association with the GIP CYCERON ( Caen): develop innovative molecules with boron for the labelling of At-211 and F-18. This work, which can benefit from all the tools developed so far, is connected to the development of the alpha targeted in Nantes.
4/This year of transition will allow us to position on future projects, with the aim of combining basic research and finalized research.

This is primarily a fundamental research project, with the aim of exploring the reactivity of astatine. The work is thus essentially valued in terms of scientific communications. The project has been the subject of 9 publications in international journals, 15 presentations (four of which were invited) at international conferences and 8 at national conferences.

The principle of Targeted Alpha Therapy (TAT) is to destroy cancer cells with alpha-emitting- radionuclides bound to cancer selective carrier molecules, such as antibodies or peptides. Alpha particle-emitting radionuclides are promising for two reasons. On the one hand, the high toxicity of alpha particles related to the high linear energy transfer (LET ˜ 100 keV/µm) confer them the possibility to destroy cells not anymore sensitive to chemotherapy or external beam radiation. On the other hand, they are particularly interesting for the treatment of small size tumors (residual disease, micro metastases) due to the short range (< 100 µm) of alpha particles in human tissue. The challenge is to deliver the radioactive atoms at the target and to find the right balance between toxicity and anti-tumour effect. The efficacy and safety of targeted alpha therapy has been shown in a large number of pre-clinical studies and has been successfully translated to clinical trials.
Among the different potential alpha-emitters, At-211 is considered to be one of the most promising. It was used in two clinical trials in the US and in Sweden, and is the subject of a wide research program in Nantes. This project is coordinated by the “Centre de Recherches en Cancérologie Nantes Angers” and is motivated by the arrival of the cyclotron ARRONAX in Nantes, which will produce At-211 by the middle of 2010. A clinical trial of prostate cancer metastases is scheduled in the frame of the project Alpharit financed by Oseo. This will correspond to the first trial of TAT in France.
At-211 binding to carrier molecules remains however a difficult task On the one hand, it is a rare element since it has only short half-life radioactive isotopes; they have to be produced by nuclear reactions, such as in cyclotron for At-211. On the other hand, it is an invisible element. The amount of astatine produced allows working at ultra trace concentrations (typically 10-11 to 10-15 M) and no spectroscopic tools can be used to evaluate astatine chemistry at the microscopic level. As a result, Astatine chemistry is not well understood.
By analogy with labelling protocols of iodide disease-targeting carrier molecules, the studies focused on formation of astatine-carbon bounds. While some approaches provide “adequate” in vivo stability to move into clinical studies, notably when the labelled molecule is administrated to a compartmental space (e.g. intraperitoneal, tumour resection etc.), additional studies still need to be conducted to develop improved labelling approaches and particularly for systemically administration.
A team of researchers in Poland have proposed a mode of fixation with At- based on the high in vivo stability of the trans-[RhCl2(cis/trans-16S4-diol)]+ complex. Thus, some AtMCl+ (M=Rh(III) or Ir(III)) entities are synthesized and complexed with chelating agents. This promising way must be optimised and validated. Another approach is to develop some ligands for a direct chelation of astatine. In this case, a metallic form of astatine is prepared and a coordination bound is created. Considering the complexity to evaluate astatine chemistry, only a few studies have been conducted on this subject. To date, there have been no examples of chelates that are stable to in vivo deastatination. The exploration of the metallic character of astatine is at the center of this project.
In a recent study, we have defined a robust pourbaix diagram of astatine in non-complexing aqueous medium showing the existence of two stable metallic forms of At, i.e. At+ and AtO+. The aim of this project is to explore the reactivity of AtO+ with respect to ligands (what are the atoms interacting with AtO+? What is the nature of the bounds formed) with the objective to synthesize some ligands that could be used for TAT. As a result, we would propose alternative labelling methods with respect to those used or under development using the “halogen” character of astatine.