Receptors of Astatine Anion: Modeling, preparation, chemical and biological stabilities – RoAstA

We plan:
• to explore the influence of structural modifications of a predefined receptor on astatide capture (and iodide by comparison),
• to understand and to propose theoretical models for astatide anion receptors,
• to create insoluble and specific matrix for At-211 purification,
• to study their in vitro stabilities and ability to trap astatide and iodide in radiochemical conditions,
• to create protein conjugates able to selectively trap I-125 or At-211, to examine their biostabilities and ultimately, to provide a new approach for protein labeling with 211At with improved in vivo stability in comparison with the conventional C-At bond approach.

RoAstA project: a predictive tool for fixing and stability of the astatine anion for the selection of drug candidates.
Supramolecular recognition of astature anions by Calix Bis-Imidazolium Boronium and stability study.
RoAstA proposal aims at exploring the supramolecular recognition of very important radioactive anions [astatide and iodide (by comparison)] by a novel family of molecular containers based on boron chemistry called calix Bis-Imidazolium Boronium (Calix-BIB), recently discovered and patented by one research group of the consortium. Little is known on the chemistry of astatine. Yet, 211At is considered as one of the most promising radionuclide for targeted alpha therapy. It appears thus essential to develop new chemical tools to associate 211At with carrier biomolecules, especially since the conventional covalent C-At bond appears insufficiently stable in vivo to allow medical uses. In this context, our work consisting in proposing theoretical models of astatide anion recognition based on multivalent H bonding interactions and, therefore, to determine the key experimental data governing the relationship of the macrocyclic structure to anion recognition. Different compounds have been synthetized. Biological stability of several 211At radiolabeled bioconjugates have been measured in order to evaluate this approach potential for therapeutical applications.

A consortium bringing together complementary skills (molecular modeling, organic synthesis, radiochemistry and biology) has been set up in order to develop new knowledge of the chemistry of astatine and propose new approaches to solve the current problems limiting the use of this radioelement in medicine.
The project was divided into several working groups:
1° Virtual design of model cavities (partner 3 CEISAM):
2° Preparation of Calix macrocycles and physico-chemical studies of anion recognition (partner 2 iSm2)
3° Physico-chemical characterization of At-/CalixBIBs systems (partner 4 Subatech)
4° Development of radiolabeling conditions and evaluation of the first generation calix-BIB (partner 1 CRCI2NA).

This work has made it possible to develop a predictive tool for the ability to fix astature. Different CalixBiB 2nd and 3rd generation compounds have been produced and tested. The manipulations of radiochemistry made it possible to determine, by the liquid/liquid extraction method, a first value of the complexation constant associated with the exchange between the iodide ion and the astature ion. The first radiolabeling results gave results that were not satisfactory enough for in vivo use.

The understanding of binding phenomena and their modeling has enabled the creation of a predictive tool which, although it has not been able to find a «champion« within the Calix-BiB proposed by our partner 2 (iSm2) has since been used by the consortium and allowed us to also test other candidate compounds from another laboratory.

No valuation is currently planned, as the screening work is still in progress.

Publications are currently being written but no patent will be filed.

RoAstA proposal aims at exploring the supramolecular recognition of very important radioactive anions [astatide and iodide (by comparison)] by a novel family of molecular containers based on boron chemistry called calix Bis-Imidazolium Boronium (Calix-BIB), recently discovered and patented by one research group of the consortium. Little is known on the chemistry of astatine. Yet, 211At is considered as one of the most promising radionuclide for targeted alpha therapy. It appears thus essential to develop new chemical tools to associate 211At with carrier biomolecules, especially since the conventional covalent C-At bond appears insufficiently stable in vivo to allow medical uses. In this context, our ambition is to propose theoretical models of astatide anion recognition based on multivalent H bonding interactions and, therefore, to determine the key experimental data governing the relationship of the macrocyclic structure to anion recognition. Ultimately, the biostability of bioconjugates labeled with 211At by this method will be assessed to probe the potential of this approach for future therapeutic applications. For this, a consortium gathering specialists of complementary skills (molecular modeling, organic synthesis, radiochemistry and biology) will be set up to develop new knowledge on astatine chemistry and propose new approaches to address the issues associated with the use of astatine in medicine. Based on impressive first results, we are hoping to break some new grounds in the blank and therefore challenging field of astatide capture. The interest in astatine has grown up recently in France with the framework of Arronax (installed in Nantes), a unique particle accelerator capable of producing exotic radionuclides dedicated to research and industrial applications. A highly competitive ecosystem has been built around Arronax and rapid developments are to be expected in the close future. The technology developed in this project may be of high interest for astatine purification processes and medical applications. This research innovation has thus relevance to both academic and industrial fields.