CE18 - Innovation biomédicale

Manganese complexes for PET and MRI: production of 52Mn and ligand design for stable and inert complexation – MANGA

Mn complexes for MRI and PET

Bispidine-derivative manganese complexes with unprecedented kinetic inertness for imaging applications

Study of bispidine complexes

The proposal has a double objective : to explore bispidine-type ligands for Mn complexation and to produce the Mn-52 isotope for the first time in France, in the cyclotron of Orléans.

Novel bispidine-derivative ligands are synthesized and their Mn complexes studied with respect to their thermodynamic stability, kinetic inertness and relaxation properties.
The production of Mn-52 by different methodologies is realized. The ligands are radiolabelled with Mn-52.

We identified bispidine complexes with unprecedented kinetic inertness which open new avenues in the development of more biocompatible MRI contrast agents and 52Mn-based PET probes. The structural variations of the ligands allowed for gaining insights into the structural features that are responsible for the excellent inertness. We evidenced that some chelates have better MRI efficacy than current clinical MRI agents. Several ligands could be also radiolabeled with 52Mn. In overall, we provided a toolbox of ligands suitable for Mn2+ complexation which can be easily derivatized for various biological targets for real imaging applications. Aside from the purely scientific aspect of the project, the as obtained Mn based relaxation agent have been protected through a European patent and a second demand of patent and are currently the object of a maturation project with the Conectus SATT in the Grand-Est region.

Other bispidine chelates are under investigation.

D. Ndiaye, M. Sy, A. Pallier, S. Même, I. de Silva, S. Lacerda, A. M. Nonat, L. J. Charbonnière and É. Tóth
Unprecedented kinetic inertness for a Mn2+-bispidine chelate: a novel structural entry for Mn2+-based imaging agents
Angew. Chem. Int. Ed. 2020, 59, 11958-11963. doi.org/10.1002/anie.202003685

M. Sy, D. Ndiaye, I. da Silva, S. Lacerda, L. J. Charbonnière, É. Tóth,* A. M. Nonat*
55/52Mn2+ complexes with a bispidine-phosphonate ligand: high kinetic inertness for imaging applications
Inorg. Chem. 2022, 61, 13421-13432. doi.org/10.1021/acs.inorgchem.2c01681

D. Ndiaye, M. Sy, W. Thor, L. J. Charbonnière, A. M. Nonat, and É. Tóth
Structural Variations in Carboxylated Bispidine Ligands: Influence of Positional Isomerism and Rigidity on the Conformation, Stability, Inertness and Relaxivity of their Mn2+ Complexes
Chem. Eur. J. 2023, doi.org/10.1002/chem.202301880

S. Lacerda, D. Ndiaye, É. Tóth
Manganese Complexes as Contrast Agents for Magnetic Resonance Imaging
In “Metal Ions in Life Sciences” Eds: A. Sigel, E. Freisinger, R. K. O. Sigel © Walter de Gruyter GmbH, Berlin, Germany 2021, 22, pp. 71–99.

S. Lacerda, D. Ndiaye, É. Tóth
MRI relaxation agents based on transition metals
In ”Advances in Inorganic Chemistry”, Eds. C.D. Hubbard, E. van Eldik, Vol. 78, Chapter 4, pp. 109-142. 2021.

European patent application PCT/EP2022/087686, W02023/126336A1, 31/12/2021, for «Novel bispidine-based metal chelating ligands displaying good relaxivity«, L. Charbonnière, E. Jakab Toth, A. Nonat, M. Sy.

Deposition of a European patent application EP23306128.2 4/07/2023 for «Novel bispidine-based metal chelating ligands displaying good relaxivity« (ed. 2), A. Nonat, L. Charbonnière, M. Sy, C. Charpentier, E. Jakab Toth.

The last decade has seen a rise in safety concerns regarding Gd-based Magnetic Resonance Imaging (MRI) contrast agents. Among safer alternatives, Mn2+ has the greatest potential, with a major advantage of being biogenic. Nevertheless, it needs to be chelated in complexes of high thermodynamic stability and kinetic inertness, while preserving one inner sphere water molecule to maintain relaxation efficiency. This remains a coordination chemistry challenge which calls for novel ligand design.
52Mn is an emerging radionuclide for Positron Emission Tomography (PET); however, its use today is limited by low availability, radiation protection concerns and the lack of dedicated ligands for stable and inert Mn2+ complexation. Mn2+ is the unique metal ion to offer detection capability in both MRI and PET. Our objective is to provide solution to the two major bottlenecks in the development of Mn2+-based PET and MRI agents which are the availability of (i) the 52Mn radionuclide and (ii) optimized ligands adapted to the requirements of MRI and/or PET applications.
To achieve this, we propose to explore and compare two different approaches for 52Mn production in the Orléans cyclotron. Special attention will be dedicated to dosimetry issues, particularly important for 52Mn which is characterized with long half-life, multiple high energy and high abundance gamma emissions. For stable and inert complexation of the Mn2+ ion, we will investigate a large variety of ligands derived from the bispidine (3,7-diazabicyclo[3.3.1]nonane) platform, which are expected to provide a pre-organized, rigid skeleton with versatile binding modes that satisfy the requirements for MRI and/or PET application. The Mn2+ complexes will be evaluated with respect to their relaxometric properties, stability and kinetic inertness. We plan to go beyond the state of the art in this field and propose to approach and model as much as possible biologically relevant conditions for thermodynamic and kinetic studies. To this end, we intend to develop new methodologies applicable for instance in the presence of serum proteins or in tissue homogenates. For the 52Mn radiolabeling of the ligands, the best conditions will be identified that provide high radiochemical yield.
Our primary goal is to provide a toolbox of ligands suitable for Mn2+ complexation which can be easily derivatized for various biological targets. Detailed biological evaluation is beyond the scope of this proposal. Nevertheless, to obtain a proof of concept of the feasibility of PET and MRI imaging by using our 52/natMn complexes, we will conjugate the best ligands with targeting functions such as folate, RGD or an antibody, and carry out preliminary in vivo imaging experiments in healthy mice and in a mouse model of cancer.

Project coordinator

Madame Eva JAKAB TOTH (Centre de biophysique moléculaire)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

CEMHTI Conditions Extrêmes et Matériaux : Haute température et Irradiation
IPHC INSTITUT PLURIDISCIPLINAIRE HUBERT CURIEN
CBM Centre de biophysique moléculaire

Help of the ANR 429,984 euros
Beginning and duration of the scientific project: October 2018 - 48 Months

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