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The "Molecular probes" team gathers chemists, radiochemists and biochemists. They all focus their efforts to the development of original radiotracers labelled with fluorine-18 and carbon-11 for PET imaging and investigation of their biotransformation in vitro and in vivo.
Team leader: Bertrand Kuhnast
The research and development efforts of the team are divided into three complementary axes.
Axis 1, medicinal chemistry and probes, concentrates on the discovery of novel imaging probes for a given pharmacological target. This axis uses state-of-the-art methodologies in organic chemistry and/or radiochemistry and includes preliminary in vitro evaluation (affinity, selectivity, structure-activity relationship, lipophilicity determination). The ultimate goal of the developments is the translation of original radiotracers from the chemistry to the clinical use in biomedical research protocols. As an example, the [18F]DPA-714 compound that was developed from the first chemical steps in our team in collaboration with other labs, is today used in different clinical trials. This radiopharmaceutical targets the TSPO 18kDa protein that is a biomarker of neuroinflammation. Research and innovation focus today on other targets (cannabinoid and purinergic receptors) of neuroinflammation in neurodegenerative diseases and gliomas within the INMiND FP7 European Program but also on the study of efflux proteins responsible for chemoresistance. These developments are conducted in tight collaboration with the Experimental Imaging and Clinical Applications teams.
Axis2, innovative radiolabelling methods for PET, concentrates on the set up of new labelling strategies using the cyclotron-produced short-lived positron emitters fluorine-18 (t1/2: 109.8 minutes) and carbon-11 (T1/2: 20.4 minutes). In fluorine-18 chemistry, efforts are dedicated to the development of original precursors to improve the radiofluorination yields, to the automation of the processes and to the development of microfluidic approaches leading to the concept of "dose-on-demand" of a radiotracer (LOTUS project). The radiolabelling of biological macromolecules with fluorine-18 requires specific strategies on which the team also dedicates efforts. In carbon-11 chemistry, most of the radiolabelling approaches consist in the transformation of the [11C]CO2, which is produced by the cyclotron, into a methylation reagent ([11C]CH3I for example) before radiolabelling the targeted compound. This is a time-consuming process that decreases the final yields due to the short half-life of carbon-11. The team develops new strategies to prepare carbon-11-labelled radiotracers bearing carbamate, urea or carbonyl functions using directly the [11C]CO2.
Axis 3, metabolism and analysis, concentrates on the evaluation of the biotransformation of radiotracers and radiopharmaceuticals and on the quantification of the probe and/or its metabolite(s) in biological tissues and fluids once in vivo administered. In vitro, incubations with microsomes (and/or hepatocytes) allow for characterizing by LC/MS the main phase I (II) metabolites and the main enzymes involved in these biotransformations. Ex vivo, radioHPLC and LC/MS analyses of biological fluids and tissues allow for investigating the presence of radiometabolites likely to confound PET images. Combined together, these results provide metabolic pathways of a radiotracer from which chemical or biological improvements can be proposed and crucial information regarding the quantification of PET images can be derived. Biological improvements involve the in vitro and in vivo inhibition of the enzymes responsible for these biotransformations. To optimize PET quantitative analyses, rapid and sensitive robust analysis methods are also developed (SPE and LC/MS) for large panels of samples, particularly in clinical trials. These developments are conducted in tight collaboration with the Experimental Imaging and Clinical Applications teams.
Team Leader: Bertrand Kuhnast, IC CEA
Fabien Caillé, IC CEA
Stéphane Demphel, Tech CEAStéphane Le Helleix, Tech CEAMarie-Anne Peyronneau, IC CEASimon Specklin, IC CEAFanny Cacheux, PhD student PSudMélanie Roche, PhD student, PSud.
CEA is a French government-funded technological research organisation in four main areas: low-carbon energies, defense and security, information technologies and health technologies. A prominent player in the European Research Area, it is involved in setting up collaborative projects with many partners around the world.