Development of a general approach to label biologics with fluorine 18

Positron emission tomography (PET) imaging stands as an indispensable diagnosis tool in modern medicine for the identification of a wide panel of diseases. This imaging technique relies on the injection to the patient of a radiopharmaceutical, a compound that is labeled with a short-lived radioactive atom such as fluorine 18 (T_1/2 = 109 min) and that will target a biological event corresponding to the disease. After injection, the patient is monitored by a PET scanner to precisely localize the injected tracer in three dimensions.

Biologics such as peptides and proteins are highly promising candidates for this imaging technique thanks to their unparalleled targeting properties, but their success is contrasted with the difficulty associated with the introduction of the radioactive label, particularly when fluorine 18 is considered. Conventional labeling methods are not compatible with the molecular fragility of these biomolecules, long and complex process are thus required, involving multistep radiosynthesis that are often tedious to automate with conventional synthesizer. Despite some direct labeling strategies, this complexity represents a strong obstacle for the development of protein/peptide-based radiopharmaceuticals at a clinical level.

This project aims to afford simplicity to the radiosynthesis workflow by relying to solid support labeling in a label-and-release strategy. It involves the loading of the peptidic structure on a resin with a reactive linker that is cleaved upon the addition of a radioactive reactive partner, releasing the corresponding labeled peptide/protein. Such ready-to-label resins could be charged in cartridges compatible with synthesizers and could deliver the labelled biomolecule without the need of purification with high molar activities.

The first approach is the design and the synthesis of a linker based on the imminosydnone click and release technology. Using site-selective bioconjugation a biotin will be linked to the biologics of interest through an iminosydnone spacer. After the capture on solid support (streptavidin), the iminosydnone will be reacted with a ¹⁸F-labelled cyclooctyne leading to both the radiolabeling of the biologics and its release from the support.

In a second strategy, all the complexity of the fluorine-18 labeling process will be concentrated on a single cartridge that will require only [¹⁸F]fluoride anion directly produced by the cyclotron to release the labelled peptide/protein. Starting from a first proof of concept with simple compounds, the corresponding linker is based on an ammonium functionalized with an electron-poor pyridine that can react with fluoride at room temperature by SNAr. We aim to use adequate directing groups to capture and locally desolvate [¹⁸F]fluoride anion from water, promoting SNAr fluorination and releasing the labelled compound. Starting from small peptides, this linker will be gradually challenged towards increasingly complex objects to afford the more versatile system possible. If successful, this technology will allows the labelling of peptidic structure with fluorine-18 following an unmet simple sequence, which can be implemented in any PET center, aiming to promote clinical translation of such radiopharmaceuticals.

The PhD will take place in two laboratories of the CEA, one at Saclay and one at Orsay Hospital. Both laboratories are located around 20 km from Paris.

https://www.biomaps.universite-paris-saclay.fr;

https://tinyurl.com/CEAJOLIOT-SCBM-LMC-eng

The selected candidate will be a member of the ISOBIOTICS doctoral network funded by the European commission. As such, the PhD student will have the opportunity to interact with the academic and industrial partners of the consortium. She/he will receive several training in the field of radiolabeling and drug development during symposiums and internships organized in the different countries of the ISOBIOTICS partners.

The PhD student will be involved in a highly multidisciplinary environment mixing organic synthesis, radiochemistry and bioconjugation of biologics at CEA, located within Plateau de Saclay near Paris. At the end of the PhD, the student will graduate with the title of PhD from the Paris-Saclay University.

Eligible candidates must not have spent more than 12 months in France in the last 3 years before the application.

They should hold a Master degree in chemistry with a specialization in organic chemistry and a strong interest in a multidisciplinary approach. Candidates are expected to be highly motivated, creativity, autonomy and organization skills are highly required. You must also possess a great team spirit and a will to share your results in a leading research environment represented by the Isobiotics consortium.