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FLow chemistry for Isotopic eXchange

Periodic Reporting for period 2 - FLIX (FLow chemistry for Isotopic eXchange)

Reporting period: 2021-01-01 to 2022-10-31

FLIX is a radically new concept for the late-stage isotopic labelling of high added-value molecules (drugs, biologics, smart materials) with stable isotopes in an easier, faster, and more effective way, using new generations of catalysts along with flow chemistry for the selective exchange of predetermined atoms and chemical motifs of end-use organic compounds.
The ultimate outcome of the project is to devise and build a modular and adaptable flow chemistry system for the straightforward and combinable isotopic labelling of complex chemicals. This ‘FLIX machinery’ will use a combination of specialized reactor modules operating under continuous flow conditions for the on-line 1H/2H, C-12/C-13, N-14/N-15 and methoxy group direct isotope exchanges with an unprecedented efficacy and without any chemical alteration of the molecules.

The project’s objectives are to:
1) develop new generations of organometallic catalysts for isotopic exchange (IE) reactions;
2) screen catalysts for the IE on a relevant portfolio of organic molecules in batch and flow chemistries and assess catalyst robustness;
3) devise and validate the ‘combinable isotope labeling’ concept;
4) design and build an adaptable multi-module machinery for combinable IE.

The project is expected to have a multi-billion euro impact on all sectors using stable isotopes in particular:
1) drug innovation, by accelerating preclinical studies, de-risking clinical trials and fostering the development of novel deuterated ‘heavy drugs’;
2) design of new tracers for diagnostic imaging with improved sensitivities (NMR) and biological properties (deuterated PET tracers);
3) streamlining the production of multi-labeled molecules for NMR studies;
4) the development of novel isotopically-enriched materials.

The project synergistically associates the expertise and innovation potential of a mixed academic/industrial multidisciplinary consortium including CEA, INSAT, LIKAT, TU/e then UvA, AU, Cominnex then X-Chem and Absiskey. The partner’s expertise in catalysis, isotope labeling and flow chemistry, but also communication and project management, will ensure the development of novel catalysts and labelling machine in view of the targeted future applications. Considering delays resulting from the Covid pademic, a 6-month extension of the project was adopted.
During the first and second reporting periods (M1-M34), Consortium Members focused on:
- The development and screening of new catalysts compatible with flow chemistry isotopic labelling of organic molecules such as engineered metal nanoparticles or heterogeneous catalysts , homogeneous and immobilized transition metal catalysts;
- The design of new catalytic reactions for deuterium/hydrogen IE, carbon-13/carbon-12 IE and nitrogen-15/nitrogen-14 IE, validation on multifunctional molecules combined with stress and compatibility tests;
- The development of innovative isotopic sources;
- The development of HIE and CIE through methoxy-groups catalytic exchange;
- The design, building and development of FLIX-BOXes for hydrogen and carbon IE;
- The construction of a preliminary FLIX-MACHINE system with associated automation system software;
- The application to the late-stage isotopic labeling of complex real-life molecules (mainly drugs) through direct HIE and CIE in order to make the proof of concept of the FLIX paradigm in both batch and flow chemistries conditions.
Dissemination of the project results led to the publication of numerous publications in peer-review journals. Communication actions, hampered by the Covid pandemic restarted with the publication of 2 newsletters and communicating results using the Project's website and social media.
The proof of concept of the FLIX paradigm will therefore be challenging since it aims to address up to date insolvable scientific, technical and industrial problems with huge human, societal and economic impacts.

--> Scientific and technological contributions to the foundation of a new future technology
As a new paradigm, FLIX is expected to revolutionize the isotope labelling approach with stable isotopes using a flow chemistry system which should help finding new reactions that are out of reach using batch chemistry techniques. FLIX may be also foundational for the labeling of organics with radioactive isotopes crucial for preclinical studies and Phase 0 clinical trials as well as for the development of new PET diagnostic imaging tracers through adapted fast and straightforward fluidic techniques, as a result of the profitable cooperation between Partners.

--> Potential for future social and economic impacts or market creation
i) FLIX has developed a portfolio of IE catalysts and reactions applicable for the late-stage isotopic labeling of complex molecules in both batch and flow chemistries such as drug candidates for preclinical and clinical studies.
ii) The high hydrogen IE obtained and reliable translation from flow chemistry to preparative chemistry and production allows to envision the synthesis of innovative molecules (with improved properties) from end-use molecules instead of precursors.
iii) Recent advances in the IE reactions developed by FLIX should also permit to enlarge the portfolio of tracers for diagnostics.
iv) It is clear that late-stage IE in particular on end-use molecules strongly accelerates the labeling process and easy access to labeled compounds.
v) Considering the advances done in mass spectrometry sensitivity and resolution, facile access to molecules labeled with stable isotopes will also help limiting the use of radioactive compounds.
vi) Using a computer-controlled integrated synthesis device working on small quantities of chemicals instead of open batch systems is more environment-friendly. Moreover, better reproducibility of flow chemistry experiments improves reliability of results and limits the number of experiments.
vii) Finally, the FLIX paradigm should find many applications using either compounds labeled with stable isotopes with very high isotopic excesses or labeled on particular positions not accessible to date. It will also permit to easily obtain a large variety of labeled molecules and to combine labeling for isotopic encryption with many applications in biochemistry or in chemical industry for instance.

--> Building leading research and innovation capacity across Europe
FLIX research consortium regroups first-class research teams across Europe and maximizes their complementarity in a synergistic way in order to achieve ambitious goals in terms of new concept development, scientific breakthrough and technical innovation. FLIX ambitions to create a new collaborative network between the beneficiaries but also to extend its cooperative pattern through cross-collaborations with existing partner contacts in order to promote the FLIX technology and initiate new innovative projects with important human, social and economic impacts. In this respect, the Consortium will also try to liaise with ongoing European project actors operating in the same research area in order to develop researcher and students’ network and to avoid unproductive duplicated research. By taking actively part to the FLIX project, ESRs/ERs will be exposed to a dual academic/industrial scientific environment and will get the opportunity to acquire specific knowledge, exceptional experience and profitable competency that will improve their employability and entrepreneurship.
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