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FLow chemistry for Isotopic eXchange

Periodic Reporting for period 1 - FLIX (FLow chemistry for Isotopic eXchange)

Reporting period: 2020-01-01 to 2020-12-31

Isotopes are variants of the same chemical element (same number of protons but a different number of neutrons) and can replace common isotopes in molecules detectable with analytical methods like mass spectroscopy (MS) and nuclear magnetic resonance (NMR).

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, INSA Toulouse, LIKAT, TU/e then UvA, AU, Cominnex and Absiskey. Together, the partner’s expertise in catalysis, isotopic 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.
During the first reporting period (M1-M12), consortium members focused on:
- The development and screening of new catalysts (FLIX-CAT) compatible with flow chemistry isotopic labelling of organic molecules such as engineered metal nanoparticles or heterogeneous catalysts (CEA, INSA Toulouse, LIKAT, TU/e + UvA, Cominnex), homogeneous and immobilized transition metal catalysts (CEA, LIKAT, AU, TU/e + UvA, Cominnex);
- The design of new catalytic reactions for deuterium/hydrogen IE (CEA, INSA Toulouse, LIKAT), carbon-13/carbon-12 IE (CEA, AU) using catalysts developed (CEA, INSA Toulouse, LIKAT, AU, TU/e + UvA) and stress and compatibility tests;
- The development of innovative isotopic sources (AU).

CEA is in charge of the coordination and management of the project with the help of Absiskey, which also ensures dissemination, communication and exploitation activities (WP5) for supporting:
(i) the participation to conferences and specific events to promote the FLIX project’s results;
(ii) the spreading of advancements through the project website and the social channels (i.e. project and partners LinkedIn and Twitter pages);
(iii) the elaboration of a methodology to plan the exploitation work.
The proof of concept of the FLIX paradigm will therefore be challenging since it aims to address and 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 labelling of organics with radioactive isotopes such as 3H and 14C and for drug preclinical studies and clinical Phase 0 trials as well as for the development of new 11C/13N-labeled tracers for PET diagnostic imaging through adapted fast and straightforward microfluidic techniques, as a result of the profitable cooperation between CEA, TUE/UvA and COMINNEX.

--> Potential for future social or economic impact or market creation
By streamlining the isotopic labelling of end-use molecules, FLIX is expected to have huge human/industrial/social impacts such as:
i) Fostering the use of stable isotopes for drug preclinical and clinical studies in order to help reducing excessive drug attrition rates and improve the pharmaceutical industry competitiveness;
ii) Boosting the development of new ‘heavy drugs’ and ‘deuterated PET imaging agents’ with improved biological stabilities for diagnostic;
iii) Promoting the development of 2H / 13C / 15N hyperpolarized organic tracers for diagnostic MRI;
iv) Accelerating the synthesis of multi-labeled compounds for biological and toxicological researches;
v) Reducing the use of radio-isotopes which raise specific safety problems, environment issues and skyrocket the expenses;
vi) Developing more environment-friendly chemical processes through the use of continuous flow systems;
viii) Stimulating the development of deuterated smart materials and their encryption to detect counterfeiting.

--> 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.