The ISOTOPICS project ended with year 2019 after four years of intensive work including not only experimental but also teaching, learning, active dissemination of results and fruitful exchanges inside and outside the consortium. These four years of implementation followed two years of preparation. It is now time to overview the project output.

Everyone familiar with project writing knows that it is tempting, easy and therefore ordinary to overestimate goals and impact of the anticipated results in order to secure the grant. When highlighting the potential of late or even last-stage labeling, efficient labeling of non-activated chemical positions (especially C-H moieties) an chemically benign engineering of complex molecules, I was wondering if I did not oversold the project, even though the consortium gathered prestigious research institutions with first-class partners. I must finally admit that all results produced by ISOTOPICS researchers reached the expected goals in most cases beyond my expectations.

If hydrogen isotope exchange was already documented, ISOTOPICS considerably enlarged this research field and filled the chemist's toolbox with highly specific and selective catalysts, the utility of which was demonstrated on a variety of drugs and drug-like molecules. Translating this concept to carbon isotopes was not obvious since breaking C-C bonds specifically was considerably different from classical C-H activation. This was done however. The concept developed on model molecules was even applied to existing drugs, thus demonstrating that this new paradigm was not only a chemical curiosity but was also an extremely attractive and promising concept. "CO₂" exchange was even the basis for the building of both granted ERC-advanced project (FASTLabEx) and an ongoing FET-OPEN project (FLIX).

An innovative late-stage labeling of drugs through "CO-NH" bond building was also done with the particular concern of making it totally compatible with the requirements and limitations of ¹¹C and ¹⁴C labeling of chemically complex and structurally fragile molecules. This was realized by adapting cutting-edge chemistry to the particular environment of radiolabeling of drugs.

The labeling of non-activated C-H positions with fluorine and polyfluorinated chemical groups (CHF₂ and CF₃) was also successfully implemented and provided considerable advances in ¹⁸F PET chemistry which is also a very active research field nowadays. The stereoselective fluorination concept undoubtedly opens new perspectives for producing stereochemically complex molecules. It also offers new solutions for labeling fluorine-containing drugs with ¹⁸F without altering their structure, even when fluorine is located on a position that is notably difficult. The modification of drugs and biomolecules with pending difluoro- and trifluoromethyl groups efficiently attached on C-H motifs is also a noticeable progress with a very broad domain of applications.

All this work was awarded by an impressive number of 29 publications (February 2020), including famous articles in high impact factor journals, thus demonstrating the scientific radiance of ISOTOPICS with an average IF of 11. But let's not forget a crucial aspect, far beyond the paper-producing question which validates the scientific value of the work but is not an end in itself. All the research was implemented with the permanent concern of easy applicability, transferability to the particular drug discovery and development (DDD) environment, and its capacity to be translated to the specific needs of in vivo assays and finally clinical trials. The very active support of the three active industrial beneficiaries testifies this. I have no doubt that ISOTOPICS findings and methods will be applied for helping the pharmaceutical industry to overcome some technical obstacles reducing their research efficiency and considerably increasing drug attrition. In this respect, ISOTOPICS is really expected to have significant human, industrial and societal impacts.

ISOTOPICS not only produced first-class research but also trained a new generation of young researchers specialized in (radio)labeling chemistry but also familiar of medicinal chemistry and aware of the particular DDD world. Most of them have been also immersed in the industrial environment through intersectorial secondments. This was an opportunity for them to discovering new countries, new routes in addressing scientific issues and new ways of life. The ISOTOPICS training also provided the 15 students not only with scientific courses and workshops but also with complementary skills, which should be decisive for exploiting and promoting their results. In particular, everyone inside the consortium has noticed the students progresses in terms of presentation and capacity to discuss about their results, but also the emergence of a self-criticism spirit which is essential in science. As all of Consortium members, they also benefited from the precious input of the advisory board, the five members of which regularly demonstrated their implication and trustworthiness.

I also would like to sincerely and warmly thank the two Project Managers who daily helped me follow up the project, organized its proper implementation and regularly solved problems. Nothing was possible without them.

The ISOTOPICS project is now over but is not an end. On the contrary, project completion, marked by several thesis defenses, is now the beginning a scientific life as independent researcher for each of the 15 students. On behalf of the whole consortium, I would like to wish them good luck for finding rewarding jobs and positions, and many successes in their starting professional lives.   

Great News to share! Congratulations Davide (PI-CEA) for being awarded an ERC consolidator grant! WOW! Wish you all the best for the future!

More information here.

Anna Vicini (ESR6-UCB) presented her results at the 6th Winter Process Chemistry Conference December 2019, in Birmingham (UK). Her oral communication was entitled: "Hydrogen Bonding Phase-Transfer Catalysis (HB-PTC) with Alkali Metal Fluorides: Enantioselective Synthesis of β-Fluoroamines". She received during these event a Science Update Young Chemist Award! Congratulation Anna!  

More information here.

Francesco Ibba (ESR5-UOXF) presented his results at the 26^th Annual Review Meeting, Catalysis and Enabling Technologies for Synthesis, December 2019, London (UK). His poster was entitled: "Hydrogen Bonding Phase-Transfer Catalysis: Discovery and Mechanistics Insights".

The final ISOTOPICS meeting was organised by CNRS-INSA beneficiary in Toulouse (France) in November 2019.

More information about this event here.

Donia Bouzouita (ESR11-CNRS) has published an article in Chemical Reviews journal entitled: 'σ-H–H, σ-C–H, and σ-Si–H Bond Activation Catalyzed by Metal Nanoparticles'

This article review the surface chemistry of nanoparticles and catalytic reactions occurring in the liquid phase, catalyzed by either colloidal or supported metal NPs. Nanoparticles prepared in solution, stabilized and tuned by polymers, ligands, and supports, were consider only. The question addressed concerns the differences and similarities between molecular complexes and metal NPs in their reactivity toward σ-bond activation and functionalization.

You can have access to this article here.

Davide Audisio (PI-CEA) and Grégory Pieters (PI-CEA) will present their research activities at the 31^stNorth American Chapter Meeting of the International Iisotope Ssociety (IIS meeting US) this Friday, October 25, 2019, in Morristown (USA).

Davide's oral communication is entitled: "Late-stage carbon isotope labeling using CO2 ".

Grégory's one is entitled:" Hydrogen isotope exchanges catalysed by Ru nano catalysts".

They visited  Rhys Salter at the Isotope Chemistry and Biotransformation lab, Janssen R&D on Tursday October 22, and Wednesday, October 23,  they met Sumei Ren at the Labeling laboratory, Merk.

Antonio Del Vecchio (ESR3-CEA) defended his PhD entitled:" New Methodologies for the Late Stage Labeling of Drug Candidates" on Friday 18.10.19!! Congratulations Antonio! All the best for the Future!

Donia Bouzouita (ESR11-CNRS) defended her PhD entitled:" Isotopic labeling catalyzed by metallic nanoparticles" on Monday 14.10.19!! Congratulations Donia! All the best for the Future!

Alberto Palazzolo (ESR2-CEA) defended his PhD entitled: "Development of new methods for the hydrogen isotope exchange catalyzed by metallic nanoparticles" on Friday 27.09.19!! Congratulations Alberto! All the best for the Future!

Viktor Pfeifer (ESR1-CEA) defended his PhD entitled: "Tritium and Deuterium Labelling of Bioactive Molecules Catalyzed by Metallic Nanoparticles" on Monday 16.09.19!! Congratulations Viktor! All the best for the Future!

First ISOTOPICS defence! Gianluca Destro (ESR4-CEA) defended his PhD entitled:" CO₂ chemistry for the synthesis of radio-labelled compounds" on Friday 13.09.19!! Congratulations Gianluca! All the best for the Future!

Anna Chiara Vicini (ESR6-UOXF) presented her results at the 3rd international Symposium on Synthesis and Catalysis (ISySyCat 2019), in Evora (Portugal). Her oral communication was entitled:" Hydrogen Bonding Phase-Transfer Catalysis (HB-PTC) with Alkali Metal Fluorides: Enantioselective Synthesis of β-Fluoroamines".  She won a prize as one of the best two oral communications. Congratulations Anna!

From left to right: Anna Vicini, Prof. Anthony Burke, conference chairman, and Dr. Dörthe Mellmann, associated editor for Wiley.

Laura Trump (ESR13-UCB) presented her results at the 19^th European Symposium on Fluorine chemistry, in Warsaw (Poland). Her oral communication was entitled:" Late stage C-H ¹⁸F-difluoromethylation of N-heteroaromatics for PET imaging".

Donia Bouzouita (ESR11-CNRS) has published an article in Nanoscale journal entitled: 'Tuning the Catalytic Activity and Selectivity of Water-Soluble Bimetallic RuPt Nanoparticles by Modifying their Surface Metal Distribution'

This article describes the preparation of Bimetalllic ruthenium-platinum nanoparticles (RuPt NPs) of different surface distributions and stabilized by a sulfonated N-heterocyclic carbene ligand.  The different bimetallic RuPt NPs, as well as their monometallic equivalents (Pt and Ru NPs), were used in isotopic H/D exchange through C–H activation on L-lysine. Interestingly, the activity and selectivity of the direct C–H deuteration were dependent upon the NP surface composition at the α position but not at the ε one. Chemical shift perturbation experiments revealed that the difference of reactivity at the α position is due to a Pt-carboxylate interaction, which hinders the H/D exchange.

You can have access to this article here.

Mégane Valero (ESR15-SAN) has published an article in Chemistry Open  journal entitled: 'Comparison of Iridium(I) catalysts in Temperature mediated Hydrogen Isotope Exchange Reactions'

This article describes a detailed comparison study with six common Iridium (I) catalysts which permitted to understand and optimize the approaches of either high selectivity or maximum deuterium incorporation. This study demonstrated that the temperature window for these studied Iridium (I) catalysts is surprisingly very broad. This principle was further proven in some hydrogen isotope exchange reactions on complex drug molecules.

You can have access to this article here.

Laura Trump (ESR13-UCB) and Agostinho Lemos (ESR12-ULG) have published an article in Angewandte Chemie journal entitled: 'Late stage 18F-difluoromethyl labeling of N-heteroaromatics with high molar activity for PET imaging'

This article describes a photoredox flow reaction for 18F-difluoromethylation of Nheteroaromatics widely used in medicinal chemistry. This method is operationally simple and affords a straightforward access to radiolabeled N-heteroaromatics with high molar activity suitable for biological in vivo studies and clinical application.

You can have access to this article here.

Anna Vicini (ESR6-UOXF) presented her results at 26t^h International Symposium : Synthesis in organic chemistry in Cambridge (UK).

Her poster was entitled: 'Hydrogen Bonding Phase-Transfer Catalysis with Potassium Fluoride: Enantioselective Synthesis of β Fluoroamines'.

Mégane Valero (ESR15-SAN) has published a review article in Journal of Labelled Compounds and Radiopharmaceuticals: 'Highlights of aliphatic C (sp3)‐H Hydrogen Isotope Exchange Reactions'.

This review summarizes the highlights of aliphatic C (sp³)‐H carbon hydrogen isotope exchange (HIE) methods developed in the last ten years. In particular, new highly selective and reactive protocols in the areas of nanoparticle and metal catalyzed homogeneous catalysis are reported.

You can have access to this article here.

Karen Hinsinger (CEA) and Gregory Pïeters (PI-CEA) have published an article in Angewandte Chemie Highlight journal entitled: 'The Emergence of Carbon Isotope Exchange'. This article highlights significant progress in C−C bond activation with transition metals, which has recently enabled the development of several carbon isotope exchange reactions.

You can have access to this article here

Alberto during his oral communication

Alberto Palazzolo (ESR2-CEA) presented his results at t the 5^th Doctoral School 2MIB day (University of Paris-Saclay) at Evry Val d'Essonne University in Evry (France) on June 11 2019.

Alberto had an oral presentation entitled:

'Development of novel techniques for the deuterium and tritium labelling of nucleosides, nucleotides and oligonucleotides '.

Anna Chiara Vicini (ESR6 – UOXF) in Pint of Science commity

Anna Chiara Vicini (ESR6 – UOXF) was a Tech me Out Event Manager of Pint of Science 2019, Oxford. She had a logistic role in the organization of the event from finding a good venue to contacting the speakers.

More information here.

Anna Chiara Vicini (ESR6-UOXF) presenting at AstraZeneca Symposium.

Anna Chiara Vicini (ESR6-UOXF) and Mateusz Imiolek (ESR7-UOXF) presented their results at the AstraZeneca symposium 2019 (Oxford, UK).

Anna had an oral presentation entitled:

"Hydrogen Bonding Phase-Transfer Catalysis with Potassium Fluoride: Enantioselective Synthesis of beta-Fluoroamines"

Mateusz's one was entitled:

"Radical fluoroalkylations for selective modification of native residues in proteins".

Anna Chiara Vicini (ESR6-UOXF) also presented a poster at the 2^nd Chem East Organic Symposium in Norwich (22 May) entitled:

"Hydrogen Bonding Phase-Transfer Catalysis with Potassium Fluoride: Enantioselective Synthesis of beta-Fluoroamines"

Congratulation to Dr. Karen Hinsinger for her new permanent position at CEA Saclay. Welcome to Dr. Emilie Nehlig as new ISOTOPICS Project Manager.

Anna Chiara Vicini (ESR6-UOXF) presenting in Southampton.

Anna Chiara Vicini (ESR6-UOXF) and Francesco Ibba (ESR5-UOXF) presented their results at the 18^th RSC Fluorine Subject Group Postgraduate Meeting (Southampton, UK; 11th-12th April 2019).

Anna had an oral presentation entitled:

"Hydrogen Bonding Phase-transfer Catalysis: enantioselective Synthesis of β-Fluoroamines".

Francesco's one was entitled:

"Mechanistic Insights on Hydrogen Bonding Phase-Transfer Catalysis: an NMR investigation".

Anna Chiara Vicini (ESR6 – UOXF) making science experiments ATOM

Anna Chiara Vicini (ESR6 – UOXF) was a Chemistry demonstrator for "ATOM Science and Festival" as part of OxHOS events (Oxford hands on Science).

She was developing free science activities in the open air for all the family.

The 5^th ISOTOPICS Meeting was held at Merton College in TS Eliot Theatre (Oxford, UK) and organised by University of Oxford beneficiary in March 2019.

 More information about this event here.

The 5^th ISOTOPICS Training was organised at the Chemistry Teaching Laboratory (South Parks Road) in Oxford (UK) in March 2019.

More information about this event here.

The third issue of ISOTOPICS Newsletters is now available.

All ISOTOPICS ESRs have participated to its publication.

You can have access to this issue here.

Gianluca Destro (ESR4 - CEA) was on secondment for 2 months at AZ. He was welcomed by Malvika Sardana (ESR14 – AZ) within Chad Elmore group in AZ-Göteborg (Sweden).

Viktor Pfeifer (ESR1 - CEA) and Antonio Del Vecchio (ESR3 – CEA) were on secondment for 2 months at SANOFI Germany. They joined Volker Derdau group and Mégane Valero (ESR15 – SAN) to carry out isotopic labeling reactions.

Viktor Pfeifer (ESR1 - CEA) and  Mégane Valero (ESR15 – SAN), Antonio Del Vecchio (ESR3 – CEA) in lab.

Alberto Palazzolo (ESR2 - CEA) did a 2-week secondment at CNRS-INSA Toulouse laboratory, within Prof. B. Chaudret group, to synthesise new nanoparticles.

Laura Trump (ESR13 – UCB) did several secondment periods at ULG in 2018 (overall duration of 2 months). She worked on the translation of her research methodology from Fluorine-19 to Fluorine-18 in collaboration with André Luxen group.

Donia Bouzouita (ESR11 – CNRS) presented her results in a poster during the 1st Stable Carbene Symposium at the University Paul Sabatier (November 30, 2018; Toulouse, France).

Laura Trump (ESR13 – UCB) presented a poster entitled "Development of a flow photoredox reaction for the addition of CHF¹⁸F to N-heteroaromatics" at MedChem2018 (November 23, 2018; Namur, Belgium) and at BMIC meet industry event (November 28, 2018; Braine l'Alleud, Belgium).

Gianluca Destro (ESR10 – KI) was on secondment at KI for 1 month. He was welcomed by local ESR, Kaisa Horkka (ESR10 – KI), and supervisors Prof. CHrsiter Halldin (KI) and Dr.; Magnus Schou (AZ). He worked on ¹¹C-labeling reactions.

Kaisa Horkka (ESR10 – KI) and Gianluca Destro (ESR4 – CEA) in KI lab

Mélodie Ferrat (ESR9 – KI) was on secondment at CEA (Audisio group, Carbon-14 team) for 2 months. She worked on the preparation of precursors and reference molecules for later ¹¹C-labelling reactions.

Mélodie Ferrat (ESR9 – KI) and Antonio Del Vecchio (ESR3 – CEA) at CEA

Chad Elmore (AZ) gave a skype conference to students of MiraCoasta college (San Diego, CA, USA) to popularise drug discovery and development (DDD) and associated jobs in pharmaceutical companies. The talk was highlighted with Chad personal career path, information about radiochemistry uses in DDD and examples of PhD student works funded by H2020-MSCA programs.

Thus, Malvika Sardana (ESR14 – AZ) research about "Light Catalyzed Aminocarbonylation of Alkyl Iodides" was mentioned.

You can have access to Chad presentation file here.

Donia Bouzouita (ESR11 – CNRS) presented a poster entitled "Isotopic Labeling Catalyzed by Metallic Nanoparticles for the Evaluation of Drug Candidates" at the 2^nd Trans Pyrenean Meeting in Catalysis TrapCat2 (October 18-19, 2018; Tarragona, Spain).

Mégane Valero (ESR15 –Sanofi), in the middle of the Tritium team at CEA

Mégane Valero (ESR15 – Sanofi) was on secondment at CEA (Pieters' group, Deuterium/Tritium team) for 2 months. She worked on Hydrogen Isotope Exchange for the labeling of bioactive complex molecules.

The 4^th ISOTOPICS Traingin was organised at Karolinska Institutet in September 2018 (Stockholm, Sweden).

More information about this event here.

ISOTOPICS consortium

The 4^th ISOTOPICS Meeting was organised by the Karolinska Institutet and the AstraZeneca Beneficiaries on 26^th-27^th September 2018 in Stockholm (Sweden).

More information about this event here.

Mégane Valero (ESR15 –Sanofi) with best posters awardees

Mégane Valero (ESR15 – Sanofi) presented her research results in a poster at the NIKAS 2018  conference (19-20 September 2018; Göttingen, Germany). She was awarded in the ACS Catalysis inorganic chemistry best poster section!

Mégane Valero (ESR15 – Sanofi) presented a poster entitled "C-H functionalization: Highly Selective Directed Iridium-Catalyzed Hydrogen Isotope Exchange Reactions of Aliphatic Amides" during the 16th Belgian Organic Synthesis Symposium BOSS XVI (July 8-13, 2018; Brussels, Belgium).

Francesco Ibba (ESR5 – UOXF) presented a poster of his research results at the Oxford Synthesis Summer Conference 2018 (25-26 June 2018; Oxford, UK). His poster was entitled: 'Asymmetric Nucleophilic Fluorination under Hydrogen Bonding Phase-Transfer Catalysis: Synthetic Approach'.

​Several members of the ISOTOPICS consortium attended the 13th International Symposium on the Synthesis and Applications of Isotopes and Isotopically Labelled Compounds (IIS 2018) held on June 3rd–7th 2018 in Prague (Czech Republic).

6 ISOTOPICS ESRs presented their research projects and results, 1 CEA researcher was invited to give a lecture and the project coordinator presented a poster.

More information and pictures here.

Malvika Sardana (ESR14 - AZ) was on secondment at CEA for 6,5 months. She worked on Carbon-14 labelling at SCBM (Audisio group) and SHFJ (Kunhast group).

Malvika Sardana (ESR14 – AZ) with Carbon-14 team in front of CEA Saclay

Donia Bouzouita (ESR11 - CNRS/INSA Toulouse) presented her PhD project at the EDSDM Doctoral School days (University of Toulouse, France) with a flash oral communication and a poster.

We have published an article in the OPEN ACCESS GOVERNMENT journal to highlight the expected impact of ISOTOPICS in de-risking drug innovation and to inform about the last research results.

You can have access to this article here.

​

​The partner SANOFI France welcomed Donia Bouzouita (ESR11-CNRS) and Alberto Palazzolo (ESR2-CEA) for secondments.

The ESRs were supervised by Jorg Blankenstein and Frank Le Strat in the Isotope Chemistry Laboratory.

Frank Le Strat, Donia Bouzouita (ESR11-CNRS), Alberto Palazzolo (ESR2-CEA) and Jorg Blankenstein at SANOFI France​.

​

The second issue of the ISOTOPICS Newsletters is now available. All the ESRs have participated to its publication.

You can have access to this issue here.

Anna Chiara Vicini (ESR6 – UOXF) in Pint of science and OxHOS committees

Anna Chiara Vicini (ESR6 – UOXF) was an Atom to Galaxy Event Manager of Pint of Science 2018, Oxford. She had a logistic role in the organization of the event from finding a good venue to contacting the speakers.

More information here.

Anna was also Chemistry Coordinator for "Marie Curious" OxHOS events (Oxford hands on Science). She was responsible for developing chemistry experiments for primary and secondary school students.

More information here.

The Mid-term Review Meeting was held on Tuesday 28th November 2017 at Liège (Belgium). All the ISOTOPICS consortium, the Project Officer and an external scientific expert attended this event to check our project implementation and progresses.

More information here.

The 3rd ISOTOPICS training was organised by ULG and UCB beneficiaries from Tuesday 28th November to Monday 4th December 2017. This 4,5-day training involved courses, workshops and visit of laboratories and cyclotron plant.

More information here.

​Malvika Sardana (ESR14-AstraZeneca) has presented a poster during the 26th International Isotope Society - UK Chapter Symposium in Cambridge (UK). More information here

​2 of the CEA ESRs, Viktor Pfeifer (ESR1) and Alberto Palazzolo (ESR2), have presented a poster during the 3rd Doctoral Day organised by the Doctoral School ED2MIB (Université Paris Saclay) at ENS Paris-Saclay (Cachan, France). More information here

Laura Trump (ESR13-UCB) realized a first secondment of 2 weeks at the University of Liège (Belgium). She was welcomed by Dr C. Lemaire and Prof. A. Luxen.

She learned how to use the fastlab for the synthesis of a ¹⁸F-reagent and used it for the insertion of [18F]CHF₂ group on N-heteroaromatics.

​

Mégane Valero (ESR15-SANOFI Germany) did a secondment in the team of Prof. B. Chaudret at CNRS (INSA Toulouse, France). She learned how to synthesise nanoparticles in glovebox.

The management team has published an article in the IMPACT journal to advertise about the objectives and expected impact of ISOTOPICS.

You can have access to this article here.

Donia Bouzouita (ESR11-CNRS) did a 1-week secondment at CEA (Saclay, France). She worked within the group of Dr. G. Pieters (Laboratory of Deuterium/Tritium labeling) on the deuteration of nicotine with Ruthenium nanoparticles.

She could also visit Paris (Louvre Museum) during the weekend.

​

The 2nd ISOTOPICS Meeting took place at the Lindner Congress Hotel in Frankfurt am Main (Germany) on 27th-28th April 2017. This 2-day meeting, organised by Sanofi.

More information here.

The 2nd ISOTOPICS training was organised at SANOFI from Sunday 23rd to Wednesday 26th April 2017. All the 15 ESRs of the ISOTOPICS project attended this 4-day training.

More information here.

​

The first ISOTOPICS Newsletter is now available. All the ESRs have participated to its publication.

You can have access to this issue here.

​All the 15 ESRs of the ISOTOPICS project have now been recruited.

See their presentations and updated CVs here.

The ISOTOPICS project is presented in the "European Projects' Newsletter" on the CEA website.

You can have access to the article here.

​

ISOTOPICS project is presented in the newsletter of the IBITECS (Institute of C. Dugave, B. Rousseau and F. Taran – CEA Partner).

You can have access to this newsletter (in French) here.