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ISOTOPIC LABELING FOR DRUG INNOVATION

Deliverables

Development of Suzuki protein chemistry for the [18F]labeling of proteins

Development of structurally benign Suzuki protein chemistry for the [18F]labeling of proteins through the Tag-and-Modify Strategy

Microfluidic [11C]carbonylation screening under radical initiated conditions

Development of novel [11C]carbonylation radiochemistry methodology that will further progress the possibility to radiolabel drug-like molecules using a microfluidic synthesizer in reaction screening for the [11C]labeling of a set of representative drugs in particular under radical initiated conditions (undertaken in close collaboration with experts in radiochemistry hardware BenCar and Scancys)

Development of new hydrophilic and air-resistant RuNps for [2H/3H]labeling of drugs & biologics

Development of new RuNPs with variable sizes, shapes, coating and poisoning to modulate their specificity and reactivity, and to improve their use in aqueous reaction media and their handling in the air.

Improvement of employability

Improvement of employability through training in job search, career paths, management & entrepreneurship

Development, evaluation and applications of new methods for asymmetric [18F]fluorination

Development, evaluation and applications of new methods for asymmetric [18F]fluorination using chiral [18F]NF reagents, asymmetric organocatalysis and transition metal catalysts

N-Methylation/C-carbonylation from CO2 for the [14C]radiolabeling of small-molecule drugs

N-Methylation/C-carbonylation from CO2 for the [14C]radiolabeling of small-molecule drugs. Evaluation of transferability to the [11C]radiolabeling of small-molecule drugs.

Cu(III)-catalyzed [18F]fluorination of arenes and heteroarenes

Cu(III)-catalyzed [18F]fluorination of aryl boronic esters of arenes and heteroarenes motifs found in small-molecule drugs

New methods for [2H/3H]labeling of biologics

Application of the RuNps-catalyzed C-H activation of organic molecules to the [2H/3H] labeling of proteins, nucleic acids and other macromolecules

Communication and presentation skills

Development of communication and presentation skills at group meetings and Network meeting as a preliminary training

New methods for [2H/3H]labeling of small molecules drugs and peptides

Development of innovative isotopic chemistry (in particular with RuNps) for the labeling of general molecular scaffolds with 2H and 3H and application to the isotopic labeling of simple molecules and then to small molecules drugs, peptides and short polynucleotides.

Supervisory Board of the Network

Effective nomination of the Supervisory Board of ISOTOPICS

Development of new fluoro- and difluoromethyl-sulfonyl reagents for the production of [18F]labeled alkenes

Development of new fluoro- and difluoromethyl-sulfonyl reagents for the GMP production of [18F]labeled alkenes using cyclotron-produced [18F-]

Patents, research and review publications, assistance for creation of start-ups and incubation

Patents, research and review publications, assistance for creation of start-ups and incubation, help to the writing of research projects

Defence of PhD Thesis

Redaction and defense of Thesis for the awarding of the doctoral degree (according to host regulations)

Cascade reactions to construct 14C-heterocycles and derivatizing peptides and proteins from K14CN

New cascade reactions for the 14C labeling of small molecule (heterocyclic) drugs, peptides, and structurally begnign labeling of proteins from [14C]labeled KCN.

Development of a photochemical flow process for addition of [18F]CHF to (hetero)aromatics

Development of a photochemical flow process for addition of [18F]CHF to (hetero)aromatic compounds through a radical process

Training in information technology skills

Training in information technology skills, ability to get relevant scientific information from the current databases and application to research, project and grant writing and exploitation of results and data

Results dissemination

Emphasizing the importance of dissemination of results through publications, industrial valorization, public engagement and participation to symposia

Development of a novel automated radio-chemistry system for [11C]carbonylation

Development (in collaboration with Scansys) of a novel automated radiochemistry system that allows for [11C]carbonylation to be performed according to GMP and thus enables clinical PET studies. In addition to transition metal catalysis, UV irradiation and/or chemical initiation will be performed to undertake radical [11C]carbonylation of alkyl substrates

Scientific meeting reports

Scientific meeting reports on months 4, 11, 27, 35, 43 and 48

Application of N-methylation and C-carbonylation from CO2 to [11C]labeling

Application of the carbonylation reactions from CO2 developed by CEA to the construction of [11C]labeled molecules and application to the [11C]labeling of small-molecule drugs.

Network-wide interdisciplinary scientific training

Network-wide interdisciplinary scientific training composed of 5 Training Schools at months 10, 18, 26, 34, 42

Website and Newsletters

Website and Newsletters regularly updated and sustained after the project completion (including partners websites)

Public Engagement

Public Website, press release, Folk High Schools, Open days, Embassy

Dissemination of main results

Dissemination of main results throughout the consortium and outside (oral and poster presentations)

Network-wide Periodic Network meetings

Network-wide Periodic Network meetings at months 3, 10, 18, 26, 34, 42, 48 and associated reports at months 4, 11, 19, 27, 35, 43, 48

ESR recruitment process

Effective recruitment of all ESRs according to the priniciple of transparency and non-discrimination

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Publications

Evaluation of a P,N-Ligated Iridium(I) Catalyst in Hydrogen Isotope Exchange Reactions of Aryl and Heteroaryl Compounds

Author(s): Mégane Valero, Annina Burhop, Kristof Jess, Remo Weck, Matthias Tamm, Jens Atzrodt, Volker Derdau
Published in: Journal of Labelled Compounds and Radiopharmaceuticals, 2017, ISSN 0362-4803
DOI: 10.1002/jlcr.3595

Selective Radical Trifluoromethylation of Native Residues in Proteins

Author(s): Mateusz Imiołek, Gogulan Karunanithy, Wai-Lung Ng, Andrew J. Baldwin, Véronique Gouverneur, Benjamin G. Davis
Published in: Journal of the American Chemical Society, 2018, ISSN 0002-7863
DOI: 10.1021/jacs.7b10230

Highly Selective Directed Iridium-Catalyzed Hydrogen Isotope Exchange Reactions of Aliphatic Amides

Author(s): Volker Derdau, Mégane Valero, Remo Weck, Jens Atzrodt, Stefan Güssregen
Published in: Angewandte Chemie International Edition, 2018, ISSN 1433-7851
DOI: 10.1002/anie.201804010

Asymmetric nucleophilic fluorination under hydrogen bonding phase-transfer catalysis

Author(s): Gabriele Pupo, Francesco Ibba, David M. H. Ascough, Anna Chiara Vicini, Paolo Ricci, Kirsten E. Christensen, Lukas Pfeifer, John Richard Morphy, John M. Brown, Robert S. Paton, Véronique Gouverneur
Published in: Science, Issue 360/6389, 2018, Page(s) 638-642, ISSN 0036-8075
DOI: 10.1126/science.aar7941

Late-Stage Isotopic Carbon Labeling of Pharmaceutically Relevant Cyclic Ureas Directly from CO 2

Author(s): Antonio Del Vecchio, Fabien Caillé, Arnaud Chevalier, Olivier Loreau, Kaisa Horkka, Christer Halldin, Magnus Schou, Nathalie Camus, Pascal Kessler, Bertrand Kuhnast, Frédéric Taran, Davide Audisio
Published in: Angewandte Chemie International Edition, Issue 57/31, 2018, Page(s) 9744-9748, ISSN 1433-7851
DOI: 10.1002/anie.201804838

Recent developments in heterocycle labeling with carbon isotopes

Author(s): Antonio Del Vecchio, Gianluca Destro, Frédéric Taran, Davide Audisio
Published in: Journal of Labelled Compounds and Radiopharmaceuticals, Issue 61/13, 2018, Page(s) 988-1007, ISSN 0362-4803
DOI: 10.1002/jlcr.3666

Dynamic Carbon Isotope Exchange of Pharmaceuticals with Labeled CO 2

Author(s): Gianluca Destro, Olivier Loreau, Elodie Marcon, Frédéric Taran, Thibault Cantat, Davide Audisio
Published in: Journal of the American Chemical Society, 2018, ISSN 0002-7863
DOI: 10.1021/jacs.8b12140

Visible-Light-Driven Reduction of CO 2 to CO and Its Subsequent Valorization in Carbonylation Chemistry and 13 C Isotope Labeling

Author(s): Philipp Gotico, Antonio Del Vecchio, Davide Audisio, Annamaria Quaranta, Zakaria Halime, Winfried Leibl, Ally Aukauloo
Published in: ChemPhotoChem, Issue 2/8, 2018, Page(s) 715-719, ISSN 2367-0932
DOI: 10.1002/cptc.201800012

Palladium-mediated enzyme activation suggests multiphase initiation of glycogenesis

Author(s): Matthew K. Bilyard, Henry J. Bailey, Lluís Raich, Maria A. Gafitescu, Takuya Machida, Javier Iglésias-Fernández, Seung Seo Lee, Christopher D. Spicer, Carme Rovira, Wyatt W. Yue, Benjamin G. Davis
Published in: Nature, Issue 563/7730, 2018, Page(s) 235-240, ISSN 0028-0836
DOI: 10.1038/s41586-018-0644-7

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

Author(s): Gabriele Pupo, Anna Chiara Vicini, David M. H. Ascough, Francesco Ibba, Kirsten E. Christensen, Amber L. Thompson, John M. Brown, Robert S. Paton, Véronique Gouverneur
Published in: Journal of the American Chemical Society, Issue 141/7, 2019, Page(s) 2878-2883, ISSN 0002-7863
DOI: 10.1021/jacs.8b12568

Efficient Access to Deuterated and Tritiated Nucleobase Pharmaceuticals and Oligonucleotides using Hydrogen-Isotope Exchange

Author(s): Alberto Palazzolo, Sophie Feuillastre, Viktor Pfeifer, Sébastien Garcia-Argote, Donia Bouzouita, Simon Tricard, Céline Chollet, Elodie Marcon, David-Alexandre Buisson, Sophie Cholet, François Fenaille, Guy Lippens, Bruno Chaudret, Grégory Pieters
Published in: Angewandte Chemie International Edition, Issue 58/15, 2019, Page(s) 4891-4895, ISSN 1433-7851
DOI: 10.1002/anie.201813946

Progress in Difluoroalkylation of Organic Substrates by Visible Light Photoredox Catalysis

Author(s): Agostinho Lemos, Christian Lemaire, André Luxen
Published in: Advanced Synthesis & Catalysis, Issue 361/7, 2019, Page(s) 1500-1537, ISSN 1615-4150
DOI: 10.1002/adsc.201801121

Surprising Differences of Alkane C‐H Activation Catalyzed by Ruthenium Nanoparticles: Complex Surface‐Substrate Recognition?

Author(s): Niels Rothermel, Donia Bouzouita, Tobias Röther, Iker de Rosal, Simon Tricard, Romuald Poteau, Torsten Gutmann, Bruno Chaudret, Hans‐Heinrich Limbach, Gerd Buntkowsky
Published in: ChemCatChem, Issue 10/19, 2018, Page(s) 4243-4247, ISSN 1867-3880
DOI: 10.1002/cctc.201801022

The Emergence of Carbon Isotope Exchange

Author(s): Karen Hinsinger, Grégory Pieters
Published in: Angewandte Chemie International Edition, 2019, ISSN 1433-7851
DOI: 10.1002/anie.201905368

Highlights of aliphatic C (sp 3 )-H Hydrogen Isotope Exchange Reactions

Author(s): Mégane Valero, Volker Derdau
Published in: Journal of Labelled Compounds and Radiopharmaceuticals, 2019, ISSN 0362-4803
DOI: 10.1002/jlcr.3783

Comparison of Iridium(I) Catalysts in Temperature Mediated Hydrogen Isotope Exchange Reactions

Author(s): Mégane Valero, Anurag Mishra, Jennifer Blass, Remo Weck, Volker Derdau
Published in: ChemistryOpen, 2019, ISSN 2191-1363
DOI: 10.1002/open.201900204

Directed Iridium‐Catalyzed Hydrogen Isotope Exchange Reactions of Phenylacetic Acid Esters and Amides

Author(s): Mégane Valero, Daniel Becker, Kristof Jess, Remo Weck, Jens Atzrodt, Thomas Bannenberg, Volker Derdau, Matthias Tamm
Published in: Chemistry – A European Journal, Issue 25/26, 2019, Page(s) 6517-6522, ISSN 0947-6539
DOI: 10.1002/chem.201901449

Tuning the catalytic activity and selectivity of water-soluble bimetallic RuPt nanoparticles by modifying their surface metal distribution

Author(s): Donia Bouzouita, Guy Lippens, Edwin A. Baquero, Pier F. Fazzini, Gregory Pieters, Yannick Coppel, Pierre Lecante, Simon Tricard, Luis M. Martínez-Prieto, Bruno Chaudret
Published in: Nanoscale, 2019, ISSN 2040-3364
DOI: 10.1039/c9nr04149d

Late-Stage 18 F-Difluoromethyl Labeling of N-Heteroaromatics with High Molar Activity for PET Imaging

Author(s): Laura Trump, Agostinho Lemos, Bénédicte Lallemand, Patrick Pasau, Joël Mercier, Christian Lemaire, André Luxen, Christophe Genicot
Published in: Angewandte Chemie International Edition, Issue 58/37, 2019, Page(s) 13149-13154, ISSN 1433-7851
DOI: 10.1002/anie.201907488

Rapid and Efficient Synthesis of 11 C-Labeled Benzimidazolones Using [ 11 C]Carbon Dioxide

Author(s): Kaisa Horkka, Kenneth Dahl, Jonas Bergare, Charles S. Elmore, Christer Halldin, Magnus Schou
Published in: ChemistrySelect, Issue 4/6, 2019, Page(s) 1846-1849, ISSN 2365-6549
DOI: 10.1002/slct.201803561

New trends and applications in carboxylation for isotope chemistry

Author(s): Ryan A. Bragg, Malvika Sardana, Markus Artelsmair, Charles S. Elmore
Published in: Journal of Labelled Compounds and Radiopharmaceuticals, Issue 61/13, 2018, Page(s) 934-948, ISSN 0362-4803
DOI: 10.1002/jlcr.3633

σ-H–H, σ-C–H, and σ-Si–H Bond Activation Catalyzed by Metal Nanoparticles

Author(s): Juan M. Asensio, Donia Bouzouita, Piet W. N. M. van Leeuwen, Bruno Chaudret
Published in: Chemical Reviews, 2019, ISSN 0009-2665
DOI: 10.1021/acs.chemrev.9b00368

Visible-Light Enabled Aminocarbonylation of Unactivated Alkyl Iodides with Stoichiometric Carbon Monoxide for Application on Late-Stage Carbon Isotope Labeling

Author(s): Malvika Sardana, Joakim Bergman, Cecilia Ericsson, Lee Peter Kingston, Magnus Schou, Christophe Dugave, Davide Audisio, Charles S. Elmore
Published in: The Journal of Organic Chemistry, 2019, ISSN 0022-3263
DOI: 10.1021/acs.joc.9b02575

“In-loop” carbonylation - a simplified method for carbon-11 labeling of drugs and radioligands

Author(s): Mélodie Ferrat, Kenneth Dahl, Christer Halldin, Magnus Schou
Published in: Journal of Labelled Compounds and Radiopharmaceuticals, 2019, ISSN 0362-4803
DOI: 10.1002/jlcr.3805

NHC-Stabilized Iridium Nanoparticles as Novel Catalysts in Hydrogen Isotope Exchange Reactions of Anilines

Author(s): Mégane Valero, Donia Bouzouita, Alberto Palazzolo, Jens Atzrodt, Christophe Dugave, Simon Tricard, Sophie Feuillastre, Grégory Pieters, Bruno Chaudret, Volker Derdau
Published in: Angewandte Chemie International Edition, 2019, ISSN 1433-7851
DOI: 10.1002/anie.201914369

Hydrogen Isotope Exchange Catalyzed by Ru Nanocatalysts: Labelling of Complex Molecules Containing N‐Heterocycles and Reaction Mechanism Insights

Author(s): Grégory Pieters, Viktor Pfeifer, Marie Certiat, Donia Bouzouita, Alberto Palazzolo, Sébastien Garcia-Argote, Elodie Marcon, David-Alexandre Buisson, Philippe Lesot, Laurent Maron, Bruno Chaudret, Simon Tricard, Iker del Rosal, Romuald Poteau, Sophie Feuillastre
Published in: Chemistry – A European Journal, 2019, ISSN 0947-6539
DOI: 10.1002/chem.201905651

C−H Functionalization-Prediction of Selectivity in Iridium(I)-Catalyzed Hydrogen Isotope Exchange Competition Reactions

Author(s): Mégane Valero, Thomas Kruissink, Jennifer Blass, Remo Weck, Stefan Güssregen, Alleyn T. Plowright, Volker Derdau
Published in: Angewandte Chemie International Edition, 2020, ISSN 1433-7851
DOI: 10.1002/anie.201914220

Development of a General Automated Flow Photoredox 18 F-Difluoromethylation of N-Heteroaromatics in an AllinOne Synthesizer

Author(s): Laura Trump, Agostinho Lemos, Jérôme Jacq, Patrick Pasau, Bénédicte Lallemand, Joël Mercier, Christophe Genicot, André Luxen, Christian Lemaire
Published in: Organic Process Research & Development, 2020, ISSN 1083-6160
DOI: 10.1021/acs.oprd.9b00442

18 F-Trifluoromethanesulfinate Enables Direct C–H 18 F-Trifluoromethylation of Native Aromatic Residues in Peptides

Author(s): Choon Wee Kee, Osman Tack, Florian Guibbal, Thomas C. Wilson, Patrick G. Isenegger, Mateusz Imiołek, Stefan Verhoog, Michael Tilby, Giulia Boscutti, Sharon Ashworth, Juliette Chupin, Roxana Kashani, Adeline W. J. Poh, Jane K. Sosabowski, Sven Macholl, Christophe Plisson, Bart Cornelissen, Michael C. Willis, Jan Passchier, Benjamin G. Davis, Véronique Gouverneur
Published in: Journal of the American Chemical Society, Issue 142/3, 2020, Page(s) 1180-1185, ISSN 0002-7863
DOI: 10.1021/jacs.9b11709

Radical C–H 18F-Difluoromethylation of Heteroarenes with [18F]Difluoromethyl Heteroaryl-Sulfones by Visible Light Photoredox Catalysis

Author(s): Agostinho Luís Pereira Lemos, Laura Trump, Bénédicte Lallemand, Patrick Pasau, Joël Mercier, Christian Lemaire, Jean-Christophe Monbaliu, Christophe Genicot, André Luxen
Published in: Catalysts, Issue 10/3, 2020, Page(s) 275, ISSN 2073-4344
DOI: 10.3390/catal10030275