Deliverables
The late stage fluorination methodology developed in batch by ESRs 1-2 will be extended to continuous-flow chemistry to improve the reaction conditions and facilitae the scale-up of fragments and leads from mg to g and kg scale.
Supervisory Board of the NetworkEffective nomination of the Supervisory Board of FLUDD
Website and NewslettersWebsite and Newsletters regularly updated and sustained including partner websites
Synthesis of 18F-radioligands to image enzyme GPCR and kinase targets (Neuro)Selection of labeled 18F-molecules for the production of 18F-radioligands to image enzyme and GPCR targets within the Janssen Neuroscience portfolio. IMAp will be involved in the design of radioligands to support JANSSEN CNS drug discovery programs involving ESR3.
Synthesis of 18F-carbohydrate probe for TBNIH and UOXFd have demonstrated that Mycobacterium tuberculosis (Mtb, the causative agent of TB) is specifically ‘labeled’ by trehalose-based probes in a manner that is dependent on an enzymatic mechanism unique to TB.
Catalytic fluorination via CH functionalization of cyclobutanes, bicycles, spirocycles, oxetanes, thietanes and azetidinesESR1 will examine the subtle geometric, steric, and electronic effects at play in auxiliary guided C−H fluorination of cyclobutanes, oxetanes, thietanes and azetidines.
Production of TB 18F-probe under GMP conditionsMycobacterium tuberculosis (Mtb, the causative agent of TB) is specifically ‘labeled’ by trehalose-based probes. ESR5 will work on a scalable enzymatic process free of endotoxins at a GMP standard.
Patents, research and review publications, assistance for creation of start-ups and incubationPatents, research and review publications, assistance for creation of start-ups and incubation, help to the writing of research projects.
(Pre)clinical evaluation of TB 18F-probeThe progression of the TB probe developed by ESR5 to (pre)clinical evaluation will be orchestrated under WP3.
Metabolic studies and preclinical evaluation of priority 19/18F-moleculesOXF and JAN will generate a number of novel 19F- and 18F-fluorinated fragments and molecules, for which metabolic stability is unclear or unknown, and will require systematic investigation. All ESRs will be involved.
18F-Labeling of cyclobutanes, bicycles, spirocycles, oxetanes, thietanes, azetidines, thiazines and thiazolesNovel methods developed by ESRs 1-2 will provide a range of novel 18F-molecules that will be tested for metabolic stability and preclinical evaluation (WP3).
Dissemination of main results throughout the consortium and outside (oral and poster presentations) (eg International conferences)Dissemination of main results throughout the consortium and outside (oral and poster presentations).
Methods based on [18F][:CF2] carbene radiochemistry to label 18F-arylOCHF2 and 18F-arylSCHF2The radiosynthesis of 18F-arylOCHF2 will be envisaged by OH insertion of directly available (hetero)arylOH with the in situ prepared 18F-labeled carbene [18F][:CF2].
Catalytic fluorocyclization of alkenes and alkynes towards thiazoles and thiazinesESR2 - Fluorination will be extended to alkenes as illustrated with the construction of fluorine-containing thiazoles and thiazines.
Metabolic studies and preclinical evaluation of priority 19/18F-biomoleculesUOXF and JANb will generate a number of novel 19F- and 18F-fluorinated fragments and biomolecules, for which metabolic stability is unclear or unknown, and will require systematic investigation. All ESRs will be involved.
Site selective 18F-Labeling of proteins eg AnnexinV, MCP1/CCL5, BACE1, GSM, APP, TauESR4 will collaborate with JANb to the development and translation of new reactions to jointly selected protein systems such as Annexin V, proleukin (IL-2), MCP1/CCL5, icosahedral virus-capsid proteins and fluoro-mAbs/ADCs.
Methods based on CH functionalization to 18F-label new 18F-chemotypes (eg (hetero)arylCHF2)ESR3 will develop novel 18F-labeling methods towards, at first instance, (hetero)arylCHF2 and (hetero)arylOCHF2 in high specific activity.
Selection and synthesis of best fragment- lead candidates for medicinal chemistryESR1 and ESR2 will develop innovative methodology based on Csp3-H and alkene functionalization to access new fluorine-containing motifs, bioisosteres and molecules for applications in medicinal chemistry.
Methods for site selective 18F-labeling of proteinsNew C–C and C–F bond forming methods under development by OXFd will allow the first exploration of this new form of protein mutagenesis, allowing the power of the F atom to be fully applied to control biology.
Defense of DPhil Thesis (Oxford)Redaction and defense of Thesis for the awarding of the doctoral degree (Oxford).
Formal annual FLUDD school with taught training component oral communications by all ESRs and plenary lecturers
Public Website, Press release, Outreach, Open days, EmbassyPublic website design and maintenance including press release outreach activities open days embassy
ESR recruitment processEffective recruitment of all ESRs according to the priniciple of transparency and non-discrimination
Improvement of employabilityImprovement of employability through training in job search, career paths, management & entrepreneurship.
Workshops and (inter)national conferencesMonitoring the atendance of all ESRs to network-wide workshops and to external workshops and (inter)national conferences.
Publications
Author(s):
Sandrine M. Hell, Claudio F. Meyer, Andrés A. Trabanco, Véronique Gouverneur
Published in:
Journal of Visualized Experiments, Issue 161, 2020, ISSN 1940-087X
Publisher:
MYJoVE Corporation
DOI:
10.3791/61384
Author(s):
B. Josephson, C. Fehl, P. G. Isenegger, S. Nadal, T. H. Wright, A. W. J. Poh, B. J. Bower, A. M. Giltrap, L. Chen, C. Batchelor-McAuley, G. Roper, O. Arisa, J. B. I. Sap, A. Kawamura, A. J. Baldwin, S. Mohammed, R. G. Compton, V. Gouverneur, B. G. Davis
Published in:
Nature, Issue 585, 2020, Page(s) 530-537, ISSN 0028-0836
Publisher:
Nature Publishing Group
DOI:
10.1038/s41586-020-2733-7
Author(s):
Claudio F. Meyer, Sandrine M. Hell, Antonio Misale, Andres A Trabanco, Veronique Gouverneur
Published in:
Angewandte Chemie International Edition, 2019, ISSN 1433-7851
Publisher:
John Wiley & Sons Ltd.
DOI:
10.1002/anie.201903801
Author(s):
Claudio F. Meyer, Sandrine M. Hell, Jeroen B.I. Sap, Antonio Misale, Aldo Peschiulli, Daniel Oehlrich, Andrés A. Trabanco, Véronique Gouverneur
Published in:
Tetrahedron, Issue 8 October 2019, 2019, Page(s) 130679, ISSN 0040-4020
Publisher:
Pergamon Press Ltd.
DOI:
10.1016/j.tet.2019.130679
Author(s):
Sandrine M. Hell, Claudio F. Meyer, Gabriele Laudadio, Antonio Misale, Michael C. Willis, Timothy Noël, Andrés A. Trabanco, Veronique Gouverneur
Published in:
Journal of the American Chemical Society, 2019, ISSN 0002-7863
Publisher:
American Chemical Society
DOI:
10.1021/jacs.9b13071
Author(s):
Sandrine Monique Hell, Claudio Flavio Meyer, Antonio Misale, Jeroen B. I. Sap, Kirsten K. Christensen, Michael C. Willis, Andrés A. Trabanco, Veronique Gouverneur
Published in:
Angewandte Chemie International Edition, 2020, ISSN 1433-7851
Publisher:
John Wiley & Sons Ltd.
DOI:
10.1002/anie.202004070
Author(s):
Jeroen B. I. Sap, Natan J. W. Straathof, Thomas Knauber, Claudio F. Meyer, Maurice Médebielle, Laura Buglioni, Christophe Genicot, Andrés A. Trabanco, Timothy Noël, Christopher W. am Ende, Véronique Gouverneur
Published in:
Journal of the American Chemical Society, Issue 142/20, 2020, Page(s) 9181-9187, ISSN 0002-7863
Publisher:
American Chemical Society
DOI:
10.1021/jacs.0c03881
Author(s):
Giulia Roagna, David M. H. Ascough, Francesco Ibba, Anna Chiara Vicini, Alberto Fontana, Kirsten E. Christensen, Aldo Peschiulli, Daniel Oehlrich, Antonio Misale, Andrés A. Trabanco, Robert S. Paton, Gabriele Pupo, Veronique Gouverneur
Published in:
Journal of the American Chemical Society, 2020, ISSN 0002-7863
Publisher:
American Chemical Society
DOI:
10.1021/jacs.0c05131
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