Click chemistry Options for Live Immuno Brain Imaging

Informations projet

COLIBRI

N° de convention de subvention: 838596

DOI

10.3030/838596

Projet clôturé

Date de signature de la CE 27 Mars 2019

Date de début 23 Avril 2019

Date de fin 22 Avril 2021

Financé au titre de

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coût total

€ 166 320,00

Contribution de l’UE

€ 166 320,00

Coordonné par

KATHOLIEKE UNIVERSITEIT LEUVEN
Belgium

Periodic Reporting for period 1 - COLIBRI (Click chemistry Options for Live Immuno Brain Imaging)

Période du rapport: 2019-04-23 au 2021-04-22

Résumé du contexte et des objectifs généraux du projet

As the world’s population is living longer, age-related neurodegenerative diseases (ND) such as Alzheimer’s and Parkinson’s are becoming a larger global issue. To date, no cure exists, and the European Union considers the understanding and the diagnosis of ND as key research areas. In this context, the overall aim of the project was the development of a versatile method for immuno based brain PET, as a general translational molecular research method that can also be applied for early diagnosis of ND and follow up of efficacy of novel ND therapies. This is realized through a pretargeting approach using in vivo click chemistry in brain. More specifically, we investigated the usefulness of 18F-TCO (transcyclooctene derivatives) for pretargeted PET imaging of α-synuclein for Parkinson’s disease. The project was divided into 4 objectives: (1) Design and synthesis of fluorine-18 labelled TCO derivatives with optimal brain uptake and clearance (“18F-brainTCO”), (2) Evaluation of in vivo kinetics of a polar peripheral blocking TCO derivative, (3) Tetrazine derivatization of an antibody (TzAb) targeting α-synuclein, investigation of in vitro and in vivo binding to α-synuclein, and in vitro and in vivo availability for click reaction, (4) In vitro (autoradiography) and in vivo (microPET/MR) imaging of the TzAb binding to α-synuclein using 18F-brainTCO. The project also included work packages dedicated to the project management, training, and dissemination and communication.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

We designed and synthetized a series of new fluorine-18 labelled TCO derivatives, with optimal brain uptake and clearance. We developed a synthetic route for five new “18F-brainTCO” (precursors and reference compounds). These compounds had never been synthetized before, thus many efforts were devoted to the optimization of the synthetic pathways. Then, the next step was the radiolabelling of the precursors. We have been able to radiolabel three of them. These reactions have never been described before and have been optimized using an automated module (Trasis AllInOne). The trans-for-cis photoisomerization reaction was carried out in Eindhoven University of Technology (Netherlands). The in vivo evaluation of brain uptake and clearance is under progress, as well as the radiolabelling of the two last compounds. The derivatization of the antibody was also achieved. A ratio of 5.8 tetrazines per antibody has been obtained.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

The results obtained thanks to COLIBRI will largely contribute to the development of an innovative method for the early diagnosis of neurodegenerative diseases. Within the group of Prof. Bormans, follow-up projects will translate the results obtained for mice to clinical application. This will be achieved in collaboration with partners of pharmaceutical industry and nuclear medicine department in Leuven. The technology will also be applied for other biologicals with low brain uptake and/or slow blood clearance (peptides, nanobodies, …) that have affinity for molecular targets in the CNS. In the same way, worldwide researchers from academic groups and pharmaceutical industry working on antibodies (or analogues) for treatment of CNS diseases will benefit of this very innovative method, in order to visualize and quantify biologicals in brain.

In vivo microPET imaging of the TzAb binding to α-synuclein using 18F-brainTCO