Click chemistry options for live immuno brain imaging
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 fellowship is 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 the efficacy of novel ND therapies. This will be realized through a pretargeting approach using in vivo click chemistry in brain. More specifically, I will investigate the usefulness of 18F-TCO (trans-cyclooctene derivatives) for pretargeted PET imaging of α-synuclein for Parkinson’s disease. The project will be 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 success of COLIBRI will rest on its interdisciplinary since various scientific fields will be covered: organic synthesis, flow chemistry, antibody derivatization, radiochemistry, in vitro/ex vivo tests, in vivo tests in animal models and PET imaging. The project also includes work packages dedicated to the project management (personal career development plan, progress monitoring, budget, ethics and risk management), training (techniques, courses, supervision of students), and dissemination and communication (publications, reports, lab meetings, conferences, popularization events, Internet presence, ...).