Accumulation of α-synuclein (α-syn) is a neuropathological hallmark of synucleinopathies. To date, no selective α-syn positron emission tomography (PET) radiotracer has been identified. Our objective was to develop the first original, selective, and specific α-syn PET radiotracer. Chemical design inspired from three structural families that demonstrated interesting α-syn binding characteristics was used as a starting point. Bioinformatics modeling of α-syn fibrils was then employed to select the best molecular candidates before their syntheses. An in vitro binding assay was performed to evaluate the affinity of the compounds. Radiotracer specificity and selectivity were assessed by in vitro autoradiography and in vivo PET studies in animal (rodents) models. Finally, gold standard in vitro autoradiography with patients' postmortem tissues was performed to confirm/infirm the α-syn binding characteristics. Two compounds exhibited a good brain availability and bound to α-syn and Aβ fibrils in a rat model. In contrast, no signal was observed in a mouse model of synucleinopathy. Experiments in human tissues confirmed these negative results.

[ 11 C]Methylation (t 1/2 = 20.4 min) is a main labeling strategy for the development of PET (positron emission tomography) radiotracers. A straight radiomethylation of amines with cyclotron-produced 11 CO 2 has been developed to obtain various radiolabeled compounds with good radiochemical

Labeling of heterocycles with carbon‐11 is generally performed through peripheral functionalizations and more scarcely inside heterocyclic core. Such less common approach usually requires preliminary multi‐step synthesis of reactive species. Herein, a cyclization reaction by direct use of cyclotron‐produced [11C]CO2 is described to obtain various heterocycles intracyclically labeled in only 10 minutes.