Radiosynthesis and in Vivo Evaluation of Two PET Radioligands for Imaging α-Synuclein

Two α-synuclein ligands, 3-methoxy-7-nitro-10H-phenothiazine (2a, K(i) = 32.1 ± 1.3 nM) and 3-(2-fluoroethoxy)-7-nitro-10H-phenothiazine (2b, K(i) = 49.0 ± 4.9 nM), were radiolabeled as potential PET imaging agents by respectively introducing (11)C and (18)F. The syntheses of [(11)C]2a and [(18)F]2b were accomplished in a good yield with high specific activity. Ex vivo biodistribution studies in rats revealed that both [(11)C]2a and [(18)F]2b crossed the blood-brain barrier (BBB) and demonstrated good brain uptake 5 min post-injection. MicroPET imaging of [(11)C]2a in a non-human primate (NHP) confirmed that the tracer was able to cross the BBB with rapid washout kinetics from brain regions of a healthy macaque. The initial studies suggested that further structural optimization of [(11)C]2a and [(18)F]2b is necessary in order to identify a highly specific positron emission tomography (PET) radioligand for in vivo imaging of α-synuclein aggregation in the central nervous system (CNS).