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 = 32.1 ± 1.3 nM) and 3-(2-fluoroethoxy)-7-nitro-10H-phenothiazine (2b, K = 49.0 ± 4.9 nM), were radiolabeled as potential PET imaging agents by respectively introducing ¹¹C and ¹⁸F. The syntheses of [¹¹C]2a and [¹⁸F]2b were accomplished in a good yield with high specific activity. Ex vivo biodistribution studies in rats revealed that both [¹¹C]2a and [¹⁸F]2b crossed the blood-brain barrier (BBB) and demonstrated good brain uptake 5 min post-injection. MicroPET imaging of [¹¹C]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 [¹¹C]2a and [¹⁸F]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).