Discovery of N-(6-Methoxypyridin-3-yl)quinoline-2-amine Derivatives for Imaging Aggregated α-Synuclein in Parkinson's Disease with Positron Emission Tomography.

The fibrillary aggregation of α-synuclein is a hallmark of Parkinson's disease (PD) and a potential target for diagnostics and therapeutics. Although substantial effort has been devoted to the development of positron emission tomography (PET) probes for detecting α-synuclein aggregates, no clinically suitable tracer has been reported. The design and synthesis of 43 new N-(6-methoxypyridin-3-yl)quinolin-2-amine derivatives and an evaluation of their α-synuclein binding affinity is reported here. Compounds 7f, 7j, and 8i exhibited high affinity for α-synuclein and were selected for (11)C, (18)F, (125)I, or (3)H radiolabeling. A photoaffinity variant, TZ-CLX, structurally related to 7j and 8i, demonstrated preferential binding to the C-terminal region of α-synuclein fibrils. PET brain imaging studies using [(11)C]7f, [(18)F]7j, and [(11)C]8i in non-human primates indicated that these three α-synuclein PET tracers penetrated the blood-brain barrier. Both [(11)C]7f and [(18)F]7j showed more favorable brain washout pharmacokinetics than [(11)C]8i. In vitro binding assays showed that [(125)I]8i is a very potent α-synuclein radioligand, with K(d) values of 5 nM for both PD brain tissues and LBD-amplified fibrils; it is also selective for PD tissues versus AD or control tissues. These results strongly suggest that the PET probes based on the N-(6-methoxypyridin-3-yl)quinoline-2-amine scaffold have potential utility in detecting α-synuclein aggregates in vivo.