A Novel Brain PET Radiotracer for Imaging Alpha Synuclein Fibrils in Multiple System Atrophy

Abnormal
α-synuclein (α-syn) aggregation characterizes
α-synucleinopathies, including Parkinson’s disease (PD)
and multiple system atrophy (MSA). However, no suitable positron emission
tomography (PET) radiotracer for imaging α-syn in PD and MSA
exists currently. Our structure–activity relationship studies
identified 4-methoxy-N-(4-(3-(pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)phenyl)benzamide
(4i) as a PET radiotracer candidate for imaging α-syn. In vitro assays revealed high binding of 4i to recombinant α-syn fibrils (inhibition constant (Ki) = 6.1 nM) and low affinity for amyloid beta
(Aβ) fibrils in Alzheimer’s disease (AD) homogenates.
However, [3H]4i also
exhibited high specific binding to AD, progressive supranuclear palsy,
and corticobasal degeneration tissues as well as PD and MSA tissues,
suggesting notable affinity to tau. Nevertheless, the specific binding
to pathologic α-syn aggregates in MSA post-mortem brain tissues
was significantly higher than in PD tissues. This finding demonstrated
the potential use of [11C]4i as a PET tracer for imaging α-syn in MSA patients.
Nonhuman primate PET studies confirmed good brain uptake and rapid
washout for [11C]4i.