Preclinical Evaluation of Novel Positron Emission Tomography (PET) Probes for Imaging Leucine-Rich Repeat Kinase 2 (LRRK2)

Parkinson’s
disease (PD) is one of the most highly debilitating
neurodegenerative disorders, which affects millions of people worldwide,
and leucine-rich repeat kinase 2 (LRRK2) mutations have been involved
in the pathogenesis of PD. Developing a potent LRRK2 positron emission
tomography (PET) tracer would allow for in vivo visualization of LRRK2
distribution and expression in PD patients. In this work, we present
the facile synthesis of two potent and selective LRRK2 radioligands
[11C]3 ([11C]PF-06447475) and [18F]4 ([18F]PF-06455943). Both radioligands
exhibited favorable brain uptake and specific bindings in rodent autoradiography
and PET imaging studies. More importantly, [18F]4 demonstrated significantly higher brain uptake in the transgenic
LRRK2-G2019S mutant and lipopolysaccharide (LPS)-injected mouse models.
This work may serve as a roadmap for the future design of potent LRRK2
PET tracers.