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

J Med Chem. 2024 Feb 22;67(4):2559-2569. doi: 10.1021/acs.jmedchem.3c01687. Epub 2024 Feb 2.

Abstract

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.

MeSH terms

  • Animals
  • Humans
  • Leucine
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism
  • Mice
  • Morpholines*
  • Mutation
  • Nitriles*
  • Parkinson Disease* / metabolism
  • Positron-Emission Tomography / methods
  • Pyrimidines*

Substances

  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • (18F)PF-06455943
  • Leucine
  • Pyrimidines
  • LRRK2 protein, human
  • Morpholines
  • Nitriles