Synthesis and Preliminary Evaluation of [ 11 C]GNE-1023 as a Potent PET Probe for Imaging Leucine-Rich Repeat Kinase 2 (LRRK2) in Parkinson's Disease

ChemMedChem. 2019 Sep 4;14(17):1580-1585. doi: 10.1002/cmdc.201900321. Epub 2019 Aug 22.

Abstract

Leucine-rich repeat kinase 2 (LRRK2) is a large protein involved in the pathogenesis of Parkinson's disease (PD). It has been demonstrated that PD is mainly conferred by LRRK2 mutations that bring about increased kinase activity. As a consequence, selective inhibition of LRRK2 may help to recover the normal functions of LRRK2, thereby serving as a promising alternative therapeutic target for PD treatment. The mapping of LRRK2 by positron emission tomography (PET) studies allows a thorough understanding of PD and other LRRK2-related disorders; it also helps to validate and translate novel LRRK2 inhibitors. However, no LRRK2 PET probes have yet been reported in the primary literature. Herein we present a facile synthesis and preliminary evaluation of [11 C]GNE-1023 as a novel potent PET probe for LRRK2 imaging in PD. [11 C]GNE-1023 was synthesized in good radiochemical yield (10 % non-decay-corrected RCY), excellent radiochemical purity (>99 %), and high molar activity (>37 GBq μmol-1 ). Excellent in vitro binding specificity of [11 C]GNE-1023 toward LRRK2 was demonstrated in cross-species studies, including rat and nonhuman primate brain tissues by autoradiography experiments. Subsequent whole-body biodistribution studies indicated limited brain uptake and urinary and hepatobiliary elimination of this radioligand. This study may pave the way for further development of a new generation of LRRK2 PET probes.

Keywords: GNE-1023; Parkinson's disease; carbon-11; leucine-rich repeat kinase 2; positron emission tomography.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Brain / metabolism
  • Carbon Radioisotopes
  • Female
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism*
  • Ligands
  • Macaca mulatta
  • Mice
  • Morpholines / chemical synthesis
  • Morpholines / pharmacology*
  • Parkinson Disease / diagnostic imaging*
  • Positron-Emission Tomography / methods
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines / chemical synthesis
  • Pyrimidines / pharmacology*
  • Radiopharmaceuticals / chemical synthesis
  • Radiopharmaceuticals / pharmacology*
  • Rats, Sprague-Dawley

Substances

  • Carbon Radioisotopes
  • Carbon-11
  • Ligands
  • Morpholines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Radiopharmaceuticals
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2