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

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 [¹¹C]GNE-1023 as a novel potent PET probe for LRRK2 imaging in PD. [¹¹C]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 [¹¹C]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.