| Affiliation: | 1. Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA, 02114 USA
These authors contributed equally to this work.;2. Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 500 Dongchuan Road, Shanghai, 200241 China;3. Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA, 02114 USA;4. Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston Salem, NC, 27157 USA;5. Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA, 02114 USA;6. Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK, 73019 USA |
| 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 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. |
