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. (22nd August 2019)

• Record Type: Journal Article
• Authors: Chen, Zhen; Shao, Tuo; Gao, Wei; Fu, Hualong; Collier, Thomas Lee; Rong, Jian; Deng, Xiaoyun; Yu, Qingzhen; Zhang, Xiaofei; Davenport, April T.; Daunais, James B.; Wey, Hsiao‐Ying; Shao, Yihan; Josephson, Lee; Qiu, Wen‐Wei; Liang, Steven
• Is Part Of: ChemMedChem. Volume 14:Number 17(2019)
• Page Start: 1580
• Page End: 1585
• Publication Date: 2019-08-22
• Subjects: carbon-11 -- GNE-1023 -- leucine-rich repeat kinase 2 -- Parkinson's disease -- positron emission tomography; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201900321
• Languages: English
• ISSNs: 1860-7179

Abstract

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. Abstract : PET project : A 11 C‐labeled PET probe [ 11 C]GNE‐1023 ([ 11 C]6 ) was synthesized in good radiochemical yield, excellent radiochemical purity, and high molar activity. Autoradiography studies demonstrated excellent in vitro specific binding of [ 11 C]6 to leucine‐rich repeat kinase 2 in several species including rat and nonhuman primate brain tissues. Whole‐body ex vivo biodistribution studies showed limited brain accumulation, along with urinary and hepatobiliary elimination of [ 11 C]6 in mice. Further modification to the [ 11 C]6 scaffold is necessary to improve its BBB permeability.