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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
Author(s) -
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 HsiaoYing,
Shao Yihan,
Josephson Lee,
Qiu WenWei,
Liang Steven
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900321
Subject(s) - lrrk2 , positron emission tomography , biodistribution , radioligand , parkinson's disease , kinase , in vivo , radiosynthesis , chemistry , in vitro , pet imaging , biochemistry , medicine , biology , disease , nuclear medicine , pathology , genetics
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.