Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.
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.
ChemMedChem. 2019 Sep 4;14(17):1580-1585. doi: 10.1002/cmdc.201900321. Epub 2019 Aug 22.
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 [ C]GNE-1023 as a novel potent PET probe for LRRK2 imaging in PD. [ 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 ). Excellent in vitro binding specificity of [ 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.
富含亮氨酸重复激酶 2（LRRK2）是一种参与帕金森病（PD）发病机制的大型蛋白。已经证明，PD 主要由 LRRK2 突变引起，这些突变导致激酶活性增加。因此，选择性抑制 LRRK2 可能有助于恢复 LRRK2 的正常功能，从而成为 PD 治疗的有前途的替代治疗靶点。正电子发射断层扫描（PET）研究对 LRRK2 的定位可以深入了解 PD 和其他 LRRK2 相关疾病；它还有助于验证和转化新型 LRRK2 抑制剂。然而，在主要文献中尚未报道任何 LRRK2 PET 探针。在此，我们提出了一种简便的合成方法，并初步评估了 [C]GNE-1023 作为一种新型有效的 PD LRRK2 成像 PET 探针。[C]GNE-1023 的放射性化学产率（10%未衰变校正 RCY）良好，放射化学纯度（>99%）高，摩尔活性（>37GBqμmol）高。通过放射自显影实验，在包括大鼠和非人灵长类动物脑组织在内的种间研究中，证明了 [C]GNE-1023 对 LRRK2 的优异体外结合特异性。随后的全身生物分布研究表明，这种放射性配体的脑摄取有限，以及尿液和肝胆排泄。这项研究可能为新一代 LRRK2 PET 探针的进一步发展铺平道路。
