F-标记的吡咯并嘧啶揭示了与帕金森病相关的脑亮氨酸丰富重复激酶 2 的表达。
F-Labelled pyrrolopyrimidines reveal brain leucine-rich repeat kinase 2 expression implicated in Parkinson's disease.
机构信息
Center for Molecular Imaging and Translational Medicine, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, Fujian, 361102, China.
Department of Neurology, Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, Fuzhou, Fujian, 350001, China; Fujian Key Laboratory of Molecular Neurology, Key Laboratory of Brain Aging and Neurodegenerative Disease, Fujian Medical University, Fuzhou, Fujian, 350001, China.
出版信息
Eur J Med Chem. 2021 Mar 15;214:113245. doi: 10.1016/j.ejmech.2021.113245. Epub 2021 Feb 4.
F-Labelled pyrrolopyrimidines were synthesized and evaluated as positron emission tomography (PET) probes to determine leucine-rich repeat kinase 2 (LRRK2) expression in the brain. With pyrrolopyrimidine derivative PF-06447475 as the lead compound, two in vivo-stable F-labelled pyrrolopyrimidines ([F]1 and [F]2) were synthesized automatically at radiochemical yields 8-10% (non-decay-corrected) with molar activities of 0.95 and 0.5 GBq/μmol, respectively. The measured K of 6.90 nM for 1 and 14.27 nM for 2 demonstrated high affinities for LRRK2. The LRRK2 G2019S mice had higher uptakes (P < 0.01) of [F]1 in the olfactory bulb, striatum, and hippocampus than WT mice during microPET/CT imaging, consistent with immunohistology results of LRRK2 distribution. [C]CFT microPET/CT imaging demonstrated a lower expression of dopamine transporter in LRRK2 G2019S mice. Parkinson's disease-like deficits in dopamine transporter synthesis and cognitive declines were noticed along with LRRK2 expression increase in the olfactory bulb, striatum, and hippocampus. Therefore, F-labelled pyrrolopyrimidines can reflect real-time LRRK2 expression changes implicated in Parkinson's disease, which paves the way for LRRK2-related neurodegenerative precise therapy.
F-标记的吡咯嘧啶被合成并评估为正电子发射断层扫描（PET）探针，以确定脑内富含亮氨酸重复激酶 2（LRRK2）的表达。以吡咯嘧啶衍生物 PF-06447475 为先导化合物，自动合成了两种体内稳定的 F-标记的吡咯嘧啶([F]1 和 [F]2)，放射性化学产率为 8-10%（未校正衰变），摩尔活度分别为 0.95 和 0.5GBq/μmol。1 的 K 值为 6.90 nM，2 的 K 值为 14.27 nM，表明对 LRRK2 具有高亲和力。在 microPET/CT 成像期间，LRRK2 G2019S 小鼠嗅球、纹状体和海马中的[F]1 摄取量（P<0.01）高于 WT 小鼠，与 LRRK2 分布的免疫组织化学结果一致。[C]CFT microPET/CT 成像显示 LRRK2 G2019S 小鼠中多巴胺转运体的表达较低。随着嗅球、纹状体和海马中 LRRK2 表达的增加，发现多巴胺转运体合成的帕金森病样缺陷和认知能力下降。因此，F-标记的吡咯嘧啶可以反映与帕金森病相关的实时 LRRK2 表达变化，为 LRRK2 相关的神经退行性精确治疗铺平了道路。
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