18F-SMBT-1: A Selective and Reversible PET Tracer for Monoamine Oxidase-B Imaging
18F-SMBT-1: A Selective and Reversible PET Tracer for Monoamine Oxidase-B Imaging
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DOI：
10.2967/jnumed.120.244400
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发表时间：
2021-02-01
影响因子：
9.3
通讯作者：
Okamura, Nobuyuki
中科院分区：
文献类型：
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作者：
Harada, Ryuichi;Hayakawa, Yoshimi;Okamura, Nobuyuki
反应性星形胶质细胞在各种神经退行性疾病的发病机制中起关键作用。单胺氧化酶-B（Monoamine oxidase-B，MAO-B）是人脑星形胶质细胞增生的一个很有前途的显像靶点。通过对第一代tau PET示踪剂F-18-THK-5351的先导优化，成功开发了一种新型的选择性和可逆的MAO-B示踪剂（S）-（2-甲基吡啶-5-基）-6-[（3- F-18-氟-2-羟基）丙氧基]喹啉（F-18-SMBT-1）。方法：SMBT-1用相应的前体用F-18放射性标记。使用饱和和竞争性结合测定法评估放射性标记化合物与MAO-B的结合亲和力。通过冷冻人脑组织的放射自显影评价F-18-SMBT 1与MAO-B的结合选择性。在正常小鼠中静脉给予F-18-SMBT-1后评估药代动力学和代谢。使用大鼠和小鼠进行静脉内给予F-18-SMBT-1后的14天毒性研究。结果：体外结合试验证明F-18-SMBT-1与MAO-B具有高结合亲和力（解离常数，3.7 nM）。相反，它显示出对MAO-A和蛋白质聚集体如淀粉样蛋白-β和tau原纤维的低结合亲和力。放射自显影分析显示，阿尔茨海默病脑切片中的F-18-SMBT-1结合量高于对照脑切片。F-18-SMBT-1结合被可逆的MAO-B抑制剂拉扎贝胺完全取代，证明F-18-SMBT-1对MAO-B的高选择性。此外，F-18-SMBT-1在正常小鼠的脑中显示出高摄取、快速洗脱和无放射性标记代谢物。F-18-SMBT-1与各种受体、离子通道或转运蛋白无显著结合，在小鼠和大鼠中未观察到与其给药相关的毒性作用。结论：F-18-SMBT-1是一种有前途的、选择性的MAO-B PET示踪剂候选物，这将有助于定量监测人脑星形胶质细胞增生。
Reactive astrocytes play a key role in the pathogenesis of various neurodegenerative diseases. Monoamine oxidase-B (MAO-B) is one of the promising targets for the imaging of astrogliosis in he human brain. A novel selective and reversible MAO-B tracer, (S)-(2-methylpyrid-5-yl)-6-[(3- F-18-fluoro-2-hydroxy)propoxy]quinoline (F-18-SMBT-1), was successfully developed via lead optimization from the first-generation tau PET tracer F-18-THK-5351. Methods: SMBT-1 was radiolabeled with F-18 using the corresponding precursor. The binding affinity of radiolabeled compounds to MAO-B was assessed using saturation and competitive binding assays. The binding selectivity of F-18-SMBT1 to MAO-B was evaluated by autoradiography of frozen human brain tissues. The pharmacokinetics and metabolism were assessed in normal mice after intravenous administration of F-18-SMBT-1. A 14d toxicity study after the intravenous administration of F-18-SMBT-1 was performed using rats and mice. Results: In vitro binding assays demonstrated a high binding affinity of F-18-SMBT-1 to MAO-B (dissociation constant, 3.7 nM). In contrast, it showed low binding affinity to MAO-A and protein aggregates such as amyloid-beta and tau fibrils. Autoradiographic analysis showed higher amounts of F-18-SMBT-1 binding in the Alzheimer disease brain sections than in the control brain sections. F-18-SMBT-1 binding was completely displaced with the reversible MAO-B inhibitor lazabemide, demonstrating the high selectivity of F-18-SMBT-1 for MAO-B. Furthermore, F-18-SMBT-1 showed a high uptake by brain, rapid washout, and no radiolabeled metabolites in the brain of normal mice. F-18-SMBT-1 showed no significant binding to various receptors, ion channels, or transporters, and no toxic effects related to its administration were observed in mice and rats. Conclusion: F-18-SMBT-1 is a promising and selective MAO-B PET tracer candidate, which would be useful for quantitative monitoring of astrogliosis in the human brain.