[ 11 C]MODAG-001——针对 α-突触核蛋白聚集体的 PET 示踪剂,European Journal of Nuclear Medicine and Molecular Imaging

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[ 11 C]MODAG-001——针对 α-突触核蛋白聚集体的 PET 示踪剂
European Journal of Nuclear Medicine and Molecular Imaging ( IF 8.6 ) Pub Date : 2020-12-28 , DOI: 10.1007/s00259-020-05133-x
Laura Kuebler ₁ , Sabrina Buss ₁ , Andrei Leonov _{2,

3} , Sergey Ryazanov _{2,

3} , Felix Schmidt ₂ , Andreas Maurer ₁ , Daniel Weckbecker ₂ , Anne M Landau _{4,

5} , Thea P Lillethorup ₅ , Daniel Bleher ₁ , Ran Sing Saw ₁ , Bernd J Pichler ₁ , Christian Griesinger _{3,

6} , Armin Giese ₂ , Kristina Herfert ₁

Affiliation

目的

人脑中错误折叠的 α-突触核蛋白 (αSYN) 聚集体的沉积是突触核蛋白病的主要标志之一。然而，仍然缺乏检测 αSYN 病理聚集体的目标特异性示踪剂。在这里，我们报告了基于 anle138b 的正电子发射断层扫描 (PET) 示踪剂的开发，anle138b 是一种在神经退行性疾病动物模型中显示具有治疗活性的化合物。

方法

^{[ 3} H]MODAG-001 的特异性和选择性在使用重组原纤维的体外结合试验中进行了测试。碳 11 放射性标记后，在小鼠中测定药代动力学和代谢谱。在由慕尼黑神经生物库 (NBM) 提供的路易体痴呆 (LBD) 病例的人脑切片中，用 αSYN 原纤维接种并使用体外放射自显影在大鼠中量化特异性结合。

结果

[ ³ H]MODAG-001 对纯 αSYN 原纤维 ( K _{d = 0.6 ± 0.1 nM) 具有非常高的亲和力，对 hTau46 原纤维 (}K _d = 19 ± 6.4 nM) 以及淀粉样蛋白-β _1– 只有中等亲和力_{42 个}原纤维 ( K _d = 20 ± 10 nM)。[ ¹¹ C]MODAG-001 表现出出色的穿透小鼠大脑的能力。存在代谢降解，但母体化合物的稳定性在前体选择性氘化后得到改善。(d ₃ )-[ ¹¹C]MODAG-001 结合使用体内 PET 成像在原纤维接种的大鼠纹状体中得到证实。体外放射自显影显示在 LBD 病例的人脑切片中未检测到与聚集的 αSYN 的结合，这很可能是因为聚集的 αSYN 与背景蛋白的丰度较低。

结论

MODAG-001 为未来的化合物开发提供了一种有前景的先导结构，因为它结合了原纤维结合试验中的高亲和力和良好的选择性以及合适的药代动力学和生物分布特性。

"点击查看英文标题和摘要"

[ 11 C]MODAG-001—towards a PET tracer targeting α-synuclein aggregates

Purpose

Deposition of misfolded alpha-synuclein (αSYN) aggregates in the human brain is one of the major hallmarks of synucleinopathies. However, a target-specific tracer to detect pathological aggregates of αSYN remains lacking. Here, we report the development of a positron emission tomography (PET) tracer based on anle138b, a compound shown to have therapeutic activity in animal models of neurodegenerative diseases.

Methods

Specificity and selectivity of [³H]MODAG-001 were tested in in vitro binding assays using recombinant fibrils. After carbon-11 radiolabeling, the pharmacokinetic and metabolic profile was determined in mice. Specific binding was quantified in rats, inoculated with αSYN fibrils and using in vitro autoradiography in human brain sections of Lewy body dementia (LBD) cases provided by the Neurobiobank Munich (NBM).

Results

[³H]MODAG-001 revealed a very high affinity towards pure αSYN fibrils (K_d = 0.6 ± 0.1 nM) and only a moderate affinity to hTau46 fibrils (K_d = 19 ± 6.4 nM) as well as amyloid-β_1–42 fibrils (K_d = 20 ± 10 nM). [¹¹C]MODAG-001 showed an excellent ability to penetrate the mouse brain. Metabolic degradation was present, but the stability of the parent compound improved after selective deuteration of the precursor. (d₃)-[¹¹C]MODAG-001 binding was confirmed in fibril-inoculated rat striata using in vivo PET imaging. In vitro autoradiography showed no detectable binding to aggregated αSYN in human brain sections of LBD cases, most likely, because of the low abundance of aggregated αSYN against background protein.

Conclusion

MODAG-001 provides a promising lead structure for future compound development as it combines a high affinity and good selectivity in fibril-binding assays with suitable pharmacokinetics and biodistribution properties.

更新日期：2020-12-28

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