11 C Radiolabeling of anle253b: a Putative PET Tracer for Parkinson's Disease That Binds to α-Synuclein Fibrils in vitro and Crosses the Blood-Brain Barrier.,ChemMedChem

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11 C Radiolabeling of anle253b: a Putative PET Tracer for Parkinson's Disease That Binds to α-Synuclein Fibrils in vitro and Crosses the Blood-Brain Barrier.
ChemMedChem ( IF 3.6 ) Pub Date : 2020-01-09 , DOI: 10.1002/cmdc.201900689
Andreas Maurer ₁ , Andrei Leonov _{2,

3} , Sergey Ryazanov ₂ , Kristina Herfert ₁ , Laura Kuebler ₁ , Sabrina Buss ₁ , Felix Schmidt ₄ , Daniel Weckbecker ₄ , Ruth Linder ₂ , Dirk Bender ₅ , Armin Giese _{3,

4} , Bernd J Pichler ₁ , Christian Griesinger _{2,

3}

Affiliation

There is an urgent clinical need for imaging of α-synuclein (αSyn) fibrils, the hallmark biomarker for Parkinson's disease, in neurodegenerative disorders. Despite immense efforts, promising tracer candidates for nuclear imaging of αSyn are rare. Diphenyl pyrazoles are known modulators of αSyn aggregation and thus bear potential for non-invasive detection of this biomarker in vivo. Here we demonstrate high-affinity binding of the family member anle253b to fibrillar αSyn and present a high-yielding site-selective radiosynthesis route for 11 C radiolabeling using in-situ generated [11 C]formaldehyde and reductive methylation. Radio-HPLC of the tracer after incubation with rat serum in vitro shows excellent stability of the molecule. Positron emission tomography in healthy animals is used to assess the pharmacokinetics and biodistribution of the tracer, showing good penetration of the blood-brain barrier and low background binding to the non-pathological brain.

中文翻译：

anle253b 的 11 C 放射性标记：一种假定的帕金森病 PET 示踪剂，可在体外与 α-突触核蛋白原纤维结合并穿过血脑屏障。

临床迫切需要对神经退行性疾病中帕金森病的标志性生物标志物 α-突触核蛋白 (αSyn) 原纤维进行成像。尽管付出了巨大的努力，用于 αSyn 核成像的有希望的候选示踪剂仍然很少。二苯基吡唑是已知的 αSyn 聚集调节剂，因此具有体内非侵入性检测该生物标志物的潜力。在这里，我们证明了家族成员 anle253b 与纤维状 αSyn 的高亲和力结合，并提出了一种使用原位生成的 [11 C]甲醛和还原甲基化进行 11 C 放射性标记的高产位点选择性放射合成路线。与大鼠血清体外孵育后示踪剂的放射性 HPLC 显示该分子具有优异的稳定性。健康动物的正电子发射断层扫描用于评估示踪剂的药代动力学和生物分布，显示出对血脑屏障的良好渗透性和与非病理性大脑的低背景结合。

更新日期：2020-01-09

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