Increased Brain Exposure of an Alpha-Synuclein Fibrillization Modulator by Utilization of an Activated Ester Prodrug Strategy.,ACS Chemical Neuroscience

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Increased Brain Exposure of an Alpha-Synuclein Fibrillization Modulator by Utilization of an Activated Ester Prodrug Strategy.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2018-06-19 , DOI: 10.1021/acschemneuro.8b00236
Andrew G Cairns ₁ , Ana Vazquez-Romero ₂ , Mohammad Mahdi Moein ₂ , Jörgen Ådén ₁ , Charles S Elmore ₃ , Akihiro Takano ₂ , Ryosuke Arakawa ₂ , Andrea Varrone ₂ , Fredrik Almqvist ₁ , Magnus Schou _{2,

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Affiliation

Previous work in our laboratories has identified a series of peptidomimetic 2-pyridone molecules as modulators of alpha-synuclein (α-syn) fibrillization in vitro. As a first step toward developing molecules from this scaffold as positron emission tomography imaging agents, we were interested in evaluating their blood-brain barrier permeability in nonhuman primates (NHP) in vivo. For this purpose, 2-pyridone 12 was prepared and found to accelerate α-syn fibrillization in vitro. Acid 12, and its acetoxymethyl ester analogue 14, were then radiolabeled with 11C ( t1/2 = 20.4 min) at high radiochemical purity (>99%) and high specific radioactivity (>37 GBq/μmol). Following intravenous injection of each compound in NHP, a 4-fold higher radioactivity in brain was observed for [11C]14 compared to [11C]12 (0.8 vs 0.2 SUV, respectively). [11C]14 was rapidly eliminated from plasma, with [11C]12 as the major metabolic product observed by radio-HPLC. The presented prodrug approach paves the way for future development of 2-pyridones as imaging biomarkers for in vivo imaging of α-synuclein deposits in brain.

中文翻译：

通过激活的酯类药物前药策略，增加大脑暴露的α-突触核蛋白原纤维化调节剂。

我们实验室的先前工作已经确定了一系列拟肽2-吡啶酮分子作为体外α-突触核蛋白（α-syn）原纤维化的调节剂。作为从该支架开发分子作为正电子发射断层显像剂的第一步，我们对评估其在非人类灵长类动物（NHP）中的血脑屏障通透性感兴趣。为此目的，制备了2-吡啶酮12，并发现其在体外加速α-syn原纤维化。然后，将酸12及其乙酰氧基甲基酯类似物14用11 C（t1 / 2 = 20.4分钟）进行放射性高纯度（> 99％）和高比放射性（> 37 GBq /μmol）的放射性标记。在NHP中静脉注射每种化合物后，与[11C] 12相比，[11C] 14在大脑中的放射性提高了4倍（分别为0.8和0.2 SUV）。[11C] 14被迅速从血浆中清除，[11C] 12是通过放射-HPLC观察到的主要代谢产物。所提出的前药方法为2-吡啶酮作为影像生物标记物的未来发展铺平了道路，该影像生物标记物用于体内对α-突触核蛋白沉积物的体内成像。

更新日期：2018-06-14

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