Discovery, Radiolabeling, and Evaluation of Subtype-Selective Inhibitors for Positron Emission Tomography Imaging of Brain Phosphodiesterase-4D.,ACS Chemical Neuroscience

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Discovery, Radiolabeling, and Evaluation of Subtype-Selective Inhibitors for Positron Emission Tomography Imaging of Brain Phosphodiesterase-4D.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-04-08 , DOI: 10.1021/acschemneuro.0c00077
Yuichi Wakabayashi ₁ , Sanjay Telu ₁ , Rachel M Dick ₁ , Masahiro Fujita ₁ , Maarten Ooms ₁ , Cheryl L Morse ₁ , Jeih-San Liow ₁ , Jinsoo S Hong ₁ , Robert L Gladding ₁ , Lester S Manly ₁ , Sami S Zoghbi ₁ , Xuesheng Mo ₂ , Emily C D'Amato ₂ , Janice A Sindac ₂ , Richard A Nugent ₂ , Brian E Marron ₂ , Mark E Gurney ₂ , Robert B Innis ₁ , Victor W Pike ₁

Affiliation

We aimed to develop radioligands for PET imaging of brain phosphodiesterase subtype 4D (PDE4D), a potential target for developing cognition enhancing or antidepressive drugs. Exploration of several chemical series gave four leads with high PDE4D inhibitory potency and selectivity, optimal lipophilicity, and good brain uptake. These leads featured alkoxypyridinyl cores. They were successfully labeled with carbon-11 (t1/2 = 20.4 min) for evaluation with PET in monkey. Whereas two of these radioligands did not provide PDE4D-specific signal in monkey brain, two others, [11C]T1660 and [11C]T1650, provided sizable specific signal, as judged by pharmacological challenge using rolipram or a selective PDE4D inhibitor (BPN14770) and subsequent biomathematical analysis. Specific binding was highest in prefrontal cortex, temporal cortex, and hippocampus, regions that are important for cognitive function. [11C]T1650 was progressed to evaluation in humans with PET, but the output measure of brain enzyme density (VT) increased with scan duration. This instability over time suggests that radiometabolite(s) were accumulating in the brain. BPN14770 blocked PDE4D uptake in human brain after a single dose, but the percentage occupancy was difficult to estimate because of the unreliability of measuring VT. Overall, these results show that imaging of PDE4D in primate brain is feasible but that further radioligand refinement is needed, most likely to avoid problematic radiometabolites.

中文翻译：

脑磷酸二酯酶-4D正电子发射断层显像的亚型选择性抑制剂的发现，放射性标记和评估。

我们旨在开发用于脑部磷酸二酯酶4D亚型（PDE4D）的PET成像的放射性配体，这是开发认知增强或抗抑郁药物的潜在目标。对几个化学系列的探索给出了四个具有高PDE4D抑制能力和选择性，最佳亲脂性以及良好的大脑摄取能力的线索。这些引线具有烷氧基吡啶基核心。他们成功地用碳11标记（t1 / 2 = 20.4分钟），用猴子的PET进行评估。鉴于其中的两个放射性配体在猴脑中未提供PDE4D特异性信号，而另两个[11C] T1660和[11C] T1650则提供了相当大的特异性信号，通过使用咯利普兰或选择性PDE4D抑制剂（BPN14770）进行药理学鉴定，随后的生物数学分析。在前额叶皮层，颞叶皮层和海马中特异性结合最高，对认知功能很重要的区域 [11C] T1650已进展为可在具有PET的人体中进行评估，但脑酶密度（VT）的输出量度随扫描时间的延长而增加。随着时间的推移，这种不稳定性表明放射性代谢产物在大脑中蓄积。BPN14770单次给药后阻止了人脑中PDE4D的摄取，但是由于测量VT的不可靠性，难以估计其占有率。总体而言，这些结果表明灵长类动物大脑中PDE4D的成像是可行的，但需要进一步完善放射性配体，最有可能避免出现问题的放射性代谢物。随着时间的推移，这种不稳定性表明放射性代谢产物在大脑中蓄积。BPN14770单次给药后阻断了人脑中PDE4D的摄取，但是由于测量VT的不可靠性，难以估计其占有率。总体而言，这些结果表明灵长类动物大脑中PDE4D的成像是可行的，但需要进一步完善放射性配体，最有可能避免出现问题的放射性代谢物。随着时间的推移，这种不稳定性表明放射性代谢产物在大脑中蓄积。BPN14770单次给药后阻止了人脑中PDE4D的摄取，但是由于测量VT的不可靠性，难以估计其占有率。总体而言，这些结果表明灵长类动物大脑中PDE4D的成像是可行的，但需要进一步完善放射性配体，最有可能避免出现问题的放射性代谢物。

更新日期：2020-03-26

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