Leveraging Open Science Drug Development for PET: Preliminary Neuroimaging of 11C-Labeled ALK2 Inhibitors,ACS Medicinal Chemistry Letters

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Leveraging Open Science Drug Development for PET: Preliminary Neuroimaging of 11C-Labeled ALK2 Inhibitors
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2021-04-23 , DOI: 10.1021/acsmedchemlett.1c00127
Emily Murrell ₁ , Junchao Tong ₁ , David Smil ₂ , Taira Kiyota ₂ , Ahmed M. Aman _{2,

3} , Methvin B. Isaac ₂ , Iain D. G. Watson ₂ , Neil Vasdev _{1,

4}

Affiliation

Mutations in the gene encoding activin receptor-like kinase 2 (ALK2) are implicated in the pathophysiology of a pediatric brainstem cancer, diffuse intrinsic pontine glioma (DIPG). Inhibitors of ALK2 that cross the blood–brain barrier have been proposed as a method of treatment for DIPG. As part of an open science approach to radiopharmaceutical and drug discovery, we developed ¹¹C-labeled radiotracers from potent and selective lead ALK2 inhibitors to investigate their brain permeability through positron emission tomography (PET) neuroimaging. Four radiotracers were synthesized by ¹¹C-methylation and assessed by dynamic PET imaging in healthy Sprague–Dawley rats. One of the compounds, [¹¹C]M4K2127, showed high initial brain uptake (SUV ∼ 2), including in the region of interest (pons). This data supports the use of this chemotype as a brain penetrant ALK2 inhibitor that permeates evenly into the pons with potential application for the treatment of DIPG.

中文翻译：

利用开放式科学药物开发PET：^11种C标签的ALK2抑制剂的初步神经成像

编码激活素受体样激酶2（ALK2）的基因中的突变与小儿脑干癌，弥漫性桥脑神经胶质瘤（DIPG）的病理生理有关。已经提出了穿越血脑屏障的ALK2抑制剂作为DIPG的治疗方法。作为开放科学的放射性药物和药物发现方法的一部分，我们从强效和选择性铅ALK2抑制剂中开发了^11种C标记的放射性示踪剂，以通过正电子发射断层扫描（PET）神经成像研究其脑通透性。通过¹¹ C-甲基化合成了四种放射性示踪剂，并通过动态PET成像对健康的Sprague-Dawley大鼠进行了评估。一种化合物，[ ¹¹ C] M4K2127，显示出高的初始大脑摄取（SUV〜2），包括在感兴趣的区域（pons）。该数据支持该化学型作为脑渗透性ALK2抑制剂的应用，该抑制剂可渗透到脑桥中，具有潜在的DIPG治疗用途。

更新日期：2021-05-13

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