Leveraging Open Science Drug Development for PET: Preliminary Neuroimaging of 11C-Labeled ALK2 Inhibitors

Emily Murrell; Junchao Tong; David Smil; Taira Kiyota; Ahmed M Aman; Methvin B Isaac; Iain D G Watson; Neil Vasdev

doi:10.1021/acsmedchemlett.1c00127

Leveraging Open Science Drug Development for PET: Preliminary Neuroimaging of ¹¹C-Labeled ALK2 Inhibitors

ACS Med Chem Lett. 2021 Apr 23;12(5):846-850. doi: 10.1021/acsmedchemlett.1c00127. eCollection 2021 May 13.

Authors

Emily Murrell¹, Junchao Tong¹, David Smil², Taira Kiyota², Ahmed M Aman^{2

3}, Methvin B Isaac², Iain D G Watson², Neil Vasdev^{1

4}

Affiliations

¹ Azrieli Centre for Neuro-Radiochemistry, Brain Health Imaging Centre, Centre for Addiction and Mental Health (CAMH), 250 College St., M5T 1R8, Toronto, Ontario Canada.
² Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, M5G 0A3, Toronto, Ontario Canada.
³ Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College St., M5S 3M2, Toronto, Ontario Canada.
⁴ Department of Psychiatry, University of Toronto, 250 College St., M5T 1R8, Toronto, Ontario Canada.

Abstract

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, [ ¹¹ C]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.