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.
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
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.
PMID: 34055235 DOI: 10.1021/acsmedchemlett.1c00127
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.

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