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

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.

SUBMITTER: Murrell E

PROVIDER: S-EPMC8155239 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Leveraging Open Science Drug Development for PET: Preliminary Neuroimaging of <sup>11</sup>C-Labeled ALK2 Inhibitors.

Murrell Emily E Tong Junchao J Smil David D Kiyota Taira T Aman Ahmed M AM Isaac Methvin B MB Watson Iain D G IDG Vasdev Neil N

ACS medicinal chemistry letters 20210423 5

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 <sup>11</sup>C-labeled radiotracers from potent and selective lead ALK2 inhibitors to investigate their brain permeabil ...[more]

PMID: 34055235

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Project description:Selective modulation of metabotropic glutamate receptor 2 (mGlu2) represents a novel therapeutic approach for treating brain disorders, including schizophrenia, depression, Parkinson's disease (PD), Alzheimer's disease (AD), drug abuse and addiction. Imaging mGlu2 using positron emission tomography (PET) would allow for in vivo quantification under physiological and pathological conditions and facilitate drug discovery by enabling target engagement studies. In this paper, we aimed to develop a novel specific radioligand derived from negative allosteric modulators (NAMs) for PET imaging of mGlu2. Methods. A focused small molecule library of mGlu2 NAMs with tetrahydro naphthyridine scaffold was synthesized for pharmacology and physicochemical evaluation. GIRK dose-response assays and CNS panel binding selectivity assays were performed to study the affinity and selectivity of mGlu2 NAMs, among which compounds 14a and 14b were selected as PET ligand candidates. Autoradiography in SD rat brain sections was used to confirm the in vitro binding specificity and selectivity of [11C]14a and [11C]14b towards mGlu2. In vivo binding specificity was then studied by PET imaging. Whole body biodistribution study and radiometabolite analysis were conducted to demonstrate the pharmacokinetic properties of [11C]14b as most promising PET mGlu2 PET ligand. Results. mGlu2 NAMs 14a-14g were synthesized in 14%-20% yields in five steps. NAMs 14a and 14b were selected to be the most promising ligands due to their high affinity in GIRK dose-response assays. [11C]14a and [11C]14b displayed similar heterogeneous distribution by autoradiography, consistent with mGlu2 expression in the brain. While PET imaging study showed good brain permeability for both tracers, compound [11C]14b demonstrated superior binding specificity compared to [11C]14a. Further radiometabolite analysis of [11C]14b showed excellent stability in the brain. Conclusions. Compound 14b exhibited high affinity and excellent subtype selectivity, which was then evaluated by in vitro autoradiography and in vivo PET imaging study after labeling with carbon-11. Ligand [11C]14b, which we named [11C]MG2-1904, demonstrated high brain uptake and excellent in vitro/in vivo specific binding towards mGlu2 with high metabolic stability in the brain. As proof-of-concept, our preliminary work demonstrated a successful example of visualizing mGlu2 in vivo derived from NAMs, which represents a promising chemotype for further development and optimization aimed for clinical translation.

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

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Leveraging Open Science Drug Development for PET: Preliminary Neuroimaging of <sup>11</sup>C-Labeled ALK2 Inhibitors.

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

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Leveraging Open Science Drug Development for PET: Preliminary Neuroimaging of <sup>11</sup>C-Labeled ALK2 Inhibitors.

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OmicsDI is part of the ELIXIR infrastructure

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