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Synthesis and preliminary evaluation of 4-hydroxy-6-(3-[¹¹C]methoxyphenethyl)pyridazin-3(2H)-one, a ¹¹C-labeled d-amino acid oxidase (DAAO) inhibitor for PET imaging.

ABSTRACT: Selective DAAO inhibitors have demonstrated promising therapeutic effects in clinical studies, including clinically alleviating symptoms of schizophrenic patients and ameliorating cognitive function in Alzheimer's patients with early phase. Herein we report the synthesis and preliminary evaluation of a ¹¹C-labeled positron emission tomography ligand based on a DAAO inhibitor, DAO-1903 (8). ¹¹C-Isotopologue of 8 was prepared in high radiochemical yield with high radiochemical purity (>99%) and high molar activity (>37 GBq/µmol). In vitro autoradiography studies indicated that the ligand possessed high in vitro specific binding to DAAO, while in vivo dynamic PET studies demonstrated that [¹¹C]8 failed to cross the blood-brain barrier possibly due to moderate brain efflux mechanism. Further chemical scaffold optimization is necessary to overcome limited brain permeability and improve specific binding.

SUBMITTER: Deng X

PROVIDER: S-EPMC7363051 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Synthesis and preliminary evaluation of 4-hydroxy-6-(3-[11C]methoxyphenethyl)pyridazin-3(2H)-one, a 11C-labeled d-amino acid oxidase (DAAO) inhibitor for PET imaging.

Deng Xiaoyun X Zhang Yiding Y Chen Zhen Z Kumata Katsushi K Van Richard R Rong Jian J Shao Tuo T Hatori Akiko A Mori Wakana W Yu Qingzhen Q Hu Kuan K Fujinaga Masayuki M Wey Hsiao-Ying HY Shao Yihan Y Josephson Lee L Murtas Giulia G Pollegioni Loredano L Zhang Ming-Rong MR Liang Steven S

Bioorganic & medicinal chemistry letters 20200609 16

Selective DAAO inhibitors have demonstrated promising therapeutic effects in clinical studies, including clinically alleviating symptoms of schizophrenic patients and ameliorating cognitive function in Alzheimer's patients with early phase. Herein we report the synthesis and preliminary evaluation of a 11C-labeled positron emission tomography ligand based on a DAAO inhibitor, DAO-1903 (8). 11C-Isotopologue of 8 was prepared in high radiochemical yield with high radiochemica ...[more]

PMID: 32631531

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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.

Dataset Information

Synthesis and preliminary evaluation of 4-hydroxy-6-(3-[¹¹C]methoxyphenethyl)pyridazin-3(2H)-one, a ¹¹C-labeled d-amino acid oxidase (DAAO) inhibitor for PET imaging.

Publications

Synthesis and preliminary evaluation of 4-hydroxy-6-(3-[<sup>11</sup>C]methoxyphenethyl)pyridazin-3(2H)-one, a <sup>11</sup>C-labeled d-amino acid oxidase (DAAO) inhibitor for PET imaging.

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