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Synthesis of a11C-labeledD-amino acid oxidase inhibitor for PET imaging

https://repo.qst.go.jp/records/80198
https://repo.qst.go.jp/records/80198
5b647da4-9791-4b95-8959-35ea8513c07e
Item type 会議発表用資料 / Presentation(1)
公開日 2020-07-08
タイトル
タイトル Synthesis of a11C-labeledD-amino acid oxidase inhibitor for PET imaging
言語
言語 eng
資源タイプ
資源タイプ識別子 http://purl.org/coar/resource_type/c_c94f
資源タイプ conference object
アクセス権
アクセス権 metadata only access
アクセス権URI http://purl.org/coar/access_right/c_14cb
著者 Deng, Xiaoyun

× Deng, Xiaoyun

WEKO 877979

Deng, Xiaoyun

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Shao, Tuo

× Shao, Tuo

WEKO 877980

Shao, Tuo

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Shao, Yihan

× Shao, Yihan

WEKO 877981

Shao, Yihan

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Josephson, Lee

× Josephson, Lee

WEKO 877982

Josephson, Lee

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Hsiao-Ying, Wey

× Hsiao-Ying, Wey

WEKO 877983

Hsiao-Ying, Wey

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Ming-Rong, Zhang

× Ming-Rong, Zhang

WEKO 877984

Ming-Rong, Zhang

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Liang, Huan

× Liang, Huan

WEKO 877985

Liang, Huan

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Ming-Rong, Zhang

× Ming-Rong, Zhang

WEKO 877986

en Ming-Rong, Zhang

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Liang, Huan

× Liang, Huan

WEKO 877987

en Liang, Huan

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抄録
内容記述タイプ Abstract
内容記述 Objectives: We have identified 4-hydroxy-6-(3-methoxyphenethyl)pyridazin-3(2H)-one (1) as a lead molecule for D-amino acid oxidase (DAAO)-specific PET ligand. It has been reported that inhibitory activity of compound 1 for human, mouse and rat DAAOs showed dose-dependent responses with IC50 valves of 8.8, 4.4 and 5.6 nM, respectively. [1] The goal of the project was to synthesize the standard and precursor molecules for this target and perform radiolabeling of compound 1 with carbon-11.

Methods: The leading compound 1 was synthesized in the following procedures. The cyclization of 3,4,6-trichloropyridazine 2 and pyrocatechol 3 led to intermediate 4 in 80% yield. Through the Sonagashira coupling reaction of compound 4 and 1-ethynyl-3-methoxybenzene 5, the alkyne 6 was obtained in 40% yield. Exchanged with phenylmethanol under base, compound 6 was converted to benzyl-protected ether 7 in 58% yield. After Pd-mediated hydrogenation of compound 7, the desired product 1 was obtained in 77% yield (Scheme 1A). The synthesis of the labeling precursor for compound 1 was showed in Scheme 1B. Phenylmethanol was used to react with compound 4 to get benzyl-protected ether 8 in 48% yield. After hydrogenation of compound 8 under hydrogen using palladium/carbon catalysis, 6-chloro-4-hydroxypyridazin-3(2H)-one 9 was obtained in 84% yield. Hydroxy groups were then protected by the treatment with chloromethyl methyl ether to give compound 10 in 40% yield, followed by the Sonagashira coupling reaction with alkyne 12 to produce compound 13 in 38% yield. At the end, benzyl protecting group was removed by palladium hydroxide/carbon catalysis under hydrogen to yield the precursor 14 in 71% yield. Preliminary 11C-labeling was carried out using precursor (14; 1.6 mg) with [11C]methyl iodide in the presence of Cs2CO3 in DMF (0.4 mL) at 80°C for 5 min to generate [11C]15 (Scheme 1C). Then, 4 M HCl in dioxane was added to remove the MOM group and the mixture was neutralized with NaHCO3 aqueous solution to get [11C]1.

Results: The synthesis of candidate compound 1 was obtained from commercially available 3,4,6-trichloropyridazine 2 and pyrocatechol 3 in four steps with overall yield of 14%. The radioligand [11C]1 was synthesized in 13 ± 3% radiochemical yield based on [11C]CH3I (decay corrected). The tracer was obtained at end-of-synthesis (70 min synthesis time) with high radiochemical purity (>99%) and molar activity (> 1.0 Ci/μmol; 37 GBq/μmol). No radiolysis was observed within 90 min.

Conclusions: We have successfully prepared one potent and selective DAAO ligand and performed 11C-labeling with a reasonable radiochemical yield and high molar activity. Preliminary in vivo evaluation by PET are underway. References: [1] T. Hondo, M. Warizaya, T. Niimi, I. Namatame, T. Yamaguchi, K. Nakanishi, T. Hamajima, K. Harada, H. Sakashita, Y. Matsumoto, J. Med. Chem. 2013, 56, 3582.
会議概要(会議名, 開催地, 会期, 主催者等)
内容記述タイプ Other
内容記述 SNMMI 2020 Annual Meeting
発表年月日
日付 2020-07-12
日付タイプ Issued
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