1‑(4‑[18F]Fluorobenzyl)-4-[(tetrahydrofuran-2-yl)methyl]piperazine: A Novel Suitable Radioligand with Low Lipophilicity for Imaging σ1 Receptors in the Brain
We have designed and synthesized novel piperazine compounds with low lipophilicity as σ1 receptor ligands. 1-(4-Fluorobenzyl)-4-[(tetrahydrofuran-2-yl)methyl]piperazine (10) possessed a low nanomolar σ1 receptor affinity and a high selectivity toward the vesicular acetylcholine transporter (>20...
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Published in | Journal of medicinal chemistry Vol. 60; no. 10; pp. 4161 - 4172 |
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Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
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American Chemical Society
25.05.2017
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Abstract | We have designed and synthesized novel piperazine compounds with low lipophilicity as σ1 receptor ligands. 1-(4-Fluorobenzyl)-4-[(tetrahydrofuran-2-yl)methyl]piperazine (10) possessed a low nanomolar σ1 receptor affinity and a high selectivity toward the vesicular acetylcholine transporter (>2000-fold), σ2 receptors (52-fold), and adenosine A2A, adrenergic α2, cannabinoid CB1, dopamine D1, D2L, γ-aminobutyric acid A (GABAA), NMDA, melatonin MT1, MT2, and serotonin 5-HT1 receptors. The corresponding radiotracer [18F]10 demonstrated high brain uptake and extremely high brain-to-blood ratios in biodistribution studies in mice. Pretreatment with the selective σ1 receptor agonist SA4503 significantly reduced the level of accumulation of the radiotracer in the brain. No radiometabolite of [18F]10 was observed to enter the brain. Positron emission tomography and magnetic resonance imaging confirmed suitable kinetics and a high specific binding of [18F]10 to σ1 receptors in rat brain. Ex vivo autoradiography showed a reduced level of binding of [18F]10 in the cortex and hippocampus of the senescence-accelerated prone (SAMP8) compared to that of the senescence-accelerated resistant (SAMR1) mice, indicating the potential dysfunction of σ1 receptors in Alzheimer’s disease. |
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AbstractList | We have designed and synthesized novel piperazine compounds with low lipophilicity as σ1 receptor ligands. 1-(4-Fluorobenzyl)-4-[(tetrahydrofuran-2-yl)methyl]piperazine (10) possessed a low nanomolar σ1 receptor affinity and a high selectivity toward the vesicular acetylcholine transporter (>2000-fold), σ2 receptors (52-fold), and adenosine A2A, adrenergic α2, cannabinoid CB1, dopamine D1, D2L, γ-aminobutyric acid A (GABAA), NMDA, melatonin MT1, MT2, and serotonin 5-HT1 receptors. The corresponding radiotracer [18F]10 demonstrated high brain uptake and extremely high brain-to-blood ratios in biodistribution studies in mice. Pretreatment with the selective σ1 receptor agonist SA4503 significantly reduced the level of accumulation of the radiotracer in the brain. No radiometabolite of [18F]10 was observed to enter the brain. Positron emission tomography and magnetic resonance imaging confirmed suitable kinetics and a high specific binding of [18F]10 to σ1 receptors in rat brain. Ex vivo autoradiography showed a reduced level of binding of [18F]10 in the cortex and hippocampus of the senescence-accelerated prone (SAMP8) compared to that of the senescence-accelerated resistant (SAMR1) mice, indicating the potential dysfunction of σ1 receptors in Alzheimer’s disease. We have designed and synthesized novel piperazine compounds with low lipophilicity as σ1 receptor ligands. 1-(4-Fluorobenzyl)-4-[(tetrahydrofuran-2-yl)methyl]piperazine (10) possessed a low nanomolar σ1 receptor affinity and a high selectivity toward the vesicular acetylcholine transporter (>2000-fold), σ2 receptors (52-fold), and adenosine A2A, adrenergic α2, cannabinoid CB1, dopamine D1, D2L, γ-aminobutyric acid A (GABAA), NMDA, melatonin MT1, MT2, and serotonin 5-HT1 receptors. The corresponding radiotracer [18F]10 demonstrated high brain uptake and extremely high brain-to-blood ratios in biodistribution studies in mice. Pretreatment with the selective σ1 receptor agonist SA4503 significantly reduced the level of accumulation of the radiotracer in the brain. No radiometabolite of [18F]10 was observed to enter the brain. Positron emission tomography and magnetic resonance imaging confirmed suitable kinetics and a high specific binding of [18F]10 to σ1 receptors in rat brain. Ex vivo autoradiography showed a reduced level of binding of [18F]10 in the cortex and hippocampus of the senescence-accelerated prone (SAMP8) compared to that of the senescence-accelerated resistant (SAMR1) mice, indicating the potential dysfunction of σ1 receptors in Alzheimer's disease. |
Author | Deuther-Conrad, Winnie Huang, Yiyun Lu, Jie Cui, Bixiao Jia, Hongmei He, Yingfang Xie, Fang Wang, Liang Brust, Peter Ye, Jiajun Steinbach, Jörg |
AuthorAffiliation | Department of Nuclear Medicine Xuanwu Hospital Capital Medical University Yale PET Center, Department of Radiology and Biomedical Imaging Helmholtz-Zentrum Dresden-Rossendorf Yale University School of Medicine Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals |
AuthorAffiliation_xml | – name: Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry – name: Yale PET Center, Department of Radiology and Biomedical Imaging – name: Helmholtz-Zentrum Dresden-Rossendorf – name: Department of Nuclear Medicine – name: Xuanwu Hospital Capital Medical University – name: Yale University School of Medicine – name: Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals |
Author_xml | – sequence: 1 givenname: Yingfang surname: He fullname: He, Yingfang organization: Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry – sequence: 2 givenname: Fang surname: Xie fullname: Xie, Fang organization: Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry – sequence: 3 givenname: Jiajun surname: Ye fullname: Ye, Jiajun organization: Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry – sequence: 4 givenname: Winnie surname: Deuther-Conrad fullname: Deuther-Conrad, Winnie organization: Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals – sequence: 5 givenname: Bixiao surname: Cui fullname: Cui, Bixiao organization: Xuanwu Hospital Capital Medical University – sequence: 6 givenname: Liang surname: Wang fullname: Wang, Liang organization: Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry – sequence: 7 givenname: Jie surname: Lu fullname: Lu, Jie organization: Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry – sequence: 8 givenname: Jörg surname: Steinbach fullname: Steinbach, Jörg organization: Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals – sequence: 9 givenname: Peter surname: Brust fullname: Brust, Peter organization: Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals – sequence: 10 givenname: Yiyun surname: Huang fullname: Huang, Yiyun organization: Yale University School of Medicine – sequence: 11 givenname: Jie surname: Lu fullname: Lu, Jie email: imaginglu@hotmail.com organization: Xuanwu Hospital Capital Medical University – sequence: 12 givenname: Hongmei orcidid: 0000-0002-1412-8158 surname: Jia fullname: Jia, Hongmei email: hmjia@bnu.edu.cn organization: Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry |
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Title | 1‑(4‑[18F]Fluorobenzyl)-4-[(tetrahydrofuran-2-yl)methyl]piperazine: A Novel Suitable Radioligand with Low Lipophilicity for Imaging σ1 Receptors in the Brain |
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