Hong-Mei Jia

Name: 贾红梅; Jia, HongMei

Organization: Key Laboratory of Radiopharmaceuticals (Beijing Normal University) , China

Department: College of Chemistry

Title: Associate Professor(PhD)

Chemicals
References

1-(4-[18F]Fluorobenzyl)-4-[(tetrahydrofuran-2-yl)methyl]piperazine: A Novel Suitable Radioligand with Low Lipophilicity for Imaging σ1 Receptors in the Brain

Co-reporter:Yingfang He, Fang Xie, Jiajun Ye, Winnie Deuther-Conrad, Bixiao Cui, Liang Wang, Jie Lu, Jörg Steinbach, Peter Brust, Yiyun Huang, Jie Lu, and Hongmei Jia

Journal of Medicinal Chemistry May 25, 2017 Volume 60(Issue 10) pp:4161-4161

Publication Date(Web):April 14, 2017

DOI:10.1021/acs.jmedchem.6b01723

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.

18F-Labeled indole-based analogs as highly selective radioligands for imaging sigma-2 receptors in the brain

Co-reporter:Liang Wang, Jiajun Ye, Yingfang He, Winnie Deuther-Conrad, Jinming Zhang, Xiaojun Zhang, Mengchao Cui, Jörg Steinbach, Yiyun Huang, Peter Brust, Hongmei Jia

Bioorganic & Medicinal Chemistry 2017 Volume 25, Issue 14(Issue 14) pp:

Publication Date(Web):15 July 2017

DOI:10.1016/j.bmc.2017.05.019

We have designed and synthesized a series of indole-based σ2 receptor ligands containing 5,6-dimethoxyisoindoline or 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline as pharmacophore. In vitro competition binding assays showed that all ten ligands possessed low nanomolar affinity (Ki = 1.79–5.23 nM) for σ2 receptors and high subtype selectivity (Ki (σ2)/Ki (σ1) = 56–708). Moreover, they showed high selectivity for σ2 receptor over the vesicular acetylcholine transporter (>1000-fold). The corresponding radiotracers [18F]16 and [18F]21 were prepared by an efficient one-pot, two-step reaction sequence with a home-made automated synthesis module, with 10–15% radiochemical yield and radiochemical purity of >99%. Both radiotracers showed high brain uptake and σ2 receptor binding specificity in mice.Download high-res image (42KB)Download full-size image

Synthesis and evaluation of a 18F-labeled 4-phenylpiperidine-4-carbonitrile radioligand for 1 receptor imaging

Co-reporter:Jiajun Ye;Xia Wang;Winnie Deuther-Conrad;Jinming Zhang;Jianzhou Li;Xiaojun Zhang;Liang Wang;Jörg Steinbach;Peter Brust;Hongmei Jia

Journal of Labelled Compounds and Radiopharmaceuticals 2016 Volume 59( Issue 9) pp:332-339

Publication Date(Web):

DOI:10.1002/jlcr.3408

We report the design and synthesis of several 4-phenylpiperidine-4-carbonitrile derivatives as σ₁ receptor ligands. In vitro radioligand competition binding assays showed that all the ligands exhibited low nanomolar affinity for σ₁ receptors (K_i(σ₁) = 1.22–2.14 nM) and extremely high subtype selectivity (K_i(σ₂) = 830–1710 nM; K_i(σ₂)/K_i(σ₁) = 680–887). [¹⁸F]9 was prepared in 42–46% isolated radiochemical yield, with a radiochemical purity of >99% by HPLC analysis after purification, via nucleophilic ¹⁸F^- substitution of the corresponding tosylate precursor. Biodistribution studies in mice demonstrated high initial brain uptakes and high brain-to-blood ratios. Administration of SA4503 or haloperidol 5 min prior to injection of [¹⁸F]9 significantly reduced the accumulation of radiotracers in organs known to contain σ₁ receptors. Two radioactive metabolites were observed in the brain at 30 min after radiotracer injection. [¹⁸F]9 may serve as a lead compound to develop suitable radiotracers for σ₁ receptor imaging with positron emission tomography.

18F-Labeled 1,4-Dioxa-8-azaspiro[4.5]decane Derivative: Synthesis and Biological Evaluation of a σ1 Receptor Radioligand with Low Lipophilicity as Potent Tumor Imaging Agent

Co-reporter:Fang Xie; Ralf Bergmann; Torsten Kniess; Winnie Deuther-Conrad; Constantin Mamat; Christin Neuber; Boli Liu; Jörg Steinbach; Peter Brust; Jens Pietzsch;Hongmei Jia

Journal of Medicinal Chemistry 2015 Volume 58(Issue 14) pp:5395-5407

Publication Date(Web):June 19, 2015

DOI:10.1021/acs.jmedchem.5b00593

We report the syntheses and evaluation of series of novel piperidine compounds with low lipophilicity as σ1 receptor ligands. 8-(4-(2-Fluoroethoxy)benzyl)-1,4-dioxa-8-azaspiro[4.5]decane (5a) possessed high affinity (Ki = 5.4 ± 0.4 nM) for σ1 receptors and selectivity for σ2 receptors (30-fold) and the vesicular acetylcholine transporter (1404-fold). [18F]5a was prepared using a one-pot, two-step labeling procedure in an automated synthesis module, with a radiochemical purity of >95%, and a specific activity of 25–45 GBq/μmol. Cellular association, biodistribution, and autoradiography with blocking experiments indicated specific binding of [18F]5a to σ1 receptors in vitro and in vivo. Small animal positron emission tomography (PET) imaging using mouse tumor xenograft models demonstrated a high accumulation in human carcinoma and melanoma. Treatment with haloperidol significantly reduced the accumulation of the radiotracer in tumors. These findings suggest that radiotracer with suitable lipophilicity and appropriate affinity for σ1 receptors could be used for tumor imaging.

Novel indole-based sigma-2 receptor ligands: synthesis, structure–affinity relationship and antiproliferative activity

Co-reporter:Fang Xie, Torsten Kniess, Christin Neuber, Winnie Deuther-Conrad, Constantin Mamat, Brian P. Lieberman, Boli Liu, Robert H. Mach, Peter Brust, Jörg Steinbach, Jens Pietzsch and Hongmei Jia

MedChemComm 2015 vol. 6(Issue 6) pp:1093-1103

Publication Date(Web):20 Apr 2015

DOI:10.1039/C5MD00079C

We report the synthesis and biological evaluation of a series of indole-based σ2 receptor ligands derived from siramesine. In vitro competition binding assays showed that these analogues possessed high to moderate affinity and selectivity for σ2 receptors. Structure–affinity relationship analyses of these indole-based σ2 receptor ligands were performed. In the 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, 1a and 1b displayed significant and comparable antiproliferative activity in DU145, MCF7 and C6 cells to siramesine. In cell cycle analyses, compounds 1a, 1b and siramesine were found to induce a G1 phase cell cycle arrest in DU145 cells using flow cytometry. The combination of 5,6-dimethoxyisoindoline scaffold and N-(4-fluorophenyl)indole moiety was identified as a new σ2 receptor ligand deserving further investigation as an antitumor agent.

Novel Cyclopentadienyl Tricarbonyl 99mTc Complexes Containing 1-Piperonylpiperazine Moiety: Potential Imaging Probes for Sigma-1 Receptors

Co-reporter:Xia Wang ; Dan Li ; Winnie Deuther-Conrad ; Jie Lu ; Ying Xie ; Bing Jia ; Mengchao Cui ; Jörg Steinbach ; Peter Brust ; Boli Liu ;Hongmei Jia

Journal of Medicinal Chemistry 2014 Volume 57(Issue 16) pp:7113-7125

Publication Date(Web):July 29, 2014

DOI:10.1021/jm5009488

We report the design, synthesis, and evaluation of a series of novel cyclopentadienyl tricarbonyl 99mTc complexes as potent σ1 receptor radioligands. Rhenium compounds 3-(4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl)propylcarbonylcyclopentadienyl tricarbonyl rhenium (10a) and 4-(4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl)butylcarbonylcyclopentadienyl tricarbonyl rhenium (10b) possessed high in vitro affinity for σ1 receptors and moderate to high selectivity for σ2 receptors and the vesicular acetylcholine transporter. Biodistribution studies in mice demonstrated high initial brain uptake for corresponding 99mTc derivatives [99mTc]23 and [99mTc]24 of 2.94 and 2.13% injected dose (ID)/g, respectively, at 2 min postinjection. Pretreatment of haloperidol significantly reduced the radiotracer accumulation of [99mTc]23 or [99mTc]24 in the brain. Studies of the cellular uptake of [99mTc]23 in C6 and DU145 tumor cells demonstrated a reduction of accumulation by incubation with haloperidol, 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine (SA4503), or 1,3-di-o-tolyl-guanidine (DTG). Furthermore, blocking studies in C6 glioma-bearing mice confirmed the specific binding of [99mTc]23 to σ1 receptors in the tumor.

Synthesis and evaluation of a 18F-labeled spirocyclic piperidine derivative as promising σ1 receptor imaging agent

Co-reporter:Yuan-Yuan Chen, Xia Wang, Jin-Ming Zhang, Winnie Deuther-Conrad, Xiao-Jun Zhang, Yiyun Huang, Yan Li, Jia-Jun Ye, Meng-Chao Cui, Jörg Steinbach, Peter Brust, Bo-Li Liu, Hong-Mei Jia

Bioorganic & Medicinal Chemistry 2014 22(19) pp: 5270-5278

Publication Date(Web):

DOI:10.1016/j.bmc.2014.08.003

Synthesis and biological evaluation of 18F labeled fluoro-oligo-ethoxylated 4-benzylpiperazine derivatives for sigma-1 receptor imaging

Co-reporter:Xia Wang, Yan Li, Winnie Deuther-Conrad, Fang Xie, Xin Chen, Meng-Chao Cui, Xiao-Jun Zhang, Jin-Ming Zhang, Jörg Steinbach, Peter Brust, Bo-Li Liu, Hong-Mei Jia

Bioorganic & Medicinal Chemistry 2013 Volume 21(Issue 1) pp:215-222

Publication Date(Web):1 January 2013

DOI:10.1016/j.bmc.2012.10.038

We report the synthesis and evaluation of a series of fluoro-oligo-ethoxylated 4-benzylpiperazine derivatives as potential σ1 receptor ligands. In vitro competition binding assays showed that 1-(1,3-benzodioxol-5-ylmethyl)-4-(4-(2-fluoroethoxy)benzyl)piperazine (6) exhibits low nanomolar affinity for σ1 receptors (Ki = 1.85 ± 1.59 nM) and high subtype selectivity (σ2 receptor: Ki = 291 ± 111 nM; Kiσ2/Kiσ1 = 157). [18F]6 was prepared in 30–50% isolated radiochemical yield, with radiochemical purity of >99% by HPLC analysis after purification, via nucleophilic 18F− substitution of the corresponding tosylate precursor. The log DpH 7.4 value of [18F]6 was found to be 2.57 ± 0.10, which is within the range expected to give high brain uptake. Biodistribution studies in mice demonstrated relatively high concentration of radiotracers in organs known to contain σ1 receptors, including the brain, lungs, kidneys, heart, and spleen. Administration of haloperidol 5 min prior to injection of [18F]6 significantly reduced the concentration of radiotracers in the above-mentioned organs. The accumulation of radiotracers in the bone was quite low suggesting that [18F]6 is relatively stable to in vivo defluorination. The ex vivo autoradiography in rat brain showed high accumulation of radiotracers in the brain areas known to possess high expression of σ1 receptors. These findings suggest that [18F]6 is a suitable radiotracer for imaging σ1 receptors with PET in vivo.

Synthesis and Evaluation of Novel 18F-Labeled Spirocyclic Piperidine Derivatives as σ1 Receptor Ligands for Positron Emission Tomography Imaging

Co-reporter:Yan Li, Xia Wang, Jinming Zhang, Winnie Deuther-Conrad, Fang Xie, Xiaojun Zhang, Jian Liu, Jinping Qiao, Mengchao Cui, Jörg Steinbach, Peter Brust, Boli Liu, and Hongmei Jia

Journal of Medicinal Chemistry 2013 Volume 56(Issue 9) pp:3478-3491

Publication Date(Web):April 8, 2013

DOI:10.1021/jm301734g

A series of spirocyclic piperidine derivatives were designed and synthesized as σ1 receptor ligands. In vitro competition binding assays showed that 1′-(4-(2-fluoroethoxy)benzyl)-3H-spiro[2-benzofuran-1,4′-piperidine] (19) possessed high σ1 receptor affinity (Ki = 0.79 nM) and excellent σ1/σ2 subtype selectivity (350-fold) as well as high σ1/VAChT selectivity (799-fold). The radiolabeled compound [18F]19 was synthesized by substitution of the tosylate precursor 24 with [18F]fluoride, with an isolated radiochemical yield of 35–60%, a radiochemical purity of >99%, and a specific activity of 30–55 GBq/μmol. Biodistribution studies in imprinting control region mice indicated that [18F]19 displayed excellent initial brain uptake and slow washout. Ex vivo autoradiography in Sprague–Dawley rats demonstrated high accumulation of the radiotracer in brain areas known to express high levels of σ1 receptors. Micro positron emission tomography imaging and blocking studies confirmed the specific binding of [18F]19 to σ1 receptors in vivo.

Synthesis and biological evaluation of a novel 99mTc cyclopentadienyl tricarbonyl complex ([(Cp-R)99mTc(CO)3]) for sigma-2 receptor tumor imaging

Co-reporter:Xin Chen, Meng-Chao Cui, Winnie Deuther-Conrad, Ying-Feng Tu, Teng Ma, Ying Xie, Bing Jia, Yan Li, Fang Xie, Xia Wang, Jörg Steinbach, Peter Brust, Bo-Li Liu, Hong-Mei Jia

Bioorganic & Medicinal Chemistry Letters 2012 Volume 22(Issue 20) pp:6352-6357

Publication Date(Web):15 October 2012

DOI:10.1016/j.bmcl.2012.08.083

We report the design, synthesis and biological evaluation of a novel 99mTc 4-(4-cyclohexylpiperazine-1-yl)-butan-1-one-1-cyclopentadienyltricarbonyl technetium ([99mTc]5) as a potential SPECT tracer for imaging of σ2 receptors in tumors. [99mTc]5 was prepared in 25 ± 5% isolated radiochemical yield with radiochemical purity of >99% via double-ligand transfer (DLT) reaction from the ferrocene precursor 2b (4-(4-cyclohexylpiperazine-1-yl)-1-ferrocenylbutan-1-one). The corresponding Re-complex 4 and the ferrocenyl complex 2b showed relatively high affinity towards σ2 receptors in in vitro competition binding assay (Ki values of 4 and 2b were 64.4 ± 18.5 nM and 43.6 ± 21.3 nM, respectively) and moderate to high selectivity versus σ1 receptors (Kiσ1/Kiσ2 ratios were 12.5 and 95.5, respectively). The log D value of [99mTc]5 was determined to be 2.52 ± 0.33. Biodistribution studies in mice revealed comparably high initial brain uptake of [99mTc]5 and slow washout. Administration of haloperidol 5 min prior to injection of [99mTc]5 significantly reduced the radiotracer uptake in brain, heart, lung, and spleen by 40–50% at 2 h p.i.. Moreover, [99mTc]5 showed high uptake in C6 glioma cell lines (8.6%) after incubation for 1 h. Blocking with haloperidol to compete with [99mTc]5 significantly reduced the cell uptake. Preliminary blocking study in C6-brain-tumor bearing rats showed that [99mTc]5 binds to σ receptors in the brain-tumor specifically. These results are encouraging for further exploration of 99mTc-labeled probes for σ2 receptor tumor imaging in vivo.

Novel (E)-5-styryl-2,2′-bithiophene derivatives as ligands for β-amyloid plaques

Co-reporter:Mengchao Cui, Zijing Li, Ruikun Tang, Hongmei Jia, Boli Liu

European Journal of Medicinal Chemistry 2011 Volume 46(Issue 7) pp:2908-2916

Publication Date(Web):July 2011

DOI:10.1016/j.ejmech.2011.04.015

In continuation of our investigation on the bithiophene structure as potential β-amyloid probes, a series of (E)-5-styryl-2,2′-bithiophene (SBTP) derivatives was designed and synthesized. In vitro binding showed that all of them displayed high binding affinities to Aβ1–42 aggregates (Ki = 0.10–41.05 nM). Moreover, two radio-iodinated probes, [125I]-(E)-5-(4-iodostyryl)-2,2′-bithiophene ([125I]8) and [125I]-(E)-5-iodo-5′-(4-methoxystyryl)-2,2′-bithiophene ([125I]31) were prepared. Both of them displayed specific labeling of Aβ plaques in the brain sections of AD model mice with low background. In vivo biodistribution in normal mice indicated that [125I]8 exhibited high initial brain uptake (2.11% ID/g at 2 min) and rapid clearance (0.41% ID/g at 30 min). These preliminary results suggest that SBTP derivatives may be served as novel β-amyloid imaging probes.Highlights► (E)-5-styryl-2,2′-bithiophene derivatives showed high affinity to Aβ aggregates. ► High tolerance for steric bulk at para position of the phenyl ring was found. ► 125I labeled probes showed excellent plaque labeling in the brain of AD model mice. ► One of the tracers showed high uptake and fast washout from the normal mice brain.

Synthesis and biological evaluation of novel 4-benzylpiperazine ligands for sigma-1 receptor imaging

Co-reporter:Zi-Jing Li, Hui-Ying Ren, Meng-Chao Cui, Winnie Deuther-Conrad, Rui-Kun Tang, Jörg Steinbach, Peter Brust, Bo-Li Liu, Hong-Mei Jia

Bioorganic & Medicinal Chemistry 2011 Volume 19(Issue 9) pp:2911-2917

Publication Date(Web):1 May 2011

DOI:10.1016/j.bmc.2011.03.037

We report the synthesis and evaluation of 4-benzylpiperazine ligands (BP-CH3, BP-F, BP-Br, BP-I, and BP-NO2) as potential σ1 receptor ligands. The X-ray crystal structure of BP-Br, which crystallized with monoclinic space group P21/c, has been determined. In vitro competition binding assays showed that all the five ligands exhibit low nanomolar affinity for σ1 receptors (Ki = 0.43–0.91 nM) and high subtype selectivity (σ2 receptor: Ki = 40–61 nM; Kiσ2/Kiσ1 = 52–94). [125I]BP-I (1-(1,3-benzodioxol-5-ylmethyl)-4-(4-iodobenzyl)piperazine) was prepared in 53 ± 10% isolated radiochemical yield, with radiochemical purity of >99% by HPLC analysis after purification, via iododestannylation of the corresponding tributyltin precursor. The log D value of [125I]BP-I was found to be 2.98 ± 0.17, which is within the range expected to give high brain uptake. Biodistribution studies in mice demonstrated relatively high concentration of radiolabeled substances in organs known to contain σ1 receptors, including the brain, lung, kidney, heart, and spleen. Administration of haloperidol 5 min prior to injection of [125I]BP-I significantly reduced the concentration of radioactivity in the above-mentioned organs. The accumulation of radiolabeled substance in the thyroid was quite low suggesting that [125I]BP-I is relatively stable to in vivo deiodination. These findings suggest that the binding of [125I]BP-I to σ1 receptors in vivo is specific.

Synthesis and biological evaluation of a radioiodinated spiropiperidine ligand as a potential 1 receptor imaging agent

Co-reporter:Rui-Qin Chen;Yan Li;Qiu-Yan Zhang;Winnie Deuther-Conrad;Dirk Schepmann;Jörg Steinbach;Peter Brust;Bernhard Wünsch;Bo-Li Liu

Journal of Labelled Compounds and Radiopharmaceuticals 2010 Volume 53( Issue 9) pp:569-574

Publication Date(Web):

DOI:10.1002/jlcr.1777

Abstract

We report the synthesis and evaluation of 1′-(4-[¹²⁵I]iodobenzyl)-3H-spiro[isobenzofuran-1,4′-piperidine] ([¹²⁵I]Spiro-I) as a potential SPECT tracer for imaging of σ₁ receptors. [¹²⁵I]Spiro-I was prepared in 55–65% isolated radiochemical yield, with radiochemical purity of >99%, via iododestannylation of the corresponding tributyltin precursor. In receptor binding studies, Spiro-I displayed low nanomolar affinity for σ₁ receptors (σ₁: K_i=2.75±0.12 nM; σ₂: K_i=340 nM) and high subtype selectivity (σ₂/σ₁=124). Biodistribution in mice demonstrated relatively high concentration of radioactivity in organs known to contain σ₁ receptors, including the lung, kidney, heart, spleen, and brain. Administration of haloperidol 5 min prior to injection of [¹²⁵I]Spiro-I significantly reduced the concentration of radioactivity in the above-mentioned organs. These findings suggest that the binding of [¹²⁵I]Spiro-I to σ₁ receptors in vivo is specific. Copyright © 2010 John Wiley & Sons, Ltd.

99mTc-Cyclopentadienyl Tricarbonyl Chelate-Labeled Compounds as Selective Sigma-2 Receptor Ligands for Tumor Imaging

Co-reporter:Dan Li; Yuanyuan Chen; Xia Wang; Winnie Deuther-Conrad; Xin Chen; Bing Jia; Chengyan Dong; Jörg Steinbach; Peter Brust; Boli Liu;Hongmei Jia

Journal of Medicinal Chemistry () pp:

Publication Date(Web):January 7, 2016

DOI:10.1021/acs.jmedchem.5b01378

We have designed and synthesized a series of cyclopentadienyl tricarbonyl rhenium complexes containing a 5,6-dimethoxyisoindoline or a 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline pharmacophore as σ2 receptor ligands. Rhenium compound 20a possessed low nanomolar σ2 receptor affinity (Ki = 2.97 nM) and moderate subtype selectivity (10-fold). Moreover, it showed high selectivity toward vesicular acetylcholine transporter (2374-fold), dopamine D2L receptor, NMDA receptor, opiate receptor, dopamine transporter, norepinephrine transporter, and serotonin transporter. Its corresponding radiotracer [99mTc]20b showed high uptake in a time- and dose-dependent manner in DU145 prostate cells and C6 glioma cells. In addition, this tracer exhibited high tumor uptake (5.92% ID/g at 240 min) and high tumor/blood and tumor/muscle ratios (21 and 16 at 240 min, respectively) as well as specific binding to σ receptors in nude mice bearing C6 glioma xenografts. Small animal SPECT/CT imaging of [99mTc]20b in the C6 glioma xenograft model demonstrated a clear visualization of the tumor at 180 min after injection.