Browsing by Author "Wang, Min"

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    A carbon-11 labeled imidazo[1,2- a]pyridine derivative as a new potential PET probe targeting PI3K/mTOR in cancer
    (e-Century Publishing, 2023-06-25) Liu, Wenqing; Ma, Wenjie; Wang, Min; Wang, Zhuangzhuang; Grega, Shaun D.; Zheng, Qi-Huang; Xu, Zhidong; Radiology and Imaging Sciences, School of Medicine
    The PI3K/Akt/mTOR pathway is frequently dysregulated in cancer due to its central role in cell growth, survival, and proliferation. Overactivation of the PI3K/Akt/mTOR pathway may occur through varying mechanisms including mutations, gene amplification, and upstream signaling events, ultimately resulting in cancer. Therefore, PI3K/Akt/mTOR pathway has emerged as an attractive target for cancer therapy and imaging. A promising approach to inhibit this pathway involves a simultaneous inhibition of both PI3K and mTOR using a dual inhibitor. Recently, a potent dual PI3K/mTOR inhibitor, 2,4-difluoro-N-(2-methoxy-5-(3-(5-(2-(4-methylpiperazin-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-6-yl)pyridin-3-yl)benzenesulfonamide (7), was discovered and demonstrated excellent kinase selectivity IC50 (PI3K/mTOR) = 0.20/21 nM; good cellular growth inhibition IC50 (HCT-116 cell) = 10 nM, modest plasma clearance, and acceptable oral bioavailability. Expanding on this discovery, here we present the synthesis of the carbon-11 labeled imidazo[1,2-a]pyridine derivative 2,4-difluoro-N-(2-methoxy-5-(3-(5-(2-(4-[11C]methylpiperazin-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-6-yl)pyridin-3-yl)benzenesulfonamide (N-[11C]7) as a new potential radiotracer for the biomedical imaging technique positron emission tomography (PET) imaging of PI3K/mTOR in cancer. The reference standard 7 and its N-demethylated precursor, 2,4-difluoro-N-(2-methoxy-5-(3-(5-(2-(piperazin-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-6-yl)pyridin-3-yl)benzenesulfonamide (11), were synthesized in 7 and 8 steps with 10% and 7% overall chemical yield, respectively. N-[11C]7 was prepared from 11 using [11C]methyl triflate ([11C]CH3OTf) through N-11C-methylation and isolated by high-performance liquid chromatography (HPLC) and solid-phase extraction (SPE) formulation in 40-50% radiochemical yield decay corrected to end of bombardment (EOB) based on [11C]CO2. The radiochemical purity was > 99% and the molar activity (Am) at EOB was in the range of 296-555 GBq/µmol (n = 5).
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    Characterization of 11C-GSK1482160 for Targeting the P2X7 Receptor as a Biomarker for Neuroinflammation
    (SNMMI, 2017-03) Territo, Paul R.; Meyer, Jill A.; Peters, Jonathan S.; Riley, Amanda A.; McCarthy, Brian P.; Gao, Mingzhang; Wang, Min; Green, Mark A.; Zheng, Qi-Huang; Hutchins, Gary D.; Radiology and Imaging Sciences, School of Medicine
    The purinergic receptor subtype 7 (P2X7R) represents a novel molecular target for imaging neuroinflammation via PET. GSK1482160, a potent P2X7R antagonist, has high receptor affinity, high blood–brain barrier penetration, and the ability to be radiolabeled with 11C. We report the initial physical and biologic characterization of this novel ligand. Methods: 11C-GSK1482160 was synthesized according to published methods. Cell density studies were performed on human embryonic kidney cell lines expressing human P2X7R (HEK293-hP2X7R) and underwent Western blotting, an immunofluorescence assay, and radioimmunohistochemistry analysis using P2X7R polyclonal antibodies. Receptor density and binding potential were determined by saturation and association–disassociation kinetics, respectively. Peak immune response to lipopolysaccharide treatment in mice was determined in time course studies and analyzed via Iba1 and P2X7R Western blotting and Iba1 immunohistochemistry. Whole-animal biodistribution studies were performed on saline- or lipopolysaccharide-treated mice at 15, 30, and 60 min after radiotracer administration. Dynamic in vivo PET/CT was performed on the mice at 72 h after administration of saline, lipopolysaccharide, or lipopolysaccharide + blocking, and 2-compartment, 5-parameter tracer kinetic modeling of brain regions was performed. Results: P2X7R changed linearly with concentrations or cell numbers. For high-specific-activity 11C-GSK1482160, receptor density and Kd were 1.15 ± 0.12 nM and 3.03 ± 0.10 pmol/mg, respectively, in HEK293-hP2X7R membranes. Association constant kon, dissociation constant koff, and binding potential (kon/koff) in HEK293-hP2X7R cells were 0.2312 ± 0.01542 min−1⋅nM−1, 0.2547 ± 0.0155 min−1, and 1.0277 ± 0.207, respectively. Whole-brain Iba1 expression in lipopolysaccharide-treated mice peaked by 72 h on immunohistochemistry, and Western blot analysis of P2X7R for saline- and lipopolysaccharide-treated brain sections showed a respective 1.8- and 1.7-fold increase in signal enhancement at 72 h. Biodistribution of 11C-GSK1482160 in saline- and lipopolysaccharide-treated mice at 72 h was statistically significant across all tissues studied. In vivo dynamic 11C-GSK1482160 PET/CT of mice at 72 h after administration of saline, lipopolysaccharide, or lipopolysaccharide + blocking showed a 3.2-fold increase and 97% blocking by 30 min. The total distribution volumes for multiple cortical regions and the hippocampus showed statistically significant increases and were blocked by an excess of authentic standard GSK1482160. Conclusion: The current study provides compelling data that support the suitability of 11C-GSK1482160 as a radioligand targeting P2X7R, a biomarker of neuroinflammation.
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    Development, validation and implementation of radio-HPLC methods for the P2X7-receptor-targeted [11C]GSK1482160 radiopharmaceutical
    (Elsevier, 2018-12) Wissman, Carmen L.; Wang, Min; Gao, Mingzhang; Zheng, Qi-Huang; Green, Mark A.; Radiology and Imaging Sciences, School of Medicine
    A radio-analytical RP-HPLC method was developed and validated to support production of the P2X7-receptor-targeted [11C]GSK1482160 radiopharmaceutical. Method validation included characterization of retention times, peak shapes, linearity, accuracy, precision, selectivity, limits of detection and quantitation (UV signal), radiochemical stability, as well as analytical method range and robustness. The validated radio-HPLC method is suitable for the definition of [11C]GSK1482160 radiochemical identity, radiochemical purity, as well as molar activity, and is being employed in support of human studies with [11C]GSK1482160.
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    Facile synthesis of carbon-11-labeled sEH/PDE4 dual inhibitors as new potential PET agents for imaging of sEH/PDE4 enzymes in neuroinflammation
    (Elsevier, 2019-07) Jia, Limeng; Miao, Caihong; Dong, Fugui; Li, Wei; Wang, Min; Zheng, Qi-Huang; Xu, Zhidong; Radiology and Imaging Sciences, School of Medicine
    To develop PET tracers for imaging of neuroinflammation, new carbon-11-labeled sEH/PDE4 dual inhibitors have been synthesized. The reference standard N-(4-methoxy-2-(trifluoromethyl)benzyl)benzamide (1) and its corresponding desmethylated precursor N-(4-hydroxy-2-(trifluoromethyl)benzyl)benzamide (2) were synthesized from (4-methoxy-2-(trifluoromethyl)phenyl)methanamine and benzoic acid in one and two steps with 84% and 49% overall chemical yield, respectively. The standard N-(4-methoxy-2-(trifluoromethyl)benzyl)-1-propionylpiperidine-4-carboxamide (MPPA, 4) and its precursor N-(4-hydroxy-2-(trifluoromethyl)benzyl)-1-propionylpiperidine-4-carboxamide (5) were synthesized from methyl 4-piperidinecarboxylate, propionyl chloride and (4-methoxy-2-(trifluoromethyl)phenyl)methanamine in two and three steps with 62% and 34% overall chemical yield, respectively. The target tracers N-(4-[11C]methoxy-2-(trifluoromethyl)benzyl)benzamide ([11C]1) and N-(4-[11C]methoxy-2-(trifluoromethyl)benzyl)-1-propionylpiperidine-4-carboxamide ([11C]MPPA, [11C]4) were prepared from their corresponding precursors 2 and 5 with [11C]CH3OTf through O-[11C]methylation and isolated by HPLC combined with SPE in 25–35% radiochemical yield, based on [11C]CO2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the molar activity (AM) at EOB was 370–740 GBq/μmol with a total synthesis time of 35–40-minutes from EOB.
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    Fully automated synthesis of [18F]T807, a PET tau tracer for Alzheimer’s disease
    (Elsevier, 2015-08) Gao, Mingzhang; Wang, Min; Zheng, Qi-Huang; Department of Radiology and Imaging Sciences, School of Medicine
    The authentic standard T807 and its nitro-precursor T807P as well as t-Boc-protected T807P precursor for radiolabeling were synthesized from (4-bromophenyl)boronic acid, 3-bromo-4-nitropyridine and 3-bromo-6-nitropyridine with overall chemical yield 27% in three steps, 4–7% in three to five steps, and 3–8% in four to five steps, respectively. [18F]T807 was synthesized from T807P by the nucleophilic [18F]fluorination with K[18F]F/Kryptofix 2.2.2 in DMSO at 140 °C followed by reduction with Fe powder/HCOOH through manual synthesis with 5–10% decay corrected radiochemical yield in two steps. [18F]T807 was also synthesized from t-Boc-protected T807P by a concurrent [18F]fluorination and deprotection with K[18F]F/Kryptofix 2.2.2 in DMSO at 140 °C and purified by HPLC-SPE method in a home-built automated [18F]radiosynthesis module with 20–30% decay corrected radiochemical yield in one step. The specific activity of [18F]T807 at end of bombardment (EOB) was 37–370 GBq/μmol.
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    Monitoring of water surface temperature of Eurasian large lakes using MODIS land surface temperature product
    (Wiley, 2020-07) Du, Jia; Jacinthe, Pierre-Andre; Zhou, Haohao; Xiang, Xiaoyun; Zhao, Boyu; Wang, Min; Song, Kaishan; Earth Sciences, School of Science
    In this study, data from MODIS land surface temperature product level 3 (MOD11A2) were used to investigate the spatiotemporal variation of Eurasian lakes water surface temperature (LSWT) from 2001 to 2015, and to examine the most influencing factors of that variation. The temperature of most lakes in the dry climate zone and in the equatorial climatic zone varied from 17 to 31°C and from 23 to 27°C, respectively. LSWTs in the warm temperate and cold climatic zones were in the range of 20 to 27°C and −0.6 and 17°C, respectively. The average day time LSWT in the polar climate zone was −0.71°C in the summer. Lakes in high latitude and in the Tibetan Plateau displayed low LSWT, ranging from −11 to 26°C during the night time. Large spatial variations of diurnal temperature difference (DTD) were observed in lakes across Eurasia. However, variations in DTDs were small in lakes located in high latitude and in tropical rainforest regions. The shallow lakes showed a rapid response of LSWT to solar and atmospheric forcing, while in the large and deep lakes, that response was sluggish. Results of this study demonstrated the applicability of remote sensing and MODIS LST products to capture the spatial–temporal variability of LSWT across continental scales, in particular for the vast wilderness areas and protected environment in high latitude regions of the world. The approach can be used in future studies examining processes and factors controlling large scale variability of LSWT.
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    Radiosynthesis of a carbon-11 labeled tetrahydrobenzisoxazole derivative as a new PET probe for γ-secretase imaging in Alzheimer's disease
    (Elsevier, 2020-01) Xu, Zhidong; Miao, Caihong; Dong, Fugui; Jia, Limeng; Li, Wei; Wang, Min; Liu, Wenqing; Zheng, Qi-Huang; Radiology and Imaging Sciences, School of Medicine
    To develop PET radiotracers for imaging of Alzheimer's disease, a new carbon-11 labeled potent and selective γ-secretase modulator (GSM) has been synthesized. The reference standard tetrahydrobenzisoxazole derivative 8 and its desmethylated precursor 9 were synthesized from cyclohex-2-en-1-one and 3-hydroxy-4-nitrobenzaldehyde in eight and nine steps with 11% and 5% overall chemical yield, respectively. The radiotracer [11C]8 was prepared from its corresponding precursor 9 with [11C]CH3OTf through O–11C-methylation and isolated by RP-HPLC combined with SPE in 45–50% radiochemical yield, based on [11C]CO2 and decay corrected to EOB. The radiochemical purity was >99%, and the molar activity (Am) at EOB was 555–740 GBq/μmol.
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    Radiosynthesis of a carbon-11-labeled AMPAR allosteric modulator as a new PET radioligand candidate for imaging of Alzheimer’s disease
    (Elsevier, 2019-05) Miao, Caihong; Dong, Fugui; Jia, Limeng; Li, Wei; Wang, Min; Zheng, Qi-Huang; Xu, Zhidong; Radiology and Imaging Sciences, School of Medicine
    To develop PET tracers for imaging of Alzheimer’s disease, a new carbon-11-labeled AMPAR allosteric modulator 4-cyclopropyl-7-(3-[11C]methoxyphenoxy)-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide ([11C]8) has been synthesized. The reference standard 4-cyclopropyl-7-(3-methoxyphenoxy)-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (8) and its corresponding desmethylated precursor 4-cyclopropyl-7-(3-hydroxyphenoxy)-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (9) were synthesized from 4-methoxyabiline and chlorosulfonyl isocyanate in eight and nine steps with 3% and 1% overall chemical yield, respectively. The target tracer [11C]8 was prepared from the precursor 9 with [11C]CH3OTf through O-[11C]methylation and isolated by HPLC combined with SPE in 10–15% radiochemical yield, based on [11C]CO2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the molar activity (AM) at EOB was 370–740 GBq/μmol with a total synthesis time of 35–40-minutes from EOB.
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    Radiosynthesis of carbon-11 labeled PDE5 inhibitors as new potential PET radiotracers for imaging of Alzheimer's disease
    (Elsevier, 2019-12) Dong, Fugui; Du, Jie; Miao, Caihong; Jia, Limeng; Li, Wei; Wang, Min; Zheng, Qi-Huang; Xu, Zhidong; Radiology and Imaging Sciences, School of Medicine
    To develop PET tracers for imaging of Alzheimer's disease, new carbon-11 labeled potent and selective PDE5 inhibitors have been synthesized. The reference standards (5) and (12), and their corresponding desmethylated precursors (6) and (13) were synthesized from methyl 2-amino-5-bromobenzoate and (4-methoxyphenyl)methanamine in multiple steps with 2%, 1%, 1% and 0.2% overall chemical yield, respectively. The radiotracers ([11C]5) and ([11C]12) were prepared from their corresponding precursors 6 and 13 with [11C]CH3OTf through O–11C-methylation and isolated by HPLC combined with SPE in 40–50% radiochemical yield, based on [11C]CO2 and decay corrected to EOB. The radiochemical purity was >99%, and the molar activity (Am) at EOB was in a range of 370–740 GBq/μmol.
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    Synthesis and in vitro biological evaluation of new P2X7R radioligands [11C]halo-GSK1482160 analogs
    (Elsevier, 2019-06) Gao, Mingzhang; Wang, Min; Meyer, Jill A.; Territo, Paul R.; Hutchins, Gary D.; Zarrinmayeh, Hamideh; Zheng, Qi-Huang; Radiology and Imaging Sciences, School of Medicine
    The reference standards halo-GSK1482160 (F-, Br-, and I-) and their corresponding precursors desmethyl-halo-GSK1482160 (F-, Br-, and I-) were synthesized from (S)-1-methyl-5-oxopyrrolidine-2-carboxylic acid or (S)-5-oxopyrrolidine-2-carboxylic acid and 2-halo-3-(trifluoromethyl)benzylamine (F-, Br-, and I-) in one step with 45–93% yields. The target tracers [11C]halo-GSK1482160 (F-, Br-, and I-) were prepared from desmethyl-halo-GSK1482160 (F-, Br-, and I-) with [11C]CH3OTf under basic conditions (NaOH-Na2CO3, solid, w/w 1:2) through N-[11C]methylation and isolated by HPLC combined with SPE in 40–50% decay corrected radiochemical yield. The radiochemical purity was >99%, and the molar activity (AM) at end of bombardment (EOB) was 370–740 GBq/μmol. The potency of halo-GSK1482160 (F-, Br-, and I-) in comparison with GSK1482160 (Cl-) was determined by a radioligand competitive binding assay using [11C]GSK1482160, and the binding affinity Ki values for halo-GSK1482160 (F-, Br-, and I-) and GSK1482160 (Cl-) are 54.2, 2.5, 1.9 and 3.1 nM, respectively.