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Qi Huang Zheng - One of the best experts on this subject based on the ideXlab platform.
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synthesis of new Carbon 11 labeled benzoxazole derivatives for pet imaging of 5 ht3 receptor
European Journal of Medicinal Chemistry, 2008Co-Authors: Min Wang, Gary D Hutchins, Qi Huang ZhengAbstract:Abstract 5-HT3 receptor is an attractive target for the development of therapeutic agents for use in brain, heart and cancer diseases, and imaging agents for use in biomedical imaging technique PET. Benzoxazole derivatives are a novel class of 5-HT3 receptor partial agonists with high binding affinity. Carbon-11 labeled benzoxazole derivatives have been synthesized as new potential PET radioligands for imaging 5-HT3 receptor. The target tracers were prepared by N-[11C]methylation of their corresponding precursors using [11C]CH3OTf and isolated by HPLC purification procedure in 40–50% radiochemical yields, which were decay corrected to the end of bombardment (EOB), based on [11C]CO2. The overall synthesis time was 20–25 min from EOB. The radiochemical purity was >99%, and specific activity was in a range of 74–111 GBq/μmol at the end of synthesis (EOS).
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synthesis of Carbon 11 labeled sulfonanilide analogues as new potential pet agents for imaging of aromatase in breast cancer
Bioorganic & Medicinal Chemistry Letters, 2007Co-Authors: Min Wang, George W. Sledge, Kathy D. Miller, Gabrielle Lacy, Qi Huang ZhengAbstract:Abstract Aromatase is a particularly good target in the treatment of estrogen receptor positive breast cancer. Novel Carbon-11 labeled sulfonanilide analogues, N-[11C]methyl-N-(2-alkyloxy-4-nitrophenyl)-methanesulfonamides ([11C]3a–f, alkyl = propyl, isopropyl, 1-ethyl-propyl, cyclopentyl, cyclohexyl, and cyclohexylethyl), were designed and synthesized as potential PET agents for imaging of aromatase in breast cancer.
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synthesis of Carbon 11 labeled fluorinated 2 arylbenzothiazoles as novel potential pet cancer imaging agents
Bioorganic & Medicinal Chemistry, 2006Co-Authors: Min Wang, Bruce H Mock, Kathy D. Miller, George W. Sledge, Gary D Hutchins, Qi Huang ZhengAbstract:Abstract Fluorinated 2-arylbenzothiazoles are new potential antitumor drugs, which show potent and selective inhibitory activity against breast, lung, and colon cancer cell lines. Carbon-11 labeled fluorinated 2-arylbenzothiazoles may serve as novel probes for positron emission tomography (PET) to image tyrosine kinase in cancers. The preparation of 4-fluorinated 2-arylbenzothiazoles 4-fluoro-2-(3-benzloxy-4-methoxyphenyl)benzothiazole ( 6a ) and 4-fluoro-2-(3,4-dimethoxyphenyl)benzothiazole ( 6b ) was achieved by a modification of Jacobson thioanilide radical cyclization chemistry. Hydrogenolytic cleavage of the benzyl ether group of compound 6a using H 2 /Pd–C provided the precursor 4-fluoro-2-(3-hydroxy-4-methoxyphenyl)benzothiazole ( 7) for radiolabeling. Synthesis of radiolabeling precursors and the reference standards 5- and 6-fluorinated arylbenzothiazoles ( 11c–n ) was achieved via the reaction of o -aminothiophenol disulfides with substituted benzaldehydes under reducing conditions. The target radiotracers Carbon-11 labeled 4-, 5-, and 6-fluorinated arylbenzothiazoles (3-[ 11 C] 6b , 4-[ 11 C] 11c , 3-[ 11 C] 11c , 5-[ 11 C] 11f , 4-[ 11 C] 11f , 4-[ 11 C] 11i , 3-[ 11 C] 11i , 5-[ 11 C] 11l , and 4-[ 11 C] 11l ) were prepared by O -[ 11 C]methylation of the phenolic hydroxyl precursors ( 7 , 11d , 11e , 11g , 11h , 11j , 11k , 11m , and 11n ) with [ 11 C]methyl triflate and isolated by solid-phase extraction (SPE) purification in 30–55% radiochemical yields.
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Synthesis of Carbon-11 labeled triphenylacetamides as novel potential PET melanoma cancer imaging agents
Synthesis, 2006Co-Authors: Deyuan Kong, Abraham Clearfield, Kathy D. Miller, George W. Sledge, Qi Huang ZhengAbstract:New Carbon-11 labeled triphenylacetamides (TPAs), N-(4-[ 11 C]methoxyphenyl)-2,2,2-triphenyl-acetamide ([ 11 C]MTA) and 3-phenyl-(R)-2-(2,2,2-triphenylacetylamino)propionic acid [ 11 C]methyl ester (["C]PAME), were designed and synthesized as potential positron emission tomography (PET) melanoma cancer imaging agents. The single crystal structure of the potent anti-melanoma agent, N-(4-methoxyphenyl)-2,2,2-triphenylacetamide (MTA) is reported.
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purification of Carbon 11 pet radiotracers from unlabeled precursors by preparative hplc and spe
Biomedical Chromatography, 2005Co-Authors: Qi Huang Zheng, Bruce H MockAbstract:A general methodology for the rapid purification of Carbon-11 positron emission tomography (PET) radiotracers from radiolabeling reaction mixtures has been developed. Preparative HPLC and solid-phase extraction (SPE) techniques are described which can separate some commonly used radiopharmaceuticals such as [11C]raclopride, [11C]β-CFT and [11C]choline from their unlabeled precursors. Copyright © 2005 John Wiley & Sons, Ltd.
Christer Halldin - One of the best experts on this subject based on the ideXlab platform.
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new methodologies for the preparation of Carbon 11 labeled radiopharmaceuticals
Clinical and Translational Imaging, 2017Co-Authors: Kenneth Dahl, Christer Halldin, Magnus SchouAbstract:Purpose This short review aims to cover the more recent and promising developments of Carbon-11 (11C) labeling radiochemistry and its utility in the production of novel radiopharmaceuticals, with special emphasis on methods that have the greatest potential to be translated for clinical positron emission tomography (PET) imaging.
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Radiolabeling of the cannabinoid receptor agonist AZD1940 with Carbon-11 and PET microdosing in non-human primate.
Nuclear Medicine and Biology, 2013Co-Authors: Magnus Schou, Christer Halldin, Katarina Varnäs, Aurelija Jucaite, Balázs Gulyás, Lars FardeAbstract:Abstract Introduction N -(2-tert-butyl-1-((4,4-difluorocyclohexyl)methyl)-1H-benzo[d]imidazol-5-yl)ethanesulfonamide (AZD1940) is a candidate drug for treatment of neuropathic pain. As part of the preclinical evaluation of AZD1940, a microdosing study with positron emission tomography (PET) was conducted to assess brain exposure. Methods AZD1940 was radiolabeled with Carbon-11 in the benzimidazole moiety. The radioactive precursor, lithium [ 11 C]pivalate was obtained via 11 C-carboxylation of tert -butyl lithium. The target compound, [ 11 C]AZD1940, was in turn obtained by the microwave assisted reaction between lithium [ 11 C]pivalate and the o- phenylene diamine analog of AZD1940 ( N -(3-amino-4-((4,4-difluorocyclohexyl)methylamino)phenyl)ethanesulfonamide) in neat phosphorous oxychloride. A brain PET measurement was performed in cynomolgus monkey. Results The overall radiochemical yield of final formulated radiochemically pure (>99%) [ 11 C]AZD1940 was 0.4% (uncorrected for decay) and the specific radioactivity was 13GBq/μmol at time of administration (58min after end of bombardment). After intravenous injection to cynomolgus monkey, the maximum concentration of radioactivity detected in the brain region of interest was 0.7% of the total injected radioactivity. The regional distribution of radioactivity within brain was homogenous. Conclusions AZD1940 was radiolabelled with Carbon-11 and its brain exposure, assessed using PET, was relatively low in comparison to peripheral organ exposure.
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Synthesis of suicide inhibitors of monoamine oxidase: Carbon‐11 labeled clorgyline, L‐deprenyl and D‐deprenyl
Journal of Labelled Compounds and Radiopharmaceuticals, 2006Co-Authors: Robert R. Macgregor, Christer Halldin, Alfred P. Wolf, Joanna S. Fowler, Bengt LångströmAbstract:The suicide inhibitors of monoamine oxidase type A and B, clorgyline and L-deprenyl have been labeled with Carbon-11 by [11C]methylation of the norbases with [11C]H3I. The less active enantiomer of deprenyl (D-deprenyl) was also labeled using this procedure. The synthesis time was 35 minutes, the radiochemical yield was 25–40% and the specific activity was 0.8–2.0 Ci/μmol (calculated to EOB). Procedures for synthesis of the precursor norbases as well as the synthesis of unlabeled clorgyline, L-deprenyl and D-deprenyl are given.
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Carbon-11 labelling of MADAM in two different positions: a highly selective PET radioligand for the serotonin transporter
Journal of Labelled Compounds and Radiopharmaceuticals, 2001Co-Authors: Jari Tarkiainen, Johnny Vercouillie, Patrick Emond, Johan Sandell, Jukka Hiltunen, Y. Frangin, Denis Guilloteau, Christer HalldinAbstract:Imaging by scintigraphy the serotonin transporter (5-HTT) in the living human brain would be of great value in research on the pathophysiology and treatment of neuropsychiatric disorders such as depression. For that reason, and in order to obtain a selective radiotracer applicable to PET, we report here the Carbon-11 labelling of a selective 5-HTT radioligand: N, N-dimethyl-2-(2-amino-4-methylphenylthio)benzylamine or MADAM in two different positions: [p-11C-methyl]MADAM and [N-11C-methyl]MADAM. The synthesis of Bu3Sn-ADAM and N-dimethyl-MADAM is described. [p-11C-methyl]MADAM was obtained by a Stille coupling reaction between Bu3Sn-ADAM and [11C]methyl iodide using palladium (0) as a catalyst without (Ia) or with copper chloride as a co-catalyst (Ib). [N-11C-methyl]MADAM was obtained by an N-methylation reaction between N-demethyl-MADAM and [11C]methyl iodide (II). The Carbon-11 incorporation yield in [p-11C-methyl]MADAM was 10–30% (Ia and Ib) and in [N-11C-methyl]MADAM was 75-80% (II). The final product in each case was obtained in 30 min total synthesis time, including HPLC purification and with >99% radiochemical purity. Copyright © 2001 John Wiley & Sons, Ltd.
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Carbon 11 flb 457 a radioligand for extrastriatal d2 dopamine receptors
The Journal of Nuclear Medicine, 1995Co-Authors: Christer Halldin, Lars Farde, Thomas Hogberg, Nina Mohell, Hakan Hall, Tetsuya Suhara, Per Karlsson, Yoshifumi Nakashima, Carlgunnar SwahnAbstract:UNLABELLED: D2 dopamine receptors in extrastriatal brain regions are of central interest for research in schizophrenia and antipsychotic drugs. This article reports the development of [11C]FLB 457 for PET examination of extrastriatal D2 dopamine receptors. METHODS: Carbon-11-FLB 457 was prepared by O-methylation of FLB 604 (2-hydroxy precursor) with [11C]methyl iodide. Total radiochemical yield was 25%-35% within a total synthesis time of 30 min. The specific radioactivity at the end of synthesis was about 1300 Ci/mmole (48 GBq/mumole). RESULTS: FLB 457 bound with high affinity to D2 and D3 dopamine receptors, whereas binding to other putative central receptors was negligible. PET studies in Cynomolgus monkeys demonstrated 15 times higher accumulation of radioactivity in the striatum than in the cerebellum after 60 min. Uptake in the thalamus and neocortex, extrastriatal regions with a low density of D2 dopamine receptors, was, respectively, 4 and 2.5 times higher than in the cerebellum. Radioactivity was displaced by raclopride and haloperidol which confirms the selectivity and reversibility of [11C]FLB 457 binding to D2 dopamine receptors in vivo in the striatum, thalamus and neocortex. CONCLUSION: Carbon-11-FLB 457 should be a useful PET ligand for quantitative examination of D2 dopamine receptors in extrastriatal regions in the human brain.
Min Wang - One of the best experts on this subject based on the ideXlab platform.
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synthesis of new Carbon 11 labeled benzoxazole derivatives for pet imaging of 5 ht3 receptor
European Journal of Medicinal Chemistry, 2008Co-Authors: Min Wang, Gary D Hutchins, Qi Huang ZhengAbstract:Abstract 5-HT3 receptor is an attractive target for the development of therapeutic agents for use in brain, heart and cancer diseases, and imaging agents for use in biomedical imaging technique PET. Benzoxazole derivatives are a novel class of 5-HT3 receptor partial agonists with high binding affinity. Carbon-11 labeled benzoxazole derivatives have been synthesized as new potential PET radioligands for imaging 5-HT3 receptor. The target tracers were prepared by N-[11C]methylation of their corresponding precursors using [11C]CH3OTf and isolated by HPLC purification procedure in 40–50% radiochemical yields, which were decay corrected to the end of bombardment (EOB), based on [11C]CO2. The overall synthesis time was 20–25 min from EOB. The radiochemical purity was >99%, and specific activity was in a range of 74–111 GBq/μmol at the end of synthesis (EOS).
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synthesis of Carbon 11 labeled sulfonanilide analogues as new potential pet agents for imaging of aromatase in breast cancer
Bioorganic & Medicinal Chemistry Letters, 2007Co-Authors: Min Wang, George W. Sledge, Kathy D. Miller, Gabrielle Lacy, Qi Huang ZhengAbstract:Abstract Aromatase is a particularly good target in the treatment of estrogen receptor positive breast cancer. Novel Carbon-11 labeled sulfonanilide analogues, N-[11C]methyl-N-(2-alkyloxy-4-nitrophenyl)-methanesulfonamides ([11C]3a–f, alkyl = propyl, isopropyl, 1-ethyl-propyl, cyclopentyl, cyclohexyl, and cyclohexylethyl), were designed and synthesized as potential PET agents for imaging of aromatase in breast cancer.
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synthesis of Carbon 11 labeled fluorinated 2 arylbenzothiazoles as novel potential pet cancer imaging agents
Bioorganic & Medicinal Chemistry, 2006Co-Authors: Min Wang, Bruce H Mock, Kathy D. Miller, George W. Sledge, Gary D Hutchins, Qi Huang ZhengAbstract:Abstract Fluorinated 2-arylbenzothiazoles are new potential antitumor drugs, which show potent and selective inhibitory activity against breast, lung, and colon cancer cell lines. Carbon-11 labeled fluorinated 2-arylbenzothiazoles may serve as novel probes for positron emission tomography (PET) to image tyrosine kinase in cancers. The preparation of 4-fluorinated 2-arylbenzothiazoles 4-fluoro-2-(3-benzloxy-4-methoxyphenyl)benzothiazole ( 6a ) and 4-fluoro-2-(3,4-dimethoxyphenyl)benzothiazole ( 6b ) was achieved by a modification of Jacobson thioanilide radical cyclization chemistry. Hydrogenolytic cleavage of the benzyl ether group of compound 6a using H 2 /Pd–C provided the precursor 4-fluoro-2-(3-hydroxy-4-methoxyphenyl)benzothiazole ( 7) for radiolabeling. Synthesis of radiolabeling precursors and the reference standards 5- and 6-fluorinated arylbenzothiazoles ( 11c–n ) was achieved via the reaction of o -aminothiophenol disulfides with substituted benzaldehydes under reducing conditions. The target radiotracers Carbon-11 labeled 4-, 5-, and 6-fluorinated arylbenzothiazoles (3-[ 11 C] 6b , 4-[ 11 C] 11c , 3-[ 11 C] 11c , 5-[ 11 C] 11f , 4-[ 11 C] 11f , 4-[ 11 C] 11i , 3-[ 11 C] 11i , 5-[ 11 C] 11l , and 4-[ 11 C] 11l ) were prepared by O -[ 11 C]methylation of the phenolic hydroxyl precursors ( 7 , 11d , 11e , 11g , 11h , 11j , 11k , 11m , and 11n ) with [ 11 C]methyl triflate and isolated by solid-phase extraction (SPE) purification in 30–55% radiochemical yields.
Joanna S. Fowler - One of the best experts on this subject based on the ideXlab platform.
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whole body pharmacokinetics of hdac inhibitor drugs butyric acid valproic acid and 4 phenylbutyric acid measured with Carbon 11 labeled analogs by pet
Nuclear Medicine and Biology, 2013Co-Authors: Jacob M Hooker, Nora D. Volkow, Colleen Shea, Lisa Muench, Nicola Otto, Pauline Carter, Payton King, Alicia E Reid, Joanna S. FowlerAbstract:Abstract The fatty acids, n -butyric acid (BA), 4-phenylbutyric acid (PBA) and valproic acid (VPA, 2-propylpentanoic acid) have been used for many years in the treatment of a variety of CNS and peripheral organ diseases including cancer. New information that these drugs alter epigenetic processes through their inhibition of histone deacetylases (HDACs) has renewed interest in their biodistribution and pharmacokinetics and the relationship of these properties to their therapeutic and side effect profiles. In order to determine the pharmacokinetics and biodistribution of these drugs in primates, we synthesized their Carbon-11 labeled analogues and performed dynamic positron emission tomography (PET) in six female baboons over 90min. The Carbon-11 labeled carboxylic acids were prepared by using 11 CO 2 and the appropriate Grignard reagents. [ 11 C]BA was metabolized rapidly (only 20% of the total Carbon-11 in plasma was parent compound at 5min post injection) whereas for VPA and PBA 98% and 85% of the radioactivity were the unmetabolized compound at 30min after their administration respectively. The brain uptake of all three carboxylic acids was very low ( VPA>PBA), which is consistent with the need for very high doses for therapeutic efficacy. Most of the radioactivity was excreted through the kidneys and accumulated in the bladder. However, the organ biodistribution between the drugs differed. [ 11 C]BA showed relatively high uptake in spleen and pancreas whereas [ 11 C]PBA showed high uptake in liver and heart. Notably, [ 11 C]VPA showed exceptionally high heart uptake possibly due to its involvement in lipid metabolism. The unique biodistribution of each of these drugs may be of relevance in understanding their therapeutic and side effect profile including their teratogenic effects.
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synthesis and positron emission tomography studies of Carbon 11 labeled imatinib gleevec
Nuclear Medicine and Biology, 2007Co-Authors: Yushin Ding, Youwen Xu, David Alexoff, Joanna S. Fowler, Colleen Shea, Lisa MuenchAbstract:Introduction Imatinib mesylate (Gleevec) is a well known drug for treating chronic myeloid leukemia and gastrointestinal stromal tumors. Its active ingredient, imatinib ([4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridyl)-2-pyrimidinyl]amino]phenyl]benzamide), blocks the activity of several tyrosine kinases. Here we labeled imatinib with Carbon-11 as a tool for determining the drug distribution and pharmacokinetics of imatinib, and we carried out positron emission tomography (PET) studies in baboons.
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Synthesis of suicide inhibitors of monoamine oxidase: Carbon‐11 labeled clorgyline, L‐deprenyl and D‐deprenyl
Journal of Labelled Compounds and Radiopharmaceuticals, 2006Co-Authors: Robert R. Macgregor, Christer Halldin, Alfred P. Wolf, Joanna S. Fowler, Bengt LångströmAbstract:The suicide inhibitors of monoamine oxidase type A and B, clorgyline and L-deprenyl have been labeled with Carbon-11 by [11C]methylation of the norbases with [11C]H3I. The less active enantiomer of deprenyl (D-deprenyl) was also labeled using this procedure. The synthesis time was 35 minutes, the radiochemical yield was 25–40% and the specific activity was 0.8–2.0 Ci/μmol (calculated to EOB). Procedures for synthesis of the precursor norbases as well as the synthesis of unlabeled clorgyline, L-deprenyl and D-deprenyl are given.
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Positron emission tomography study of human prostatic adenocarcinoma using Carbon-11 putrescine.
Nuclear Medicine and Biology, 2004Co-Authors: Gene-jack Wang, Alfred P. Wolf, David J. Schlyer, Nora D. Volkow, Stefan Madajewicz, Joanna S. Fowler, Robert R. MacgregorAbstract:Abstract To evaluate [1- 11 C]putrescine ([ 11 C]PUT) as a potential tracer for imaging and characterization of human prostatic adenocarcinoma, positron emission tomography (PET) was performed in eight patients and three normal controls. In addition, four of the patients and the three normal controls also had a prostate scan with 2-deoxy-2-[ 18 F]fluoro-d-glucose ( 18 FDG). Three of the patients had undergone resection of the prostate tumor and all of the patients except for one had bone metastasis. Carbon-11 rapidly accumulated in prostate, bone and rectum after injection of [ 11 C]PUT. Maximal uptake was achieved 5 min after injection with minimal washout during the 50 min study period. The uptake of Carbon-11 in the prostate of normal controls was significantly higher than that in the patients. However, three of the four patients scanned for metastatic bone lesions showed higher uptake in bone metastasis than in normal bone. Quantitation of 18 FDG uptake in the prostate was hindered by the high accumulation of activity in the urinary bladder. [ 11 C]PUT does not appear to be a useful tracer for assessing proliferation of human prostate adenocarcinoma. Its utility in the imaging of other cancers with high polyamine concentration remains to be investigated.
Magnus Schou - One of the best experts on this subject based on the ideXlab platform.
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new methodologies for the preparation of Carbon 11 labeled radiopharmaceuticals
Clinical and Translational Imaging, 2017Co-Authors: Kenneth Dahl, Christer Halldin, Magnus SchouAbstract:Purpose This short review aims to cover the more recent and promising developments of Carbon-11 (11C) labeling radiochemistry and its utility in the production of novel radiopharmaceuticals, with special emphasis on methods that have the greatest potential to be translated for clinical positron emission tomography (PET) imaging.
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Radiolabeling of the cannabinoid receptor agonist AZD1940 with Carbon-11 and PET microdosing in non-human primate.
Nuclear Medicine and Biology, 2013Co-Authors: Magnus Schou, Christer Halldin, Katarina Varnäs, Aurelija Jucaite, Balázs Gulyás, Lars FardeAbstract:Abstract Introduction N -(2-tert-butyl-1-((4,4-difluorocyclohexyl)methyl)-1H-benzo[d]imidazol-5-yl)ethanesulfonamide (AZD1940) is a candidate drug for treatment of neuropathic pain. As part of the preclinical evaluation of AZD1940, a microdosing study with positron emission tomography (PET) was conducted to assess brain exposure. Methods AZD1940 was radiolabeled with Carbon-11 in the benzimidazole moiety. The radioactive precursor, lithium [ 11 C]pivalate was obtained via 11 C-carboxylation of tert -butyl lithium. The target compound, [ 11 C]AZD1940, was in turn obtained by the microwave assisted reaction between lithium [ 11 C]pivalate and the o- phenylene diamine analog of AZD1940 ( N -(3-amino-4-((4,4-difluorocyclohexyl)methylamino)phenyl)ethanesulfonamide) in neat phosphorous oxychloride. A brain PET measurement was performed in cynomolgus monkey. Results The overall radiochemical yield of final formulated radiochemically pure (>99%) [ 11 C]AZD1940 was 0.4% (uncorrected for decay) and the specific radioactivity was 13GBq/μmol at time of administration (58min after end of bombardment). After intravenous injection to cynomolgus monkey, the maximum concentration of radioactivity detected in the brain region of interest was 0.7% of the total injected radioactivity. The regional distribution of radioactivity within brain was homogenous. Conclusions AZD1940 was radiolabelled with Carbon-11 and its brain exposure, assessed using PET, was relatively low in comparison to peripheral organ exposure.