共查询到20条相似文献,搜索用时 0 毫秒
1.
Adam Siddiqui-Jain Jacob P. Hoj David W. Cescon Marc D. Hansen 《Bioorganic & medicinal chemistry letters》2018,28(5):934-941
Microtubule-targeting agents are important tools in cancer treatment. Generating novel microtubule targeting agents with novel pharmacology could dramatically expand the utility of this class of drugs. Here we characterize the pharmacology of recently described small molecule microtubule polymerization inhibitors. Pharmacokinetic experiments show oral bioavailability through gastric absorption. In vitro assays designed to predict absorption, distribution, metabolism, and excretion (ADME) and safety reveal a scaffold that is metabolically stable, evades P-glycoprotein, does not inhibit CYP enzymes, occurs as a significant free fraction in serum, and has exceptionally high cellular permeability. Together with in vivo efficacy models, pharmacology supports further development as a treatment for solid tumors. 相似文献
2.
J.S. Dileep Kumar Francesca Zanderigo Jaya Prabhakaran Harry Rubin-Falcone Ramin V. Parsey J. John. Mann 《Bioorganic & medicinal chemistry letters》2018,28(23-24):3592-3595
Overexpression of Cyclooxygenase-2 (COX-2) enzyme is associated with the pathogenesis of inflammation, cancers, stroke, arthritis, and neurological disorders. Because of the involvement of COX-2 in these diseases, quantification of COX-2 expression using Positron Emission Tomography (PET) may be a biological marker for early diagnosis, monitoring of disease progression, and an indicator of effective treatment. At present there is no target-specific or validated PET tracer available for in vivo quantification of COX-2. The objective of this study is to evaluate [11C]TMI, a selective COX-2 inhibitor (Ki?≤?1?nM) in nonhuman primates using PET imaging. PET imaging in baboons showed that [11C]TMI penetrates the blood brain barrier (BBB) and accumulates in brain in a somewhat heterogeneous pattern. Metabolite analyses indicated that [11C]TMI undergoes no significant metabolism of parent tracer in the plasma for baseline scans, however a relative faster metabolism was found for blocking scan. All the tested quantification approaches provide comparable tracer total distribution volume (VT) estimates in the range of 3.2–7?(mL/cm3). We observed about 25% lower VT values in blocking studies with meloxicam, a nonselective COX-2 inhibitor, compared to baseline [11C]TMI binding. Our findings indicate that [11C]TMI may be a suitable PET tracer for the quantification of COX-2 in vivo. Further experiments are needed to confirm the potential of this tracer in COX-2 overexpressing models for brain diseases. 相似文献
3.
Jaya Prabhakaran Kiran Kumar Solingapuram Sai Anirudh Sattiraju Akiva Mintz J. John Mann J.S. Dileep Kumar 《Bioorganic & medicinal chemistry letters》2019,29(6):778-781
Dysfunction of GSK3 is implicated in the etiology of many brain, inflammatory, cardiac diseases, and cancer. PET imaging would enable in vivo detection and quantification of GSK3 and can impact the choice of therapy, allow non-invasive monitoring of disease progression and treatment effects. In this report, the synthesis and evaluation of a high affinity GSK3 ligand, [11C]2-(cyclopropanecarboxamido)-N-(4-methoxypyridin-3-yl)isonicotinamide, ([11C]CMP, (3), (IC50?=?3.4?nM, LogP?=?1.1) is described. [11C]CMP was synthesized in 25?±?5% yield by radiomethylating the corresponding phenolate using [11C]CH3I. The radioligand exhibited modest uptake in U251 human glioblastoma cell lines with ~50% specific binding. MicroPET studies in rats indicated negligible blood–brain barrier (BBB) penetration of [11C]CMP, despite its high affinity and suitable logP value for BBB penetration. However, administration of cyclosporine prior to [11C]CMP injection showed significant improvement in brain radioactivity uptake and the tracer binding. This finding indicates that [11C]CMP might be a P-gp efflux substrate and therefore has some limitations for routine in vivo PET evaluations in brain. 相似文献
4.
Jaya Prabhakaran Kiran Kumar Solingapuram Sai Francesca Zanderigo Harry Rubin-Falcone Matthew J. Jorgensen Jay R. Kaplan Katharine I. Tooke Akiva Mintz J. John Mann J.S. Dileep Kumar 《Bioorganic & medicinal chemistry letters》2017,27(1):21-23
We recently reported the radiosynthesis and in vitro evaluation of [18F]-2-(4-bromo-2,5-dimethoxyphenyl)-N-(2-(2-fluoroethoxy)benzyl)ethanamine, ([18F]FECIMBI-36) or ([18F]1), an agonist radioligand for 5HT2A/2C receptors in postmortem samples of human brain. Herein we describe the in vivo evaluation of [18F]FECIMBI-36 in vervet/African green monkeys by PET imaging. PET images show that [18F]FECIMBI-36 penetrates the blood-brain barrier and a low retention of radioactivity is observed in monkey brain. Although the time activity curves indicate a somehow heterogeneous distribution of the radioligand in the brain, the low level of [18F]FECIMBI-36 in brain may limit the use of this tracer for quantification of 5-HT2A/2C receptors by PET. 相似文献
5.
Jaya Prabhakaran Mark Underwood Francesca Zanderigo Norman R. Simpson Anna R. Cooper Jeffrey Matthew Harry Rubin-Falcone Ramin V. Parsey J. John Mann J.S. Dileep Kumar 《Bioorganic & medicinal chemistry letters》2018,28(14):2432-2435
Radiosynthesis and in vivo evaluation of [11C]4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (methoxy analogue of valdecoxib, [11C]MOV), a COX-2 inhibitor, was conducted in rat and baboon. Synthesis of the reference standard MOV (3), and its desmethyl precursor 2 for radiolabeling were performed using 1,2-diphenylethan-1-one as the starting material in five steps with 15% overall yield. Radiosynthesis of [11C]MOV was accomplished in 40?±?10% yield and?>99% radiochemical purity by reacting the precursor 2 in dimethyl formamide (DMF) with [11C]CH3I followed by removal of the dimethoxytrityl (DMT) protective group using trifluroacetic acid. PET studies in anesthetized baboon showed very low uptake and homogeneous distribution of [11C]MOV in brain. The radioligand underwent rapid metabolism in baboon plasma. MicroPET studies in male Sprague Dawley rats revealed [11C]MOV binding in lower thorax. The tracer binding in rats was partially blocked in heart and duodenum by the administration of 1?mg/kg oral dose of COX-2 inhibitor valdecoxib. 相似文献
6.
Abstract: Isolated microtubule-associated protein 2 (MAP2), τ factor, and tubulin were phosphorylated by a purified Ca2+ , calmodulin-dependent protein kinase (640K enzyme) from rat brain. The phosphorylation of MAP2 and τ factor separately induced the inhibition of microtubule assembly, in accordance with the degree. Tubulin phosphorylation by the 640K enzyme induced the inhibition of microtubule assembly, whereas the effect of tubulin phosphorylation by the catalytic subunit was undetectable. The effects of tubulin and MAPs phosphorylation on microtubule assembly were greater than that of either tubulin or MAPs phosphorylation. Because MAP2, τ factor, and tubulin were also phosphorylated by the catalytic subunit of type-II cyclic AMP-dependent protein kinase from rat brain, the kinetic properties and phosphorylation sites were compared. The amount of phosphate incorporated into each microtubule protein was three to five times higher by the 640K enzyme than by the catalytic subunit. The K m values of the 640K enzyme for microtubule proteins were four to 24 times lower than those of the catalytic subunit. The peptide mapping analysis showed that the 640K enzyme and the catalytic subunit incorporated phosphate into different sites on MAP2, τ factor, and tubulin. Investigation of phosphoamino acids revealed that only the seryl residue was phosphorylated by the catalytic subunit, whereas both seryl and threonyl residues were phosphorylated by the 640K enzyme. These data suggest that the Ca2+ , calmodulin system via phosphorylation of MAP2, τ factor, and tubulin by the 640K enzyme is more effective than the cyclic AMP system on the regulation of microtubule assembly. 相似文献
7.
Jaya Prabhakaran Stephen L. Dewey Richard McClure Norman R. Simpson Mohammed N. Tantawy J. John Mann Wellington Pham J.S. Dileep Kumar 《Bioorganic & medicinal chemistry letters》2017,27(4):941-943
In vivo evaluation of [18F]BMS-754807 binding in mice and rats using microPET and biodistribution methods is described herein. The radioligand shows consistent binding characteristics, in vivo, in both species. Early time frames of the microPET images and time activity curves of brain indicate poor penetration of the tracer across the blood brain barrier (BBB) in both species. However, microPET experiments in mice and rats show high binding of the radioligand outside the brain to heart, pancreas and muscle, the organs known for higher expression of IGF1R/1R. Biodistribution analysis 2 h after injection of [18F]BMS-754807 in rats show negligible [18F]defluorination as reflected by the low bone uptake and clearance from blood. Overall, the data indicate that [18F]BMS-754807 can potentially be a radiotracer for the quantification of IGF1R/IR outside the brain using PET. 相似文献
8.
Changning Wang Christian K. Moseley Stephen M. Carlin Colin M. Wilson Ramesh Neelamegam Jacob M. Hooker 《Bioorganic & medicinal chemistry letters》2013,23(11):3389-3392
EMPA is a selective antagonist of orexin 2 (OX2) receptors. Previous literature with [3H]-EMPA suggest that it may be used as an imaging agent for OX2 receptors; however, brain penetration is known to be modest. To evaluate the potential of EMPA as a PET radiotracer in non-human primate (as a step to imaging in man), we radiolabeled EMPA with carbon-11. Radiosynthesis of [11C]N-ethyl-2-(N-(6-methoxypyridin-3-yl)-2-methylphenylsulfonamido)-N-(pyridin-3-ylmethyl)acetamide ([11C]EMPA), and evaluation as a potential PET tracer for OX2 receptors is described. Synthesis of an appropriate non-radioactive O-desmethyl precursor was achieved from EMPA with sodium iodide and chlorotrimethylsilane. Selective O-methylation using [11C]CH3I in the presence of cesium carbonate in DMSO at room temp afforded [11C]EMPA in 1.5–2.5% yield (non-decay corrected relative to trapped [11C]CH3I at EOS) with ?95% chemical and radiochemical purities. The total synthesis time was 34–36 min from EOB. Studies in rodent suggested that uptake in tissue was dominated by nonspecific binding. However, [11C]EMPA also showed poor uptake in both rats and baboon as measured with PET imaging. 相似文献
9.
Vattoly J. Majo Matthew S. Milak Jaya Prabhakaran Pratap Mali Lyudmila Savenkova Norman R. Simpson J. John Mann Ramin V. Parsey J. S. Dileep Kumar 《Bioorganic & medicinal chemistry》2013,21(17):5598-5604
The 5-HT1AR partial agonist PET radiotracer, [11C]CUMI-101, has advantages over an antagonist radiotracer as it binds preferentially to the high affinity state of the receptor and thereby provides more functionally meaningful information. The major drawback of C-11 tracers is the lack of cyclotron facility in many health care centers thereby limiting widespread clinical or research use. We identified the fluoroethyl derivative, 2-(4-(4-(2-(2-fluoroethoxy)phenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)dione (FECUMI-101) (Ki = 0.1 nM; Emax = 77%; EC50 = 0.65 nM) as a partial agonist 5-HT1AR ligand of the parent ligand CUMI-101. FECUMI-101 is radiolabeled with F-18 by O-fluoroethylation of the corresponding desmethyl analogue (1) with [18F]fluoroethyltosylate in DMSO in the presence of 1.6 equiv of K2CO3 in 45 ± 5% yield (EOS). PET shows [18F]FECUMI-101 binds specifically to 5-HT1AR enriched brain regions of baboon. The specificity of [18F]FECUMI-101 binding to 5-HT1AR was confirmed by challenge studies with the known 5-HT1AR ligand WAY100635. These findings indicate that [18F]FECUMI-101 can be a viable agonist ligand for the in vivo quantification of high affinity 5-HT1AR with PET. 相似文献
10.
Kun-Eek Kil Zhaoda Zhang Kimmo Jokivarsi Chunyu Gong Ji-Kyung Choi Sreekanth Kura Anna-Liisa Brownell 《Bioorganic & medicinal chemistry》2013,21(19):5955-5962
N-(Chloro-3-methoxyphenyl)-2-picolinamide (3, ML128, VU0361737) is an mGlu4 positive allosteric modulator (PAM), which is potent and centrally penetrating. 3 is also the first mGlu4 PAM to show efficacy in a preclinical Parkinson disease model upon systemic dosing. As a noninvasive medical imaging technique and a powerful tool in neurological research, positron emission tomography (PET) offers a possibility to investigate mGlu4 expression in vivo under physiologic and pathological conditions. We synthesized a carbon-11 labeled ML128 ([11C]3) as a PET radiotracer for mGlu4, and characterized its biological properties in Sprague Dawley rats. [11C]3 was synthesized from N-(4-chloro-3-hydroxyphenyl)-2-picolinamide (2) using [11C]CH3I. Total synthesis time was 38 ± 2.2 min (n = 7) from the end of bombardment to the formulation. The radioligand [11C]3 was obtained in 27.7 ± 5.3% (n = 5) decay corrected radiochemical yield based on the radioactivity of [11C]CO2. The radiochemical purity of [11C]3 was >99%. Specific activity was 188.7 ± 88.8 GBq/mol (n = 4) at the end of synthesis (EOS).PET images were conducted in 20 normal male Sprague Dawley rats including 11 control studies, 6 studies blocking with an mGlu4 modulator (4) to investigate specificity and 3 studies blocking with an mGlu5 modulator (MTEP) to investigate selectivity. These studies showed fast accumulation of [11C]3 (peak activity between 1–3 min) in several brain areas including striatum, thalamus, hippocampus, cerebellum, and olfactory bulb following with fast washout. Blocking studies with the mGlu4 modulator 4 showed 22–28% decrease of [11C]3 accumulation while studies of selectivity showed only minor decrease supporting good selectivity over mGlu5. Biodistribution studies and blood analyses support fast metabolism. Altogether this is the first PET imaging ligand for mGlu4, in which the labeled ML128 was used for imaging its in vivo distribution and pharmacokinetics in brain. 相似文献
11.
《Bioorganic & medicinal chemistry letters》2014,24(22):5219-5223
Herein we report the identification of (+)-N-(2-((1H-pyrazol-1-yl)methyl)-3-((1R,3r,5S)-6′-fluoro-8-azaspiro[bicyclo[3.2.1]octane-3,1′-isochroman]-8-yl)propyl)-N-[3H]-methylacetamide {[3H]PF-7191 [(+)-11]} as a promising radiotracer for the nociceptin opioid peptide (NOP) receptor. (+)-11 demonstrated high NOP binding affinity (Ki = 0.1 nM), excellent selectivity over other opioid receptors (>1000×) and good brain permeability in rats (Cb,u/Cp,u = 0.29). Subsequent characterization of [3H](+)-11 showed a high level of specific binding and a brain bio-distribution pattern consistent with known NOP receptor expression. Furthermore, the in vivo brain binding of [3H](+)-11 in rats was inhibited by a selective NOP receptor antagonist in a dose–responsive manner. This overall favorable profile indicated that [3H](+)-11 is a robust radiotracer for pre-clinical in vivo receptor occupancy (RO) measurements and a possible substrate for carbon-11 labeling for positron emission tomography (PET) imaging in higher species. 相似文献
12.
E. Johanna L. Stéen Jesper T. J?rgensen Ida N. Petersen Kamilla N?rregaard Szabolcs Lehel Vladimir Shalgunov Alexander Birke Patricia E. Edem Elina T. LEstrade Hanne D. Hansen Jonas Villadsen Maria Erlandsson Tomas Ohlsson Abdolreza Yazdani John F. Valliant Jesper L. Kristensen Matthias Barz Gitte M. Knudsen Matthias M. Herth 《Bioorganic & medicinal chemistry letters》2019,29(8):986-990
Pretargeted nuclear imaging based on the ligation between tetrazines and nano-sized targeting agents functionalized with trans-cyclooctene (TCO) has recently been shown to improve both imaging contrast and dosimetry in nuclear imaging of nanomedicines. Herein, we describe the improved radiosynthesis of a 11C-labeled tetrazine ([11C]AE-1) and its preliminary evaluation in both mice and pigs. Pretargeted imaging in mice was carried out using both a new TCO-functionalized polyglutamic acid and a previously reported TCO-functionalized bisphosphonate system as targeting agents. Unfortunately, pretargeted imaging was not successful using these targeting agents in pair with [11C]AE-1. However, brain imaging in pig indicated that the tracer crossed the blood-brain-barrier. Hence, we suggest that this tetrazine scaffold could be used as a starting point for the development of pretargeted brain imaging, which has so far been a challenging task. 相似文献
13.
Heying Duan Lucia Baratto Negin Hatami Tie Liang Carina Mari Aparici Guido Alejandro Davidzon Andrei Iagaru 《Translational oncology》2022,15(1)
Objectives68Ga-PSMA11 PET/CT is excellent for evaluating biochemically recurrent prostate cancer (BCR PC). Here, we compared the positivity rates of dual-time point imaging using a PET/CT scanner (DMI) with silicon photomultiplier (SiPM) detectors and a PET/CT scanner (D690) with photomultiplier tubes (PMT), in patients with BCR PC.MethodsFifty-eight patients were prospectively recruited and randomized to receive scans on DMI followed by D690 or vice-versa. Images from DMI were reconstructed using the block sequential regularized expectation maximization (BSREM) algorithm and images from D690 were reconstructed using ordered subset expectation maximization (OSEM), according to the vendor''s recommendations. Two readers independently reviewed all images in randomized order, recorded the number and location of lesions, as well as standardized uptake value (SUV) measurements.ResultsTwenty-eight patients (group A) had DMI as first scanner followed by D690, while 30 patients (group B) underwent scans in reversed order. Mean PSA was 30±112.9 (range 0.3–600.66) ng/mL for group A and 41.5 ± 213.2 (range 0.21–1170) ng/mL for group B (P = 0.796). The positivity rate in group A was 78.6% (22/28 patients) vs. 73.3% (22/30 patients) in group B. Although the performance of the two scanners was equivalent on a per-patient basis, DMI identified 5 additional sites of suspected recurrent disease when used as first scanner. The second scan time point did not reveal additional abnormal uptake.ConclusionsThe delayed time point in 68Ga-PSMA11 PET/CT did not show a higher positivity rate. SiPM-based PET/CT identified additional lesions. Further studies with larger cohorts are needed to confirm these results. 相似文献
14.
《Bioorganic & medicinal chemistry》2014,22(9):2648-2654
The radiosyntheses and in vivo evaluation of four carbon-11 labeled quinoline group-containing radioligands are reported here. Radiolabeling of [11C]1–4 was achieved by alkylation of their corresponding desmethyl precursors with [11C]CH3I. Preliminary biodistribution evaluation in Sprague-Dawley rats demonstrated that [11C]1 and [11C]2 had high striatal accumulation (at peak time) for [11C]1 and [11C]2 were 6.0-fold and 4.5-fold at 60 min, respectively. Following MP-10 pretreatment, striatal uptake in rats of [11C]1 and [11C]2 was reduced, suggesting that the tracers bind specifically to PDE10A. MicroPET studies of [11C]1 and [11C]2 in nonhuman primates (NHP) also showed good tracer retention in the striatum with rapid clearance from non-target brain regions. Striatal uptake (SUV) of [11C]1 reached 1.8 at 30 min with a 3.5-fold striatum:cerebellum ratio. In addition, HPLC analysis of solvent extracts from NHP plasma samples suggested that [11C]1 had a very favorable metabolic stability. Our preclinical investigations suggest that [11C]1 is a promising candidate for quantification of PDE10A in vivo using PET. 相似文献
15.
Treatment of Chinese hamster ovary cells with dibutyryl cyclic AMP, which results in a net increase of the intracellular cyclic AMP level, converts the epithelial-like cells to a fibroblast-like shape. Protein kinase activity in cells treated with 1 mM dibutyryl cyclic AMP show a 3-fold increase in Vmax but no appreciable changes in the apparent Km for ATP. When cells are treated with dibutyryl cyclic AMP, there is a time-dependent conversion of cyclic AMP-stimulable protein kinase to cyclic AMP-independent catalytic subunits, as demonstrated by Sephadex G-100 gel filtration. These experiments demonstrate the activation of the cyclic AMP-dependent protein kinase . This activation may lead to phosphorylation of certain cellular constituent(s) and thus may be involved in the observed morphological transformation. 相似文献
16.
《Bioorganic & medicinal chemistry letters》2020,30(16):127326
Selective DAAO inhibitors have demonstrated promising therapeutic effects in clinical studies, including clinically alleviating symptoms of schizophrenic patients and ameliorating cognitive function in Alzheimer’s patients with early phase. Herein we report the synthesis and preliminary evaluation of a 11C-labeled positron emission tomography ligand based on a DAAO inhibitor, DAO-1903 (8). 11C-Isotopologue of 8 was prepared in high radiochemical yield with high radiochemical purity (>99%) and high molar activity (>37 GBq/µmol). In vitro autoradiography studies indicated that the ligand possessed high in vitro specific binding to DAAO, while in vivo dynamic PET studies demonstrated that [11C]8 failed to cross the blood–brain barrier possibly due to moderate brain efflux mechanism. Further chemical scaffold optimization is necessary to overcome limited brain permeability and improve specific binding. 相似文献
17.
Christopher Montemagno Benjamin Serrano Jérôme Durivault Valérie Nataf François Mocquot Régis Amblard Valérie Vial Cyril Ronco Rachid Benhida Maeva Dufies Marc Faraggi Gilles Pagès 《Biochemistry and Biophysics Reports》2021
The chemokine receptors CXCR1/2 play a key role in the aggressiveness of several types of cancers including head and neck squamous cell carcinomas (HNSCCs). In HNSCCs, CXCR1/2 signaling promotes cell proliferation and angiogenesis leading to tumor growth and metastasis. The competitive inhibitor of CXCR1/2, C29, inhibits the growth of experimental HNSCCs in mice. However, a non-invasive tool to monitor treatment response is essential to implement the use of C29 in clinical practices. 18F-FDG PET/CT is a gold-standard tool for the staging and the post-therapy follow-up of HNSCCs patients. Our study aimed to perform the first in vivo monitoring of C29 efficacy by non-invasive 18F-FDG PET/CT imaging. Mice bearing experimental HNSCCs (CAL33) were injected with 18F-FDG (T0) and thereafter treated (n = 7 mice, 9 tumors, 50 mg/kg by gavage) or not (n = 7 mice, 10 tumors) with C29 for 4 consecutive days. Final 18F-FDG-tumor uptake was determined at day 4 (TF). The average relative change (TF-T0) in 18F-FDG tumor uptake was +25.85 ± 10.93 % in the control group vs ?5.72 ± 10.07 % in the C29-treated group (p < 0.01). These results were consistent with the decrease of the tumor burden and with the decrease of tumor proliferating Ki67+ cells. These results paved the way for the use of 18F-FDG to monitor tumor response following C29 treatment. 相似文献
18.
W. Ewan Hume Tomotaka Shingaki Tadayuki Takashima Yoshinobu Hashizume Takashi Okauchi Yumiko Katayama Emi Hayashinaka Yasuhiro Wada Hiroyuki Kusuhara Yuichi Sugiyama Yasuyoshi Watanabe 《Bioorganic & medicinal chemistry》2013,21(24):7584-7590
In order to develop a new positron emission tomography (PET) probe to study hepatobiliary transport mediated by the multi-drug and toxin extrusion transporter 1 (MATE1), 11C-labelled metformin was synthesized and then evaluated as a PET probe. [11C]Metformin ([11C]4) was synthesized in three steps, from [11C]methyl iodide. Evaluation by small animal PET of [11C]4 showed that there was increased concentrations of [11C]4 in the livers of mice pre-treated with pyrimethamine, a potential inhibitor of MATEs, inhibiting the hepatobiliary excretion of metformin. Radiometabolite analysis showed that [11C]4 was not degraded in vivo during the PET scan. Biodistribution studies were undertaken and the organ distributions were extrapolated into a standard human model. In conclusion, [11C]4 may be useful as a PET probe to non-invasively study the in vivo function of hepatobiliary transport and drug–drug interactions, mediated by MATE1 in future clinical investigations. 相似文献
19.
《Bioorganic & medicinal chemistry letters》2014,24(18):4455-4459
The reference standard AZD8931{2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-N-methylacetamide} (11a) was synthesized from methyl 4,5-dimethoxy-2-nitrobenzoate or ethyl 4,5-dimethoxy-2-nitrobenzoate and 2-chloro-N-methylacetamide in 11 steps with 2–5% overall chemical yield. The precursor N-desmethyl-AZD8931{2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)acetamide} (11b) was synthesized from methyl 4,5-dimethoxy-2-nitrobenzoate or ethyl 4,5-dimethoxy-2-nitrobenzoate and 2-bromoacetamide in 11 steps with 2–4% overall chemical yield. The target tracer [11C]AZD8931 {2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-N-[11C]methylacetamide} ([11C]11a) was prepared from N-desmethyl-AZD8931 (11b) with [11C]CH3OTf under basic condition (NaH) through N-[11C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) in 40–50% radiochemical yield based on [11C]CO2 and decay corrected to end of bombardment (EOB) with 370–1110 GBq/μmol specific activity at EOB. 相似文献
20.
Vasdev N Garcia A Stableford WT Young AB Meyer JH Houle S Wilson AA 《Bioorganic & medicinal chemistry letters》2005,15(23):5270-5273
N-(4-Methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea (AR-A014418), a highly selective inhibitor of glycogen synthase kinase-3beta (GSK-3beta), was radiolabelled with carbon-11 (half-life=20.4min) for cerebral positron emission tomography (PET) studies. Reaction of desmethyl AR-A014418 with [(11)C]CH(3)I produced [(11)C]AR-A014418 in 17% decay-corrected radiochemical yield, based on [(11)C]CO(2), with 3230mCi/micromol specific activity after a 30min synthesis time. The desmethyl precursor of AR-A014418 was synthesized in 23% yield by a novel one-pot reaction of 2-amino-5-nitrothiazole with in situ generated TMS-protected 4-hydroxybenzylisocyanate, following deprotection with acid. Ex vivo biodistribution studies were conducted after [(11)C]AR-A014418 was administered via tail vein injection into Sprague-Dawley rats. Very low levels of radioactivity were found in all brain regions (0.08% injected dose/gram of tissue) at 5 and 30min post-injection, uncorrected for vascular compartment. Considering the extremely poor brain penetration of [(11)C]AR-A014418 this compound cannot be used to study GSK-3beta in cerebral PET studies. Furthermore, the specific pharmacological mechanism(s) of antidepressant-like activity attributed to AR-A014418 should be investigated. 相似文献