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1.
Eur J Nucl Med Mol Imaging ; 47(9): 2123-2130, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31938892

RESUMO

PURPOSE: To assess the safety, biodistribution, and radiation dosimetry of the novel positron emission tomography (PET) radiopharmaceutical 1-((2-fluoro-6-[[18F]]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([18F]DASA-23) in healthy volunteers. METHODS: We recruited 5 healthy volunteers who provided a written informed consent. Volunteers were injected with 295.0 ± 8.2 MBq of [18F]DASA-23 intravenously. Immediately following injection, a dynamic scan of the brain was acquired for 15 min. This was followed by serial whole-body PET/MRI scans acquired up to 3 h post-injection. Blood samples were collected at regular intervals, and vital signs monitored pre- and post-radiotracer administration. Regions of interest were drawn around multiple organs, time-activity curves were calculated, and organ uptake and dosimetry were estimated with OLINDA/EXM (version 1.1) software. RESULTS: All subjects tolerated the PET/MRI examination, without adverse reactions to [18F]DASA-23. [18F]DASA-23 passively crossed the blood-brain barrier, followed by rapid clearance from the brain. High accumulation of [18F]DASA-23 was noted in organs such as the gallbladder, liver, small intestine, and urinary bladder, suggesting hepatobiliary and urinary clearance. The effective dose of [18F]DASA-23 was 23.5 ± 5.8 µSv/MBq. CONCLUSION: We successfully completed a pilot first-in-human study of [18F]DASA-23. Our results indicate that [18F]DASA-23 can be used safely in humans to evaluate pyruvate kinase M2 levels. Ongoing studies are evaluating the ability of [18F]DASA-23 to visualize intracranial malignancies, NCT03539731. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03539731 (registered 28 May 2018).

2.
Mol Imaging Biol ; 22(1): 124-133, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-30989436

RESUMO

PURPOSE: Pyruvate kinase M2 (PKM2) catalyzes the final step in glycolysis, the key process of tumor metabolism. PKM2 is found in high levels in glioblastoma (GBM) cells with marginal expression within healthy brain tissue, rendering it a key biomarker of GBM metabolic re-programming. Our group has reported the development of a novel radiotracer, 1-((2-fluoro- 6-[18F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([18F]DASA- 23), to non-invasively detect PKM2 levels with positron emission tomography (PET). PROCEDURE: U87 human GBM cells were treated with the IC50 concentration of various agents used in the treatment of GBM, including alkylating agents (temozolomide, carmustine, lomustine, procarbazine), inhibitor of topoisomerase I (irinotecan), vascular endothelial and epidermal growth factor receptor inhibitors (cediranib and erlotinib, respectively) anti-metabolite (5-fluorouracil), microtubule inhibitor (vincristine), and metabolic agents (dichloroacetate and IDH1 inhibitor ivosidenib). Following drug exposure for three or 6 days (n = 6 replicates per condition), the radiotracer uptake of [18F]DASA-23 and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) was assessed. Changes in PKM2 protein levels were determined via Western blot and correlated to radiotracer uptake. RESULTS: Significant interactions were found between the treatment agent (n = 12 conditions total comprised 11 drugs and vehicle) and the duration of treatment (3- or 6-day exposure to each drug) on the cellular uptake of [18F]DASA-23 (p = 0.0001). The greatest change in the cellular uptake of [18F]DASA-23 was found after exposure to alkylating agents (p < 0. 0001) followed by irinotecan (p = 0. 0012), erlotinib (p = 0. 02), and 5-fluorouracil (p = 0. 005). Correlation of PKM2 protein levels and [18F]DASA-23 cellular uptake revealed a moderate correlation (r = 0.44, p = 0.15). CONCLUSIONS: These proof of principle studies emphasize the superiority of [18F]DASA-23 to [18F]FDG in detecting the glycolytic response of GBM to multiple classes of anti-neoplastic drugs in cell culture. A clinical trial evaluating the diagnostic utility of [18F]DASA-23 PET in GBM patients (NCT03539731) is ongoing.

3.
J Nucl Med ; 60(12): 1812-1817, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31171595

RESUMO

The aim of this study was development of an improved PET radiotracer for measuring xC - activity with increased tumor uptake and reduced uptake in inflammatory cells compared with (S)-4-(3-18F-fluoropropyl)-l-glutamate (18F-FSPG). Methods: A racemic glutamate derivative, 18F-hGTS13, was evaluated in cell culture and animal tumor models. 18F-hGTS13 was separated into C5 epimers, and the corresponding 18F-hGTS13-isomer1 and 18F-hGTS13-isomer2 were evaluated in H460 tumor-bearing rats. Preliminary studies investigated the cellular uptake of 18F-hGTS13-isomer2 in multiple immune cell populations and states. Results: 18F-hGTS13 demonstrated excellent H460 tumor visualization with high tumor-to-background ratios, confirmed by ex vivo biodistribution studies. Tumor-associated radioactivity was significantly higher for 18F-hGTS13 (7.5 ± 0.9 percentage injected dose [%ID]/g, n = 3) than for 18F-FSPG (4.6 ± 0.7 %ID/g, n = 3, P = 0.01). 18F-hGTS13-isomer2 exhibited excellent H460 tumor visualization (6.3 ± 1.1 %ID/g, n = 3) and significantly reduced uptake in multiple immune cell populations relative to 18F-FSPG. 18F-hGTS13-isomer2 exhibited increased liver uptake relative to 18F-FSPG (4.6 ± 0.8 vs. 0.7 ± 0.01 %ID/g), limiting its application in hepatocellular carcinoma. Conclusion: 18F-hGTS13-isomer2 is a new PET radiotracer for molecular imaging of xC - activity that may provide information on tumor oxidation states. 18F-hGTS13-isomer2 has potential for clinical translation for imaging cancers of the thorax because of the low background signal in healthy tissue.

4.
Proc Natl Acad Sci U S A ; 116(23): 11402-11407, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31123153

RESUMO

There is a growing need for monitoring or imaging gene therapy in the central nervous system (CNS). This can be achieved with a positron emission tomography (PET) reporter gene strategy. Here we report the development of a PET reporter gene system using the PKM2 gene with its associated radiotracer [18F]DASA-23. The PKM2 reporter gene was delivered to the brains of mice by adeno-associated virus (AAV9) via stereotactic injection. Serial PET imaging was carried out over 8 wk to assess PKM2 expression. After 8 wk, the brains were excised for further mRNA and protein analysis. PET imaging at 8 wk post-AAV delivery showed an increase in [18F]DASA-23 brain uptake in the transduced site of mice injected with the AAV mice over all controls. We believe PKM2 shows great promise as a PET reporter gene and to date is the only example that can be used in all areas of the CNS without breaking the blood-brain barrier, to monitor gene and cell therapy.


Assuntos
Sistema Nervoso Central/metabolismo , Genes Reporter/genética , Animais , Linhagem Celular Tumoral , Sistema Nervoso Central/virologia , Dependovirus/genética , Feminino , Radioisótopos de Flúor/administração & dosagem , Terapia Genética/métodos , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Tomografia por Emissão de Pósitrons/métodos
5.
Nat Biotechnol ; 37(5): 531-539, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30886438

RESUMO

Endogenous biomarkers remain at the forefront of early disease detection efforts, but many lack the sensitivities and specificities necessary to influence disease management. Here, we describe a cell-based in vivo sensor for highly sensitive early cancer detection. We engineer macrophages to produce a synthetic reporter on adopting an M2 tumor-associated metabolic profile by coupling luciferase expression to activation of the arginase-1 promoter. After adoptive transfer in colorectal and breast mouse tumor models, the engineered macrophages migrated to the tumors and activated arginase-1 so that they could be detected by bioluminescence imaging and luciferase measured in the blood. The macrophage sensor detected tumors as small as 25-50 mm3 by blood luciferase measurements, even in the presence of concomitant inflammation, and was more sensitive than clinically used protein and nucleic acid cancer biomarkers. Macrophage sensors also effectively tracked the immunological response in muscle and lung models of inflammation, suggesting the potential utility of this approach in disease states other than cancer.


Assuntos
Arginase/sangue , Detecção Precoce de Câncer , Macrófagos/imunologia , Neoplasias/sangue , Animais , Arginase/genética , Arginase/imunologia , Biomarcadores Tumorais/sangue , Engenharia Celular , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Humanos , Luciferases/sangue , Luciferases/genética , Luciferases/imunologia , Camundongos , Neoplasias/imunologia , Neoplasias/patologia
6.
Mol Imaging Biol ; 20(6): 1015-1024, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29736561

RESUMO

PURPOSE: There is a strong, unmet need for superior positron emission tomography (PET) imaging agents that are able to measure biochemical processes specific to prostate cancer. Pyruvate kinase M2 (PKM2) catalyzes the concluding step in glycolysis and is a key regulator of tumor growth and metabolism. Elevation of PKM2 expression was detected in Gleason 8-10 tumors compared to Gleason 6-7 carcinomas, indicating that PKM2 may potentially be a marker of aggressive prostate cancer. We have recently reported the development of a PKM2-specific radiopharmaceutical [18F]DASA-23 and herein describe its evaluation in cell culture and preclinical models of prostate cancer. PROCEDURE: The cellular uptake of [18F]DASA-23 was evaluated in a panel of prostate cancer cell lines and compared to that of [18F]FDG. The specificity of [18F]DASA-23 to measure PKM2 levels in cell culture was additionally confirmed through the use of PKM2-specific siRNA. PET imaging studies were then completed utilizing subcutaneous prostate cancer xenografts using either PC3 or DU145 cells in mice. RESULTS: [18F]DASA-23 uptake values over 60-min incubation period in PC3, LnCAP, and DU145 respectively were 23.4 ± 4.5, 18.0 ± 2.1, and 53.1 ± 4.6 % tracer/mg protein. Transient reduction in PKM2 protein expression with siRNA resulted in a 50.1 % reduction in radiotracer uptake in DU145 cells. Small animal PET imaging revealed 0.86 ± 0.13 and 1.6 ± 0.2 % ID/g at 30 min post injection of radioactivity in DU145 and PC3 subcutaneous tumor bearing mice respectively. CONCLUSION: Herein, we evaluated a F-18-labeled PKM2-specific radiotracer, [18F]DASA-23, for the molecular imaging of prostate cancer with PET. [18F]DASA-23 revealed rapid and extensive uptake levels in cellular uptake studies of prostate cancer cells; however, there was only modest tumor uptake when evaluated in mouse subcutaneous tumor models.


Assuntos
Compostos de Diazônio/química , Fluordesoxiglucose F18/química , Imagem Molecular/métodos , Tomografia por Emissão de Pósitrons/métodos , Neoplasias da Próstata/diagnóstico , Ácidos Sulfanílicos/química , Animais , Linhagem Celular Tumoral , Compostos de Diazônio/farmacocinética , Feminino , Fluordesoxiglucose F18/farmacocinética , Glicólise/fisiologia , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Nus , Transplante de Neoplasias , Células PC-3 , Valor Preditivo dos Testes , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Ácidos Sulfanílicos/farmacocinética
7.
J Labelled Comp Radiopharm ; 61(5): 408-414, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29314161

RESUMO

The aim of this study was to develop a positron emission tomography (PET) tracer to visualize and monitor therapeutic response to bacterial infections. In our continued efforts to find maltose based PET tracers that can image bacterial infections, we have designed and prepared 6''-[18 F]fluoromaltotriose as a second generation PET imaging tracer targeting the maltodextrin transporter of bacteria. We have developed methods to synthesize 6''-deoxy-6''-[18 F]fluoro-α-D-glucopyranosyl-(1-4)-O-α-D-glucopyranosyl-(1-4)-O-D-glucopyranose (6''-[18 F]-fluoromaltotriose) as a bacterial infection PET imaging agent. 6''-[18 F]fluoromaltotriose was prepared from precursor, 2'',3'',4''-tri-O-acetyl-6''-O-nosyl-α-D-glucopyranosyl-(1-4)-O-2',3',6'-tri-O-acetyl-α-D-glucopyranosyl-(1-4)-1,2,3,6-tetra-O-acetyl-D-glucopyranose (per-O-acetyl-6''-O-nosyl-maltotriose 4). This method utilizes the reaction between precursor 4 and anhydrous [18 F]KF/Kryptofix 2.2.2 in dimethylformamide (DMF) at 85°C for 10 minutes to yield per-O-acetyl-6''-deoxy-6-'' [18 F]-fluoromaltotriose (7). Successive acidic and basic hydrolysis of the acetyl protecting groups in 7 produced 6''-[18 F]fluoromaltotriose (8). Also, cold 6''- [19 F]fluoromaltotriose was prepared from per-O-acetyl-6''-hydroxymaltotriose via a diethylaminosulfur trifluoride reaction followed by a basic hydrolysis. A successful synthesis of 6''-[18 F]-fluoromaltotriose has been accomplished in 8 ± 1.2% radiochemical yield (decay corrected). Total synthesis time was 120 minutes. Serum stability of 6''-[18 F]fluoromaltotriose at 37°C indicated that 6''-[18 F]-fluoromaltotriose remained intact up to 2 hours. In conclusion, we have successfully synthesized 6''-[18 F]-fluoromaltotriose via direct fluorination of an appropriate precursor of a protected maltotriose.


Assuntos
Infecções Bacterianas/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/síntese química , Trissacarídeos/síntese química , Animais , Feminino , Humanos , Camundongos , Compostos Radiofarmacêuticos/farmacocinética , Distribuição Tecidual , Trissacarídeos/farmacocinética
8.
Mol Imaging Biol ; 19(5): 665-672, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28236227

RESUMO

PURPOSE: A hallmark of cancer is metabolic reprogramming, which is exploited by cancer cells to ensure rapid growth and survival. Pyruvate kinase M2 (PKM2) catalyzes the final step in glycolysis, a key step in tumor metabolism and growth. Recently, we reported the radiosynthesis of the first positron emission tomography tracer for visualizing PKM2 in vivo-i.e., [11C]DASA-23. Due to the highly promising imaging results obtained with [11C]DASA-23 in rodent model glioblastoma, we set out to generate an F-18-labeled version of this tracer, with the end goal of clinical translation in mind. Herein, we report the radiosynthesis of 1-((2-fluoro-6-[18F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([18F]DASA-23) and our initial investigation of its binding properties in cancer cells. PROCEDURE: We synthesized [18F]DASA-23 via fluorination of 1-((2-fluoro-6-nitrophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine (10) with K[18F]F/K2.2.2 in N,N-dimethylformamide at 110 °C for 20 min. Subsequently, we evaluated uptake of [18F]DASA-23 in HeLa cervical adenocarcinoma cells and in vitro stability in human and mouse serum. RESULTS: We successfully prepared [18F]DASA-23 in 2.61 ± 1.54 % radiochemical yield (n = 10, non-decay corrected at end of synthesis) with a specific activity of 2.59 ± 0.44 Ci/µmol. Preliminary cell uptake experiments revealed high uptake in HeLa cells, which was effectively blocked by pretreating cells with the structurally distinct PKM2 activator, TEPP-46. [18F]DASA-23 remained intact in human and mouse serum up to 120 min. CONCLUSION: Herein, we have identified a F-18-labeled PKM2 specific radiotracer which shows potential for in vivo imaging. The promising cell uptake results reported herein warrant the further evaluation of [18F]DASA-23 for its ability to detect and monitor cancer noninvasively.


Assuntos
Neoplasias/metabolismo , Piperazinas/química , Piruvato Quinase/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Ativadores de Enzimas/farmacologia , Glicólise , Células HeLa , Humanos , Camundongos , Neoplasias/enzimologia , Piperazinas/síntese química
9.
EJNMMI Res ; 6(1): 80, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27826950

RESUMO

BACKGROUND: The availability of GABAA receptor binding sites in the brain can be assessed by positron emission tomography (PET) using the radioligand, [18F]flumazenil. However, the brain uptake and binding of this PET radioligand are influenced by anesthetic drugs, which are typically needed in preclinical imaging studies and clinical imaging studies involving patient populations that do not tolerate relatively longer scan times. The objective of this study was to examine the effects of anesthesia on the binding of [18F]flumazenil to GABAA receptors in mice. METHODS: Brain and whole blood radioactivity concentrations were measured ex vivo by scintillation counting or in vivo by PET in four groups of mice following administration of [18F]flumazenil: awake mice and mice anesthetized with isoflurane, dexmedetomidine, or ketamine/dexmedetomidine. Dynamic PET recordings were obtained for 60 min in mice anesthetized by either isoflurane or ketamine/dexmedetomidine. Static PET recordings were obtained at 25 or 55 min after [18F]flumazenil injection in awake or dexmedetomidine-treated mice acutely anesthetized with isoflurane. The apparent distribution volume (VT*) was calculated for the hippocampus and frontal cortex from either the full dynamic PET scans using an image-derived input function or from a series of ex vivo experiments using whole blood as the input function. RESULTS: PET images showed persistence of high [18F]flumazenil uptake (up to 20 % ID/g) in the brains of mice scanned under isoflurane or ketamine/dexmedetomidine anesthesia, whereas uptake was almost indiscernible in late samples or static scans from awake or dexmedetomidine-treated animals. The steady-state VT* was twofold higher in hippocampus of isoflurane-treated mice and dexmedetomidine-treated mice than in awake mice. CONCLUSIONS: Anesthesia has pronounced effects on the binding and blood-brain distribution of [18F]flumazenil. Consequently, considerable caution must be exercised in the interpretation of preclinical and clinical PET studies of GABAA receptors involving the use of anesthesia.

10.
Curr Pharm Des ; 22(14): 2134-51, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26818858

RESUMO

Homomeric α7 nicotinic acetylcholine receptors (nAChRs) are implicated in the regulation of cognitive processes such as memory and attention and have potential as therapeutic targets for the treatment of the cognitive deficits associated with schizophrenia. Though numerous α7 nAChR agonists have been developed, and several have progressed to clinical trials, these are derived from few common chemotypes. Consequently, many of these α7 nAChR clinical candidates share unfavorable side-effect profile. SEN12333 represents a novel chemotype for the development of α7 nAChR agonists, and exploration of this scaffold has produced structurally diverse ligands with promising pharmacological properties. This review will summarize structure-affinity and -activity relationships surrounding analogs of SEN12333.


Assuntos
Doenças do Sistema Nervoso Central/tratamento farmacológico , Morfolinas/farmacologia , Agonistas Nicotínicos/farmacologia , Piridinas/farmacologia , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Animais , Humanos , Ligantes , Morfolinas/química , Agonistas Nicotínicos/química , Piridinas/química
11.
CNS Drugs ; 29(7): 529-42, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26242477

RESUMO

Homomeric α7 nicotinic acetylcholine receptors (α7 nAChRs) have implications in the regulation of cognitive processes such as memory and attention, and have shown promise as a therapeutic target for the treatment of the cognitive deficits associated with schizophrenia. Multiple α7 nAChR agonists have entered human trials; however, unfavorable side effects and pharmacokinetic issues have hindered the development of a clinical α7 nAChR agonist. Currently, EVP-6124 is in phase III clinical trials, and several other α7 nAChR agonists (GTS-21 and AQW051) are in earlier stages of development. This review will summarize the recent advances and failures of α7 nAChR agonists in clinical trials for the treatment of the aforementioned pathology.


Assuntos
Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/fisiopatologia , Agonistas Nicotínicos/uso terapêutico , Nootrópicos/uso terapêutico , Esquizofrenia/fisiopatologia , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Animais , Ensaios Clínicos como Assunto , Transtornos Cognitivos/etiologia , Humanos , Agonistas Nicotínicos/farmacologia , Nootrópicos/farmacologia , Esquizofrenia/complicações , Esquizofrenia/tratamento farmacológico , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
12.
ACS Chem Neurosci ; 6(9): 1546-59, 2015 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-26134475

RESUMO

Synthetic cannabinoid (SC) designer drugs based on indole and indazole scaffolds and featuring l-valinamide or l-tert-leucinamide side chains are encountered with increasing frequency by forensic researchers and law enforcement agencies and are associated with serious adverse health effects. However, many of these novel SCs are unprecedented in the scientific literature at the time of their discovery, and little is known of their pharmacology. Here, we report the synthesis and pharmacological characterization of AB-FUBINACA, ADB-FUBINACA, AB-PINACA, ADB-PINACA, 5F-AB-PINACA, 5F-ADB-PINACA, ADBICA, 5F-ADBICA, and several analogues. All synthesized SCs acted as high potency agonists of CB1 (EC50 = 0.24-21 nM) and CB2 (EC50 = 0.88-15 nM) receptors in a fluorometric assay of membrane potential, with 5F-ADB-PINACA showing the greatest potency at CB1 receptors. The cannabimimetic activities of AB-FUBINACA and AB-PINACA in vivo were evaluated in rats using biotelemetry. AB-FUBINACA and AB-PINACA dose-dependently induced hypothermia and bradycardia at doses of 0.3-3 mg/kg, and hypothermia was reversed by pretreatment with a CB1 (but not CB2) antagonist, indicating that these SCs are cannabimimetic in vivo, consistent with anecdotal reports of psychoactivity in humans.


Assuntos
Agonistas de Receptores de Canabinoides/farmacologia , Drogas Desenhadas/farmacologia , Indazóis/farmacologia , Indóis/farmacologia , Animais , Temperatura Corporal/efeitos dos fármacos , Agonistas de Receptores de Canabinoides/síntese química , Agonistas de Receptores de Canabinoides/química , Antagonistas de Receptores de Canabinoides/farmacologia , Linhagem Celular Tumoral , Estudos de Coortes , Drogas Desenhadas/síntese química , Drogas Desenhadas/química , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Frequência Cardíaca/efeitos dos fármacos , Humanos , Indazóis/síntese química , Indazóis/química , Indóis/síntese química , Indóis/química , Masculino , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Estrutura Molecular , Ratos Wistar , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/genética , Receptor CB2 de Canabinoide/metabolismo
13.
ACS Chem Neurosci ; 6(8): 1445-58, 2015 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-25921407

RESUMO

Synthetic cannabinoid (SC) designer drugs featuring bioisosteric fluorine substitution are identified by forensic chemists and toxicologists with increasing frequency. Although terminal fluorination of N-pentyl indole SCs is sometimes known to improve cannabinoid type 1 (CB1) receptor binding affinity, little is known of the effects of fluorination on functional activity of SCs. This study explores the in vitro functional activities of SC designer drugs JWH-018, UR-144, PB-22, and APICA, and their respective terminally fluorinated analogues AM-2201, XLR-11, 5F-PB-22, and STS-135 at human CB1 and CB2 receptors using a FLIPR membrane potential assay. All compounds demonstrated agonist activity at CB1 (EC50 = 2.8-1959 nM) and CB2 (EC50 = 6.5-206 nM) receptors, with the fluorinated analogues generally showing increased CB1 receptor potency (∼2-5 times). Additionally, the cannabimimetic activities and relative potencies of JWH-018, AM-2201, UR-144, XLR-11, PB-22, 5F-PB-22, APICA, and STS-135 in vivo were evaluated in rats using biotelemetry. All SCs dose-dependently induced hypothermia and reduced heart rate at doses of 0.3-10 mg/kg. There was no consistent trend for increased potency of fluorinated SCs over the corresponding des-fluoro SCs in vivo. Based on magnitude and duration of hypothermia, the SCs were ranked for potency (PB-22 > 5F-PB-22 = JWH-018 > AM-2201 > APICA = STS-135 = XLR-11 > UR-144).


Assuntos
Canabinoides/química , Canabinoides/farmacologia , Drogas Desenhadas/química , Drogas Desenhadas/farmacologia , Adamantano/análogos & derivados , Adamantano/química , Adamantano/farmacologia , Animais , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hipotermia/induzido quimicamente , Indóis/química , Indóis/farmacologia , Masculino , Camundongos , Estrutura Molecular , Naftalenos/química , Naftalenos/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Ratos Wistar , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/genética , Receptor CB2 de Canabinoide/metabolismo , Telemetria
14.
Eur J Med Chem ; 95: 277-301, 2015 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-25827398

RESUMO

Alpha7 nicotinic acetylcholine receptors (nAChRs) have implications in the regulation of cognitive processes such as memory and attention and have been identified as a promising therapeutic target for the treatment of the cognitive deficits associated with schizophrenia and Alzheimer's disease (AD). Structure affinity relationship studies of the previously described α7 agonist SEN12333 (8), have resulted in the identification of compound 45, a potent and selective agonist of the α7 nAChR with enhanced affinity and improved physicochemical properties over the parent compound (SEN12333, 8).


Assuntos
Descoberta de Drogas , Morfolinas/química , Morfolinas/metabolismo , Piridinas/química , Piridinas/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Células HEK293 , Humanos , Modelos Moleculares , Morfolinas/farmacologia , Ligação Proteica , Conformação Proteica , Piridinas/farmacologia , Relação Estrutura-Atividade , Receptor Nicotínico de Acetilcolina alfa7/química
15.
Eur J Med Chem ; 93: 392-400, 2015 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-25725375

RESUMO

Sixteen new phenyl alkyl ether derivatives (12, 14-28) of the 5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-ylacetamide (DPA) class were synthesized and evaluated in a competition binding assay against [(3)H]PK11195 using 18 kDa translocator protein (TSPO) derived from rat kidney mitochondrial fractions. All analogues showed superior binding affinities for TSPO compared to DPA-713 (5) and DPA-714 (6). Picomolar affinities were observed for this class of TSPO ligands in this assay for the first time, with phenethyl ether 28 showing the greatest affinity (Ki = 0.13 nM). Additionally, all analogues increased pregnenolone biosynthesis (134-331% above baseline) in a rat C6 glioma cell steroidogenesis assay.


Assuntos
Proteínas de Transporte/metabolismo , Éteres/química , Pirazóis/química , Pirazóis/metabolismo , Pirimidinas/química , Pirimidinas/metabolismo , Receptores de GABA-A/metabolismo , Acetamidas/química , Acetamidas/metabolismo , Animais , Linhagem Celular Tumoral , Ligação Proteica , Ratos
16.
Eur J Med Chem ; 84: 200-5, 2014 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-25019477

RESUMO

Several lines of experimental evidence support the involvement of the α7 nAChR in schizophrenia and Alzheimer's disease. Modulators of the α7 nAChR have been extensively reviewed for the treatment of the cognitive deficits associated with these pathologies. SEN12333 represents a novel α7 nAChR agonist chemotype with potential for reduced side effects but requiring further SAR exploration. The present work investigates the amide bond of SEN12333, specifically its connectivity and replacement with the tetrazole functionality, a known cis amide isostere. The results reveal the original amide bond connectivity of SEN12333 to be favorable for binding affinity and agonist activity at α7 nAChRs. The use of a tetrazole isostere completely abolishes affinity and functional activity and suggests that SEN12333 binds in a linear conformation. Results reported herein also suggest the pyridine nitrogen within the terminal aromatic ring of SEN12333 is not essential for binding affinity or functional activity. Further SAR investigations involving manipulation of other moieties contained within SEN12333 are warranted.


Assuntos
Amidas/química , Morfolinas/química , Morfolinas/farmacologia , Agonistas Nicotínicos/química , Agonistas Nicotínicos/farmacologia , Piridinas/química , Piridinas/farmacologia , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Morfolinas/síntese química , Agonistas Nicotínicos/síntese química , Piridinas/síntese química , Relação Estrutura-Atividade
17.
Bioorg Med Chem Lett ; 24(3): 828-30, 2014 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-24412068

RESUMO

GluN2B subtype-selective NMDA antagonists represent promising therapeutic targets for the symptomatic treatment of multiple CNS pathologies. A series of N-benzyl substituted benzamidines were synthesised and the benzyl ring was further replaced with various polycyclic moieties. Compounds were evaluated for activity at GluN2B containing NMDA receptors where analogues 9, 12, 16 and 18 were the most potent of the series, replacement of the benzyl ring with polycycles resulted in a complete loss of activity.


Assuntos
Benzamidinas/química , Benzamidinas/farmacologia , Flúor/química , Glutamatos/química , Receptores de N-Metil-D-Aspartato/química , Benzamidinas/síntese química , Ciclização , Glutamatos/metabolismo , Compostos Policíclicos/síntese química , Compostos Policíclicos/química , Ligação Proteica/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Relação Estrutura-Atividade
18.
Bioorg Med Chem Lett ; 22(7): 2380-4, 2012 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-22410083

RESUMO

A series of ligands based on SEN12333, containing either contracted or elongated alkyl chains, were synthesized and evaluated in molecular docking studies against a homology model of the α7 nicotinic acetylcholine receptor (nAChR) subtype. The predicted binding of all ligands was highly similar, with the exception of the analog containing a 5 methylene unit spacer. However, in vitro competition binding assays revealed that the ligands possessed dissimilar binding affinities, with a K(i) range of more than an order of magnitude (K(i)=0.50 to >10 µM), and only SEN12333 itself exhibited functional activity at the α7 nAChR.


Assuntos
Morfolinas/síntese química , Agonistas Nicotínicos/síntese química , Piridinas/síntese química , Sítios de Ligação , Simulação por Computador , Humanos , Cinética , Ligantes , Modelos Moleculares , Morfolinas/metabolismo , Agonistas Nicotínicos/metabolismo , Ligação Proteica , Piridinas/metabolismo , Receptores Nicotínicos/química , Receptores Nicotínicos/metabolismo , Receptor Nicotínico de Acetilcolina alfa7
19.
Bioorg Med Chem Lett ; 21(1): 38-41, 2011 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-21146989

RESUMO

In our continued exploration of trishomocubane derivatives with central nervous system (CNS) activity, N-arylalkyl-8-aminopentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecanes (10-13) displaying affinity for the sigma (σ) receptor were also found, in several cases, to interact with the dopamine transporter (DAT). Compound 12 was identified as the first trishomocubane-derived high affinity DAT ligand (K(i) = 1.2 nM), with greater than 8300-fold selectivity over the monoamine transporters NET and SERT, and only low to moderate affinity for σ(1) and σ(2) receptors.


Assuntos
Alcanos/química , Benzilaminas/química , Hidrocarbonetos Aromáticos com Pontes/química , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Inibidores da Captação de Dopamina/química , Alcanos/síntese química , Alcanos/farmacologia , Benzilaminas/síntese química , Benzilaminas/farmacologia , Hidrocarbonetos Aromáticos com Pontes/síntese química , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Inibidores da Captação de Dopamina/síntese química , Inibidores da Captação de Dopamina/farmacologia , Ligantes , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Ligação Proteica , Receptores sigma/antagonistas & inibidores , Receptores sigma/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/química , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Relação Estrutura-Atividade
20.
J Med Chem ; 53(16): 6228-39, 2010 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-20662542

RESUMO

A series of N-(benzofuran-2-ylmethyl)-N'-benzylpiperazines bearing alkyl or fluoroalkyl aryl ethers were synthesized and evaluated at various central nervous system receptors. Examination of in vitro sigma1 {[3H]+-pentazocine} and sigma2 ([3H]DTG) receptor binding profiles of piperazines 11-13 and 25-36 revealed several highly potent and sigma1 selective ligands, notably, N-(benzofuran-2-ylmethyl)-N'-(4'-methoxybenzyl)piperazine (13, Ki=2.7 nM, sigma2/sigma1=38) and N-(benzofuran-2-ylmethyl)-N'-(4'-(2''-fluoroethoxy)benzyl)piperazine (30, Ki=2.6 nM, sigma2/sigma1=187). Structural features for optimal sigma1 receptor affinity and selectivity over the sigma2 receptor were identified. On the basis of its favorable log D value, 13 was selected as a candidate for the development of a sigma1 receptor positron emission tomography radiotracer. [11C]13 showed high uptake in the brain and other sigma receptor-rich organs of a Papio hamadryas baboon. The in vivo evaluation of [11C]13 indicates that this radiotracer is a suitable candidate for imaging the sigma1 receptor in neurodegenerative processes.


Assuntos
Benzofuranos/síntese química , Piperazinas/síntese química , Compostos Radiofarmacêuticos/síntese química , Receptores sigma/metabolismo , Animais , Benzofuranos/química , Benzofuranos/farmacocinética , Ligação Competitiva , Encéfalo/metabolismo , Radioisótopos de Carbono , Éteres/síntese química , Éteres/química , Éteres/farmacocinética , Técnicas In Vitro , Ligantes , Células PC12 , Papio , Piperazinas/química , Piperazinas/farmacocinética , Tomografia por Emissão de Pósitrons , Ensaio Radioligante , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Distribuição Tecidual
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