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1.
Mol Pharm ; 15(2): 695-702, 2018 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-29298483

RESUMO

Dyshomeostasis or abnormal accumulation of metal ions such as copper, zinc, and iron have been linked to the pathogenesis of multiple neurodegenerative disorders including Alzheimer's disease (AD) and Huntington's disease (HD). 5,7-Dichloro-2-((dimethylamino)methyl)quinolin-8-ol, PBT2, is a second generation metal protein-attenuating compound that has recently advanced in Phase II clinical trials for the treatment of AD and HD based on promising preclinical efficacy data. Herein, we report the first radiosynthesis and preclinical positron emission tomography (PET) neuroimaging evaluation of [11C]PBT2 in rodents and nonhuman primates. Carbon-11 labeled PBT2 was synthesized in 4.8 ± 0.5% (nondecay corrected) radiochemical yield (RCY) at end-of-synthesis, based upon [11C]CH3I (n = 6), with >99% radiochemical purity and 80-90 GBq/µmol molar activity (Am) from the corresponding normethyl precursor. In the nonhuman primate brain, [11C]PBT2 uptake was extensive with peak concentration SUVpeak of 3.2-5.2 within 2.5-4.5 min postinjection in all cortical and subcortical gray matter regions (putamen > caudate > cortex ≫ white matter) followed by rapid washout from normal brain tissues. Furthermore, it is shown that [11C]PBT2 binds specifically in AD human brain tissue in vitro. The results presented here, combined with the clinical data available for PBT2, warrant the evaluation of [11C]PBT2 as an exploratory PET radiotracer in humans.


Assuntos
Radioisótopos de Carbono , Clioquinol/análogos & derivados , Neuroimagem/métodos , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/administração & dosagem , Doença de Alzheimer/patologia , Animais , Autorradiografia , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/patologia , Clioquinol/administração & dosagem , Clioquinol/síntese química , Clioquinol/farmacocinética , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Masculino , Camundongos Endogâmicos BALB C , Papio anubis , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética
2.
Angew Chem Int Ed Engl ; 55(33): 9601-5, 2016 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-27355874

RESUMO

Glycogen synthase kinase-3 (GSK-3) regulates multiple cellular processes in diabetes, oncology, and neurology. N-(3-(1H-1,2,4-triazol-1-yl)propyl)-5-(3-chloro-4-methoxyphenyl)oxazole-4-carboxamide (PF-04802367 or PF-367) has been identified as a highly potent inhibitor, which is among the most selective antagonists of GSK-3 to date. Its efficacy was demonstrated in modulation of tau phosphorylation in vitro and in vivo. Whereas the kinetics of PF-367 binding in brain tissues are too fast for an effective therapeutic agent, the pharmacokinetic profile of PF-367 is ideal for discovery of radiopharmaceuticals for GSK-3 in the central nervous system. A (11) C-isotopologue of PF-367 was synthesized and preliminary PET imaging studies in non-human primates confirmed that we have overcome the two major obstacles for imaging GSK-3, namely, reasonable brain permeability and displaceable binding.


Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/diagnóstico por imagem , Neuroimagem , Oxazóis/farmacologia , Tomografia por Emissão de Pósitrons , Inibidores de Proteínas Quinases/farmacologia , Triazóis/farmacologia , Proteínas tau/antagonistas & inibidores , Encéfalo/metabolismo , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Oxazóis/síntese química , Oxazóis/química , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Triazóis/síntese química , Triazóis/química , Proteínas tau/metabolismo
3.
Biol Psychiatry ; 62(9): 1059-61, 2007 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-17511972

RESUMO

BACKGROUND: The dopamine transporter (DAT) is known to be a key regulator of dopamine, and recent studies of genetics, treatment, and imaging have highlighted the role of DAT in attention-deficit/hyperactivity disorder (ADHD). The findings of in vivo neuroimaging of DAT in ADHD have been somewhat discrepant, however. METHOD: Dopamine transporter binding was measured using a highly selective ligand (C-11 altropane) and positron emission tomography (PET). The sample consisted of 47 well-characterized, treatment-naïve, nonsmoking, non-comorbid adults with and without ADHD. Additionally, control subjects had few symptoms of ADHD. RESULTS: Results showed significantly increased DAT binding in the right caudate in adults with ADHD compared with matched control subjects without this disorder. CONCLUSIONS: These results confirm abnormal DAT binding in the striatum of adults with ADHD and provide further support that dysregulation of DAT may be an important component of the pathophysiology of ADHD.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Cocaína/análogos & derivados , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Tomografia por Emissão de Pósitrons , Adolescente , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico por imagem , Transtorno do Deficit de Atenção com Hiperatividade/patologia , Distribuição de Qui-Quadrado , Corpo Estriado/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
4.
Am J Psychiatry ; 163(3): 387-95, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16513858

RESUMO

OBJECTIVE: The abuse potential of methylphenidate has been related to the drug's capacity to produce a rapid onset of blockade of the presynaptic dopamine transporter in the brain. An oral once-a-day osmotic controlled-release formulation of methylphenidate produces a more gradual rise in plasma methylphenidate concentration, compared with immediate-release methylphenidate. The authors hypothesized that osmotic-release methylphenidate would also produce a slower onset of blockade of the presynaptic dopamine transporter and would be associated with a lower risk for detection and likeability, compared to immediate-release methylphenidate. METHOD: Twelve healthy adults were randomly assigned to receive single doses of immediate-release methylphenidate or osmotic-release methylphenidate. Doses predicted to produce equivalent maximum concentration (C(max)) values were selected (40 mg of immediate-release methylphenidate and 90 mg of osmotic-release methylphenidate). Plasma d-methylphenidate levels and responses to detection/likeability questionnaire items were obtained hourly for 10 hours after administration of methylphenidate on two separate occasions for each subject. Dopamine transporter receptor occupancies were measured at hours 1, 3, 5, and 7 by using a carbon-11-labeled imaging agent (Altropane) and positron emission tomography. RESULTS: Despite similar C(max) values for both formulations, osmotic-release methylphenidate was associated with a longer time to maximum concentration, longer time to maximum CNS dopamine transporter occupancy, and no detection/likeability, compared with immediate-release methylphenidate. CONCLUSIONS: The findings suggest that the abuse potential of oral methylphenidate is strongly influenced by the rate of delivery and not solely by the magnitude of plasma concentration or brain transporter occupancy. These results advance understanding of the underlying central effects of methylphenidate in humans and identify a potentially less abusable methylphenidate formulation.


Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Metilfenidato/farmacocinética , Tomografia por Emissão de Pósitrons , Administração Oral , Adolescente , Adulto , Comportamento Aditivo/etiologia , Encéfalo/efeitos dos fármacos , Cocaína/análogos & derivados , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Preparações de Ação Retardada , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Metilfenidato/efeitos adversos , Metilfenidato/sangue , Pessoa de Meia-Idade , Osmose , Detecção do Abuso de Substâncias
5.
Life Sci ; 73(12): 1577-85, 2003 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-12865097

RESUMO

Methyl 2-(methoxycarbonyl) -2-(methylamino) bicyclo[2.1.1] -hexane -5-carboxylate (MMMHC) is developed as a potential neuroprotective drug. It was labeled with C-11 from the desmethyl precursor methyl 2-(methoxycarbonyl)-2-amino bicyclo[2.1.1]-hexane-5-carboxylate with [11C]methyl triflate in acetone solution at 60 degrees C with labeling yield of 69% and with radiochemical purity of >99%. Positron Emission Tomography (PET) studies in a normal rat showed that Methyl 2-(methoxycarbonyl)-2-([11C]methylamino)bicyclo[2.1.1]-hexane-5-carboxylate ([11C] MMMHC) accumulated mainly in the cortical brain areas after iv administration. Frontal cortex/cerebellum ratios in a rat brain were 8.0/6.0, 6.8/4.2, 6.3/4.3, 5.5/4.2 and 5.2/4.5 percent of the injected dose in 100 ml at 2 min, 5 min, 10 min, 20 min and 40 min respectively after i.v. injection. During 20-40 min, 2.9+/-0.4% of the total activity stayed in the brain. These results showed that MMMHC could be labeled with C-11 with high yield, and it passed the brain-blood barrier and accumulated in several brain regions.


Assuntos
Encéfalo/metabolismo , Compostos Bicíclicos com Pontes/farmacocinética , Fármacos Neuroprotetores/farmacocinética , Animais , Encéfalo/diagnóstico por imagem , Radioisótopos de Carbono , Cromatografia Líquida de Alta Pressão , Marcação por Isótopo/métodos , Ratos , Distribuição Tecidual , Tomografia Computadorizada de Emissão
6.
Neuroimage ; 19(3): 1049-60, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12880831

RESUMO

Over the last decade, it has become possible to study theories of cognition using positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). These methods yield statistical parametric maps of changes in cerebral blood flow (CBF) elicited by cognitive tasks. A limitation of these studies is that they provide no information about the underlying neurochemistry. However, it is possible to extend the concept of activation studies to include measurements targeting neurotransmitters and specific receptor populations. Cognitive activation increases neuronal firing rate, increasing the endogenous neurotransmitter level. The increased neurotransmitter level can be used to alter the kinetics of specifically bound radioligands. We describe a new approach to the design and analysis of neuromodulation experiments. This approach uses PET, a single-scan session design, and a linear extension of the simplified reference region model (LSSRM) that accounts for changes in ligand binding induced by cognitive tasks or drug challenge. In the LSSRM, an "activation" parameter is included that represents the presence or absence of change in apparent dissociation rate. Activation of the neurotransmitter is detected statistically when the activation parameter is shown to violate the null hypothesis. Simulation was used to explore the properties of the LSSRM with regard to model identifiability, effect of statistical noise, and confounding effects of CBF-related changes. Simulation predicted that it is possible to detect and map neuromodulatory changes in single-subject designs. A human study was conducted to confirm the predictions of simulation using (11)C-raclopride and a motor planning task. Parametric images of transport, binding potential, areas of significant dopamine release, and statistical parameters were computed. Examination of the kinetics of activation demonstrated that maximum dopamine release occurred immediately following task initiation and then decreased with a half-time of about 3 min. This method can be extended to explore neurotransmitter involvement in other behavioral and cognitive domains.


Assuntos
Mapeamento Encefálico/métodos , Encéfalo/fisiologia , Neurotransmissores/fisiologia , Adulto , Algoritmos , Cognição/fisiologia , Simulação por Computador , Antagonistas de Dopamina/farmacocinética , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Cinética , Modelos Lineares , Masculino , Modelos Neurológicos , Neurotransmissores/líquido cefalorraquidiano , Projetos Piloto , Desempenho Psicomotor/fisiologia , Racloprida/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Tomografia Computadorizada de Emissão
7.
Neuroimage ; 20(2): 1064-75, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-14568476

RESUMO

Neurophysiological studies of the brain in normal and Parkinson's disease (PD) patients have indicated intricate connections for basal ganglia-induced control of signaling into the motor cortex. To investigate if similar mechanisms are controlling function in the primate brain (Macaca fascicularis) after MPTP-induced neurotoxicity, we conducted PET studies of cerebral blood flow, oxygen and glucose metabolism, dopamine transporter, and D2 receptor function. Our observations after MPTP-induced dopamine terminal degeneration of the caudate and putamen revealed increased blood flow (15%) in the globus pallidus (GP), while blood flow was moderately decreased (15-25%) in the caudate, putamen, and thalamus and 40 % in the primary motor cortex (PMC). Oxygen extraction fraction was moderately increased (10-20%) in other brain areas but the thalamus, where no change was observable. Oxygen metabolism was increased in the GP and SMA (supplementary motor area including premotor cortex, Fig. 3) by a range of 20-40% and decreased in the putamen and caudate and in the PMC. Glucose metabolism was decreased in the caudate, putamen, thalamus, and PMC (range 35-50%) and enhanced in the GP by 15%. No change was observed in the SMA. In the parkinsonian primate, [(11)C]CFT (2beta-carbomethoxy-3beta-(4-fluorophenyltropane) dopamine transporter binding was significantly decreased in the putamen and caudate (range 60-65%). [(11)C]Raclopride binding of dopamine D(2) receptors did not show any significant changes. These experimental results obtained in primate studies of striato-thalamo-cortico circuitry show a similar trend as hypothetized in Parkinson's disease-type degeneration.


Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Mapeamento Encefálico , Encéfalo/fisiopatologia , Dopaminérgicos/toxicidade , Glicoproteínas de Membrana , Proteínas do Tecido Nervoso , Doença de Parkinson Secundária/fisiopatologia , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Química Encefálica/fisiologia , Circulação Cerebrovascular/fisiologia , Proteínas da Membrana Plasmática de Transporte de Dopamina , Metabolismo Energético/fisiologia , Glucose/metabolismo , Macaca fascicularis , Imageamento por Ressonância Magnética , Masculino , Proteínas de Membrana Transportadoras/metabolismo , Atividade Motora/fisiologia , Oxigênio/sangue , Consumo de Oxigênio/fisiologia , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/patologia , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D2/metabolismo , Reprodutibilidade dos Testes , Tomografia Computadorizada de Emissão
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