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1.
J Med Chem ; 60(16): 6897-6910, 2017 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-28696690

RESUMO

The proto-oncogenes NTRK1/2/3 encode the tropomyosin receptor kinases TrkA/B/C which play pivotal roles in neurobiology and cancer. We describe herein the discovery of [11C]-(R)-3 ([11C]-(R)-IPMICF16), a first-in-class positron emission tomography (PET) TrkB/C-targeting radiolabeled kinase inhibitor lead. Relying on extensive human kinome vetting, we show that (R)-3 is the most potent and most selective TrkB/C inhibitor characterized to date. It is demonstrated that [11C]-(R)-3 readily crosses the blood-brain barrier (BBB) in rodents and selectively binds to TrkB/C receptors in vivo, as evidenced by entrectinib blocking studies. Substantial TrkB/C-specific binding in human brain tissue is observed in vitro, with specific reduction in the hippocampus of Alzheimer's disease (AD) versus healthy brains. We additionally provide preliminary translational data regarding the brain disposition of [11C]-(R)-3 in primates including first-in-human assessment. These results illustrate for the first time the use of a kinome-wide selective radioactive chemical probe for endogenous kinase PET neuroimaging in human.


Assuntos
Imidazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridazinas/farmacologia , Compostos Radiofarmacêuticos/farmacologia , Receptor trkB/antagonistas & inibidores , Receptor trkC/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Doença de Alzheimer/diagnóstico por imagem , Animais , Benzamidas/farmacologia , Barreira Hematoencefálica/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Radioisótopos de Carbono , Cães , Humanos , Imidazóis/síntese química , Imidazóis/farmacocinética , Indazóis/farmacologia , Macaca mulatta , Células Madin Darby de Rim Canino , Glicoproteínas de Membrana/antagonistas & inibidores , Camundongos , Neuroimagem , Tomografia por Emissão de Pósitrons , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Piridazinas/síntese química , Piridazinas/farmacocinética , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Ratos Sprague-Dawley , Receptor trkA/antagonistas & inibidores , Estereoisomerismo , Relação Estrutura-Atividade
2.
ACS Chem Neurosci ; 8(7): 1530-1542, 2017 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-28322043

RESUMO

Fluorine-18 labeled phenethylguanidines are currently under development in our laboratory as radiotracers for quantifying regional cardiac sympathetic nerve density using PET imaging techniques. In this study, we report an efficient synthesis of 18F-hydroxyphenethylguanidines consisting of nucleophilic aromatic [18F]fluorination of a protected diaryliodonium salt precursor followed by a single deprotection step to afford the desired radiolabeled compound. This approach has been shown to reliably produce 4-[18F]fluoro-m-hydroxyphenethylguanidine ([18F]4F-MHPG, [18F]1) and its structural isomer 3-[18F]fluoro-p-hydroxyphenethylguanidine ([18F]3F-PHPG, [18F]2) with good radiochemical yields. Preclinical evaluations of [18F]2 in nonhuman primates were performed to compare its imaging properties, metabolism, and myocardial kinetics with those obtained previously with [18F]1. The results of these studies have demonstrated that [18F]2 exhibits imaging properties comparable to those of [18F]1. Myocardial tracer kinetic analysis of each tracer provides quantitative metrics of cardiac sympathetic nerve density. Based on these findings, first-in-human PET studies with [18F]1 and [18F]2 are currently in progress to assess their ability to accurately measure regional cardiac sympathetic denervation in patients with heart disease, with the ultimate goal of selecting a lead compound for further clinical development.


Assuntos
Guanidinas , Coração/inervação , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Sistema Nervoso Simpático/diagnóstico por imagem , Animais , Avaliação Pré-Clínica de Medicamentos , Guanidinas/sangue , Guanidinas/síntese química , Guanidinas/química , Coração/diagnóstico por imagem , Técnicas In Vitro , Isomerismo , Cinética , Macaca mulatta , Masculino , Estrutura Molecular , Compostos Radiofarmacêuticos/sangue , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Ratos Sprague-Dawley
3.
J Pharmacol Exp Ther ; 359(2): 366-373, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27625351

RESUMO

The goal of this study was to evaluate the effects of intranasally administered opioids in rhesus monkeys using the tail-withdrawal assay, and to correlate these effects with measures of receptor occupancy using positron emission tomography (PET) imaging. Initial experiments characterized the antinociceptive effects of intranasal (IN) fentanyl and buprenorphine relative to intramuscular (IM) injection. Fentanyl (0.010-0.032 mg/kg) and buprenorphine (0.1-1.0 mg/kg) produced dose-dependent increases in tail-withdrawal latency that did not differ between routes of delivery. The second experiment compared the ability of IN and intravenous (IV) naloxone (NLX) to block the antinociceptive effects IV fentanyl, and to measure receptor occupancy at equipotent doses of NLX using PET imaging. IN and IV NLX (0.0032-0.032 mg/kg) produced dose-dependent decreases in fentanyl-induced antinociception. Again, there was no difference observed in overall potency between routes. PET imaging showed that IV and IN NLX produced similar decreases in receptor occupancy as measured by [11C]carfentanil blocking, although there was a trend for IV NLX to produce marginally greater occupancy changes. This study validated the first procedures to evaluate the IN effects of opioids in rhesus monkeys.


Assuntos
Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/farmacologia , Nociceptividade/efeitos dos fármacos , Tomografia por Emissão de Pósitrons , Administração Intranasal , Animais , Comportamento Animal/efeitos dos fármacos , Fentanila/administração & dosagem , Fentanila/farmacologia , Injeções Intramusculares , Macaca mulatta , Masculino , Naloxona/administração & dosagem , Naloxona/farmacologia
4.
ACS Med Chem Lett ; 7(8): 746-50, 2016 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-27563397

RESUMO

Clarithromycin is a potential treatment for hypersomnia acting through proposed negative allosteric modulation of GABAA receptors. We were interested whether this therapeutic benefit might extend to Parkinson's disease (PD) patients because GABAergic neurotransmission is implicated in postural control. Prior to initiating clinical studies in PD patients, we wished to better understand clarithromycin's mechanism of action. In this work we investigated whether the proposed activity of clarithromycin at the GABAA receptor is associated with the benzodiazepine binding site using in vivo [(11)C]flumazenil positron emission tomography (PET) in primates and ex vivo [(3)H]flumazenil autoradiography in rat brain. While the studies demonstrate that clarithromycin does not change the K d of FMZ, nor does it competitively displace FMZ, there is preliminary evidence from the primate PET imaging studies that clarithromycin delays dissociation and washout of flumazenil from the primate brain in a dose-dependent fashion. These findings would be consistent with the proposed GABAA allosteric modulator function of clarithromycin. While the results are only preliminary, further investigation of the interaction of clarithromycin with GABA receptors and/or GABAergic medications is warranted, and therapeutic applications of clarithromycin alone or in combination with flumazenil, to treat hyper-GABAergic status in PD at minimally effective doses, should also be pursued.

5.
Bioconjug Chem ; 27(5): 1382-9, 2016 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-27043721

RESUMO

Three new positron emission tomography (PET) radiotracers of interest to our functional neuroimaging and translational oncology programs have been prepared through new developments in [(11)C]CO2 fixation chemistry. [(11)C]QZ (glutaminyl cyclase) was prepared via a tandem trapping of [(11)C]CO2/intramolecular cyclization; [(11)C]tideglusib (glycogen synthase kinase-3) was synthesized through a tandem trapping of [(11)C]CO2 followed by an intermolecular cycloaddition between a [(11)C]isocyanate and an isothiocyanate to form the 1,2,4-thiadiazolidine-3,5-dione core; [(11)C]ibrutinib (Bruton's tyrosine kinase) was synthesized through a HATU peptide coupling of an amino precursor with [(11)C]acrylic acid (generated from [(11)C]CO2 fixation with vinylmagnesium bromide). All radiochemical syntheses are fully automated on commercial radiochemical synthesis modules and provide radiotracers in 1-5% radiochemical yield (noncorrected, based upon [(11)C]CO2). All three radiotracers have advanced to rodent imaging studies and preliminary PET imaging results are also reported.


Assuntos
Dióxido de Carbono/química , Dióxido de Carbono/síntese química , Radioisótopos de Carbono , Tomografia por Emissão de Pósitrons , Animais , Técnicas de Química Sintética , Ciclização , Camundongos , Traçadores Radioativos , Ratos
6.
ACS Chem Neurosci ; 7(3): 391-8, 2016 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-26771209

RESUMO

The receptor for advanced glycation endproducts (RAGE) is a 35 kDa transmembrane receptor that belongs to the immunoglobulin superfamily of cell surface molecules. Its role in Alzheimer's disease (AD) is complex, but it is thought to mediate influx of circulating amyloid-ß into the brain as well as amplify Aß-induced pathogenic responses. RAGE is therefore of considerable interest as both a diagnostic and a therapeutic target in AD. Herein we report the synthesis and preliminary preclinical evaluation of [(18)F]RAGER, the first small molecule PET radiotracer for RAGE (Kd = 15 nM). Docking studies proposed a likely binding interaction between RAGE and RAGER, [(18)F]RAGER autoradiography showed colocalization with RAGE identified by immunohistochemistry in AD brain samples, and [(18)F]RAGER microPET confirmed CNS penetration and increased uptake in areas of the brain known to express RAGE. This first generation radiotracer represents initial proof-of-concept and a promising first step toward quantifying CNS RAGE activity using PET. However, there were high levels of nonspecific [(18)F]RAGER binding in vitro, likely due to its high log P (experimental log P = 3.5), and rapid metabolism of [(18)F]RAGER in rat liver microsome studies. Therefore, development of second generation ligands with improved imaging properties would be advantageous prior to anticipated translation into clinical PET imaging studies.


Assuntos
Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Receptor para Produtos Finais de Glicação Avançada/análise , Doença de Alzheimer/metabolismo , Animais , Autorradiografia , Encéfalo/metabolismo , Cromatografia Líquida de Alta Pressão , Radioisótopos de Flúor/farmacocinética , Humanos , Imuno-Histoquímica , Macaca mulatta , Simulação de Acoplamento Molecular , Tomografia por Emissão de Pósitrons , Ratos , Ratos Sprague-Dawley
7.
ACS Chem Neurosci ; 6(12): 1965-71, 2015 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-26393369

RESUMO

The isozymes of monoamine oxidase (MAO-A and MAO-B) are important enzymes involved in the metabolism of numerous biogenic amines, including the neurotransmitters serotonin, dopamine, and norepinephrine. Recently, changes in concentrations of MAO-B have been proposed to be an in vivo marker of neuroinflammation associated with Alzheimer's disease. Previous developments of in vivo radiotracers for imaging changes in MAO enzyme expression or activity have utilized the irreversible propargylamine-based suicide inhibitors or high-affinity reversibly binding inhibitors. As an alternative approach, we have investigated 1-[(11)C]methyl-4-aryloxy-1,2,3,6-tetrahydropyridines as metabolic trapping agents for the monoamine oxidases. MAO-mediated oxidation and spontaneous hydrolysis yield 1-[(11)C]methyl-2,3-dihydro-4-pyridinone as a hydrophilic metabolite that is trapped within brain tissues. Radiotracers with phenyl, biphenyl, and 7-coumarinyl ethers were evaluated using microPET imaging in rat and primate brains. No isozyme selectivity for radiotracer trapping was observed in the rat brain for any compound, but in the monkey brain, the phenyl ether demonstrated MAO-A selectivity and the coumarinyl ether showed MAO-B selectivity. These are lead compounds for further development of 1-[(11)C]methyl-4-aryloxy-1,2,3,6-tetrahydropyridines with optimized brain pharmacokinetics and isozyme selectivity.


Assuntos
Monoaminoxidase/metabolismo , Radioquímica , Animais , Isótopos de Carbono/farmacologia , Diagnóstico por Imagem , Humanos , Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia
8.
Medchemcomm ; 6(6): 1065-1068, 2015 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-26101580

RESUMO

The phenol of 1-(3-(1H-imidazol-1-yl)propyl)-3-(4-hydroxy-3-methoxyphenyl)thiourea was selectively carbon-11 labelled to generate [11C]PBD150 in 7.3% yield from [11C]methyl triflate (non-decay corrected; radiochemical purity ≥95%, specific activity = 5.7 Ci/µmol, n=5). Evaluation of [11C]PBD150 by small animal PET imaging (mouse and rat) determined it does not permeate the blood brain barrier, indicating previously described therapeutic effect in transgenic mice was likely not the result of inhibiting central nervous system glutaminyl cyclase.

9.
ACS Med Chem Lett ; 6(5): 548-52, 2015 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-26005531

RESUMO

Quantifying glycogen synthase kinase-3 (GSK-3) activity in vivo using positron emission tomography (PET) imaging is of interest because dysregulation of GSK-3 is implicated in numerous diseases and neurological disorders for which GSK-3 inhibitors are being considered as therapeutic strategies. Previous PET radiotracers for GSK-3 have been reported, but none of the published examples cross the blood-brain barrier. Therefore, we have an ongoing interest in developing a brain penetrating radiotracer for GSK-3. To this end, we were interested in synthesis and preclinical evaluation of [(11)C]SB-216763, a high-affinity inhibitor of GSK-3 (K i = 9 nM; IC50 = 34 nM). Initial radiosyntheses of [(11)C]SB-216763 proved ineffective in our hands because of competing [3 + 3] sigmatropic shifts. Therefore, we have developed a novel one-pot two-step synthesis of [(11)C]SB-216763 from a 2,4-dimethoxybenzyl-protected maleimide precursor, which provided high specific activity [(11)C]SB-216763 in 1% noncorrected radiochemical yield (based upon [(11)C]CH3I) and 97-100% radiochemical purity (n = 7). Initial preclinical evaluation in rodent and nonhuman primate PET imaging studies revealed high initial brain uptake (peak rodent SUV = 2.5 @ 3 min postinjection; peak nonhuman primate SUV = 1.9 @ 5 min postinjection) followed by washout. Brain uptake was highest in thalamus, striatum, cortex, and cerebellum, areas known to be rich in GSK-3. These results make the arylindolemaleimide skeleton our lead scaffold for developing a PET radiotracer for quantification of GSK-3 density in vivo and ultimately translating it into clinical use.

10.
ACS Med Chem Lett ; 6(2): 112-116, 2015 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-25705326

RESUMO

Interest in quantifying metal-Aß species in vivo led to the synthesis and evaluation of [11C]L2-b and [18F]FL2-b as radiopharmaceuticals for studying the metallobiology of Alzheimer's disease (AD) using positron emission tomography (PET) imaging. [11C]L2-b was synthesized in 3.6% radiochemical yield (nondecay corrected, n = 3), >95% radiochemical purity, from the corresponding desmethyl precursor. [18F]FL2-b was synthesized in 1.0% radiochemical yield (nondecay corrected, n = 3), >99% radiochemical purity, from a 6-chloro pyridine precursor. Autoradiography experiments with AD positive and healthy control brain samples were used to determine the specificity of binding for the radioligands compared to [11C]PiB, a known imaging agent for ß-amyloid (Aß) aggregates. The Kd for [11C]L2-b and [18F]FL2-b were found to be 3.5 and 9.4 nM, respectively, from those tissue studies. Displacement studies of [11C]L2-b and [18F]FL2-b with PiB and AV-45 determined that L2-b binds to Aß aggregates differently from known radiopharmaceuticals. Finally, brain uptake of [11C]L2-b was examined through microPET imaging in healthy rhesus macaque, which revealed a maximum uptake at 2.5 min (peak SUV = 2.0) followed by rapid egress (n = 2).

11.
ACS Chem Neurosci ; 5(8): 718-30, 2014 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-24896980

RESUMO

Abnormally aggregated tau is the hallmark pathology of tauopathy neurodegenerative disorders and is a target for development of both diagnostic tools and therapeutic strategies across the tauopathy disease spectrum. Development of carbon-11- or fluorine-18-labeled radiotracers with appropriate affinity and specificity for tau would allow noninvasive quantification of tau burden using positron emission tomography (PET) imaging. We have synthesized [(18)F]lansoprazole, [(11)C]N-methyl lansoprazole, and [(18)F]N-methyl lansoprazole and identified them as high affinity radiotracers for tau with low to subnanomolar binding affinities. Herein, we report radiosyntheses and extensive preclinical evaluation with the aim of selecting a lead radiotracer for translation into human PET imaging trials. We demonstrate that [(18)F]N-methyl lansoprazole, on account of the favorable half-life of fluorine-18 and its rapid brain entry in nonhuman primates, favorable kinetics, low white matter binding, and selectivity for binding to tau over amyloid, is the lead compound for progression into clinical trials.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Lansoprazol , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Paralisia Supranuclear Progressiva/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Autorradiografia , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Radioisótopos de Carbono/química , Radioisótopos de Carbono/farmacocinética , Avaliação Pré-Clínica de Medicamentos , Radioisótopos de Flúor/química , Radioisótopos de Flúor/farmacocinética , Humanos , Lansoprazol/química , Lansoprazol/farmacocinética , Camundongos , Fragmentos de Peptídeos/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Primatas , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Paralisia Supranuclear Progressiva/metabolismo , Proteínas tau/metabolismo
12.
J Med Chem ; 56(18): 7312-23, 2013 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-23965035

RESUMO

4-[(18)F]Fluoro-m-hydroxyphenethylguanidine ([(18)F]4F-MHPG, [(18)F]1) is a new cardiac sympathetic nerve radiotracer with kinetic properties favorable for quantifying regional nerve density with PET and tracer kinetic analysis. An automated synthesis of [(18)F]1 was developed in which the intermediate 4-[(18)F]fluoro-m-tyramine ([(18)F]16) was prepared using a diaryliodonium salt precursor for nucleophilic aromatic [(18)F]fluorination. In PET imaging studies in rhesus macaque monkeys, [(18)F]1 demonstrated high quality cardiac images with low uptake in lungs and the liver. Compartmental modeling of [(18)F]1 kinetics provided net uptake rate constants Ki (mL/min/g wet), and Patlak graphical analysis of [(18)F]1 kinetics provided Patlak slopes Kp (mL/min/g). In pharmacological blocking studies with the norepinephrine transporter inhibitor desipramine (DMI), each of these quantitative measures declined in a dose-dependent manner with increasing DMI doses. These initial results strongly suggest that [(18)F]1 can provide quantitative measures of regional cardiac sympathetic nerve density in human hearts using PET.


Assuntos
Guanidinas , Coração/inervação , Fenetilaminas , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Sistema Nervoso Simpático/diagnóstico por imagem , Glândulas Suprarrenais/metabolismo , Animais , Transporte Biológico , Feminino , Radioisótopos de Flúor , Guanidinas/química , Guanidinas/metabolismo , Guanidinas/farmacocinética , Haplorrinos , Humanos , Masculino , Fenetilaminas/química , Fenetilaminas/metabolismo , Fenetilaminas/farmacocinética , Doses de Radiação , Radioquímica , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/metabolismo , Compostos Radiofarmacêuticos/farmacocinética , Ratos
13.
Nucl Med Biol ; 40(7): 906-11, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23891203

RESUMO

INTRODUCTION: [(11)C] PBR28 binding to translocator protein (TSPO) was evaluated for imaging of acute and chronic inflammation using two established rat models. METHODS: Acute inflammation was induced by local carrageenan injection into the paw of Fisher 344 rats (model A). T-cell mediated adjuvant arthritis was induced by heat-inactivated Mycobacterium butyricum injection in Lewis rats (model B). Micro-PET scan was performed after injection of approximately 35 MBq [(11)C]PBR28. In model A, volumes of interest (VOIs) were defined in the paw of Fisher 344 rats (n=6) with contralateral sham treatment as control. For model B, VOIs were defined in the tail, sacroiliac joints, hips, knees and thigh muscles of M. butyricum treated animals (n=8) and compared with sham-treated controls (n=4). The peak (11)C-PBR28 SUV (SUVpeak) and area under the curve (AUCSUV) of 60-minute time-activity data were calculated. Immunohistochemistry for CD68, a macrophage stain, was performed from paw tissues. In addition, the [(11)C]PBR28 cell uptake was measured in lipopolysaccharide (LPS)-stimulated and non-stimulated macrophage cultures. RESULTS: LPS-stimulated macrophages displayed dose-dependent increased [(11)C]PBR28 uptake, which was blocked by non-labeled PBR28. In both models, radiotracer uptake of treated lesions increased rapidly within minutes and displayed overall accumulative kinetics. The SUVpeak and AUCSUV of carrageenan-treated paws was significantly increased compared to controls. Also, the [(11)C]PBR28 uptake ratio of carrageenan-treated vs. sham-treated paw correlated significantly with CD68 staining ratios of the same animals. In adjuvant arthritis, significantly increased [(11)C]PBR28 SUVpeak and AUCSUV values were identified at the tail, knees, and sacroiliac joints, while no significant differences were identified in the lumbar spine and hips. CONCLUSIONS: Based on our initial data, [(11)C]PBR28 PET appears to have potential for imaging of various inflammatory processes involving macrophage activation.


Assuntos
Artrite Experimental/diagnóstico por imagem , Carragenina/efeitos adversos , Tomografia por Emissão de Pósitrons , Pirimidinas , Animais , Artrite Experimental/patologia , Transporte Biológico , Feminino , Inflamação/induzido quimicamente , Inflamação/diagnóstico por imagem , Inflamação/imunologia , Macrófagos/metabolismo , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Ratos
14.
J Nucl Med ; 54(9): 1645-52, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23886728

RESUMO

UNLABELLED: Most cardiac sympathetic nerve radiotracers are substrates of the norepinephrine transporter (NET). Existing tracers such as (123)I-metaiodobenzylguanidine ((123)I-MIBG) and (11)C-(-)-meta-hydroxyephedrine ((11)C-HED) are flow-limited tracers because of their rapid NET transport rates. This prevents successful application of kinetic analysis techniques and causes semiquantitative measures of tracer retention to be insensitive to mild-to-moderate nerve losses. N-(11)C-guanyl-(-)-meta-octopamine ((11)C-GMO) has a much slower NET transport rate and is trapped in storage vesicles. The goal of this study was to determine whether analyses of (11)C-GMO kinetics could provide robust and sensitive measures of regional cardiac sympathetic nerve densities. METHODS: PET studies were performed in a rhesus macaque monkey under control conditions or after intravenous infusion of the NET inhibitor desipramine (DMI). Five desipramine dose levels were used to establish a range of available cardiac NET levels. Compartmental modeling of (11)C-GMO kinetics yielded estimates of the rate constants K1 (mL/min/g), k2 (min(-1)), and k3 (min(-1)). These values were used to calculate a net uptake rate constant K(i) (mL/min/g) = (K1k3)/(k2 + k3). In addition, Patlak graphical analyses of (11)C-GMO kinetics yielded Patlak slopes K(p) (mL/min/g), which represent alternative measurements of the net uptake rate constant K(i). (11)C-GMO kinetics in isolated rat hearts were also measured for comparison with other tracers. RESULTS: In isolated rat hearts, the neuronal uptake rate of (11)C-GMO was 8 times slower than (11)C-HED and 12 times slower than (11)C-MIBG. (11)C-GMO also had a long neuronal retention time (>200 h). Compartmental modeling of (11)C-GMO kinetics in the monkey heart proved stable under all conditions. Calculated net uptake rate constants K(i) tracked desipramine-induced reductions of available NET in a dose-dependent manner, with a half maximal inhibitory concentration (IC50) of 0.087 ± 0.012 mg of desipramine per kilogram. Patlak analysis provided highly linear Patlak plots, and the Patlak slopes Kp also declined in a dose-dependent manner (IC50 = 0.068 ± 0.010 mg of desipramine per kilogram). CONCLUSION: Compartmental modeling and Patlak analysis of (11)C-GMO kinetics each provided quantitative parameters that accurately tracked changes in cardiac NET levels. These results strongly suggest that PET studies with (11)C-GMO can provide robust and sensitive quantitative measures of regional cardiac sympathetic nerve densities in human hearts.


Assuntos
Guanina/análogos & derivados , Coração/diagnóstico por imagem , Coração/inervação , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Octopamina/análogos & derivados , Sistema Nervoso Simpático/diagnóstico por imagem , Sistema Nervoso Simpático/metabolismo , Animais , Radioisótopos de Carbono/administração & dosagem , Radioisótopos de Carbono/farmacocinética , Simulação por Computador , Relação Dose-Resposta a Droga , Guanina/administração & dosagem , Guanina/farmacocinética , Interpretação de Imagem Assistida por Computador/métodos , Taxa de Depuração Metabólica , Modelos Biológicos , Octopamina/administração & dosagem , Octopamina/farmacocinética , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
15.
Contrast Media Mol Imaging ; 8(4): 366-74, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23613440

RESUMO

Perfluorocarbon (PFC) double emulsions loaded with a water-soluble, therapeutic agent can be triggered by ultrasound in a process known as acoustic droplet vaporization. Elucidating the stability and biodistribution of these sonosensitive vehicles and encapsulated agents is critical in developing targeted drug delivery strategies using ultrasound. [(18) F]fluorodeoxyglucose (FDG) was encapsulated in a PFC double emulsion and the in vitro diffusion of FDG was assessed using a Franz diffusion cell. Using dynamic micro-positron emission tomography and direct tissue sampling, the biodistribution of FDG administered as a solution (i.e. non-emulsified) or as an emulsion was studied in Fisher 344 rats (n = 6) bearing subcutaneous 9L gliosarcoma. Standardized uptake values (SUVs) and area under the curve of the SUV (AUCSUV ) of FDG were calculated for various tissues. The FDG flux from the emulsion decreased by up to a factor of 6.9 compared with the FDG solution. FDG uptake, calculated from the AUCSUV , decreased by 36% and 44% for brain and tumor, respectively, when comparing FDG solution vs FDG emulsion (p < 0.01). Decreases in AUCSUV in highly metabolic tissues such as brain and tumor demonstrated retention of FDG within the double emulsion. No statistically significant differences in lung AUCSUV were observed, suggesting minimal accumulation of the emulsion in the pulmonary capillary bed. The liver AUCSUV increased by 356% for the FDG emulsion, thus indicating significant hepatic retention of the emulsion.


Assuntos
Fluorocarbonos/química , Fluordesoxiglucose F18/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Animais , Linhagem Celular Tumoral , Feminino , Ratos , Ratos Endogâmicos F344
16.
Bioorg Med Chem Lett ; 23(6): 1612-6, 2013 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-23416009

RESUMO

A new cardiac sympathetic nerve imaging agent, [(18)F]4-fluoro-m-hydroxyphenethylguanidine ([(18)F]4F-MHPG), was synthesized and evaluated. The radiosynthetic intermediate [(18)F]4-fluoro-m-tyramine ([(18)F]4F-MTA) was prepared and then sequentially reacted with cyanogen bromide and NH4Br/NH4OH to afford [(18)F]4F-MHPG. Initial bioevaluations of [(18)F]4F-MHPG (biodistribution studies in rats and kinetic studies in the isolated rat heart) were similar to results previously reported for the carbon-11 labeled analog [(11)C]4F-MHPG. The neuronal uptake rate of [(18)F]4F-MHPG into the isolated rat heart was 0.68ml/min/g wet and its retention time in sympathetic neurons was very long (T1/2 >13h). A PET imaging study in a nonhuman primate with [(18)F]4F-MHPG provided high quality images of the heart, with heart-to-blood ratios at 80-90min after injection of 5-to-1. These initial kinetic and imaging studies of [(18)F]4F-MHPG suggest that this radiotracer may allow for more accurate quantification of regional cardiac sympathetic nerve density than is currently possible with existing neuronal imaging agents.


Assuntos
Meios de Contraste/síntese química , Guanidinas/síntese química , Metoxi-Hidroxifenilglicol/química , Fenetilaminas/síntese química , Animais , Meios de Contraste/farmacocinética , Radioisótopos de Flúor/química , Guanidinas/farmacocinética , Meia-Vida , Coração/diagnóstico por imagem , Macaca mulatta , Metoxi-Hidroxifenilglicol/farmacocinética , Miocárdio/metabolismo , Fenetilaminas/farmacocinética , Tomografia por Emissão de Pósitrons , Ratos , Distribuição Tecidual
17.
ACS Med Chem Lett ; 3(11): 936-41, 2012 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-24900410

RESUMO

[(11)C]N-Methyl lansoprazole ([(11)C]NML, 3) was synthesized and evaluated as a radiopharmaceutical for quantifying tau neurofibrillary tangle (NFT) burden using positron emission tomography (PET) imaging. [(11)C]NML was synthesized from commercially available lansoprazole in 4.6% radiochemical yield (noncorrected RCY, based upon [(11)C]MeI), 99% radiochemical purity, and 16095 Ci/mmol specific activity (n = 5). Log P was determined to be 2.18. A lack of brain uptake in rodent microPET imaging revealed [(11)C]NML to be a substrate for the rodent permeability-glycoprotein 1 (PGP) transporter, but this could be overcome by pretreating with cyclosporin A to block the PGP. Contrastingly, [(11)C]NML was not found to be a substrate for the primate PGP, and microPET imaging in rhesus revealed [(11)C]NML uptake in the healthy primate brain of ∼1600 nCi/cc maximum at 3 min followed by rapid egress to 500 nCi/cc. Comparative autoradiography between wild-type rats and transgenic rats expressing human tau (hTau +/+) revealed 12% higher uptake of [(11)C]NML in the cortex of brains expressing human tau. Further autoradiography with tau positive brain samples from progressive supranuclear palsy (PSP) patients revealed colocalization of [(11)C]NML with tau NFTs identified using modified Bielschowsky staining. Finally, saturation binding experiments with heparin-induced tau confirmed K d and Bmax values of [(11)C]NML as 700 pM and 0.214 fmol/µg, respectively.

18.
ACS Nano ; 5(11): 8967-73, 2011 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-22003968

RESUMO

For better examination of inflammation, we designed inflammation-targeted nuclear and optical dual-modality contrast agents prepared by I-125 radiolabeling of gold nanorods (GdNRs) conjugated with anti-intercellular adhesion molecule 1 (ICAM-1) antibody. The bioactivity and specific binding of the PEGylated (125)I-ICAM-GdNR conjugates to the ICAM-1 was validated through ELISA testing. Inflammation-targeted imaging was then conducted on an adjuvant-induced arthritic rat model which demonstrated an elevation of ICAM-1 level in the affected ankle joints. Facilitated by the I-125 radioisotope and the whole-body imaging via the Gamma camera, the time-dependent distribution of the systemically injected agent as well as the uptake of the agent in the inflammatory articular tissues could be examined conveniently and quantitatively. The success in targeted delivery of gold nanoparticles to inflammatory tissue enables both nuclear and optical imaging of inflammation at molecular or cellular level. Other than diagnosis, radiolabeled gold nanoparticles also hold promise for targeted therapy of a variety of disorders.


Assuntos
Meios de Contraste/química , Ouro/química , Nanoconjugados/química , Nanotubos/química , Cintilografia/métodos , Animais , Articulação do Tornozelo/diagnóstico por imagem , Anticorpos/química , Anticorpos/imunologia , Artrite/diagnóstico por imagem , Artrite/metabolismo , Artrite/microbiologia , Transporte Biológico , Meios de Contraste/metabolismo , Citocinas/metabolismo , Estudos de Viabilidade , Feminino , Regulação da Expressão Gênica , Inflamação/diagnóstico por imagem , Inflamação/metabolismo , Molécula 1 de Adesão Intercelular/imunologia , Radioisótopos do Iodo , Marcação por Isótopo , Mycobacterium/fisiologia , Ratos
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