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1.
Molecules ; 20(6): 9550-9, 2015 May 26.
Artículo en Inglés | MEDLINE | ID: mdl-26016546

RESUMEN

In the interest of developing in vivo positron emission tomography (PET) probes for neuroimaging of calcium channels, we have prepared a carbon-11 isotopologue of a dihydropyridine Ca2+-channel antagonist, isradipine. Desmethyl isradipine (4-(benzo[c][1,2,5]oxadiazol-4-yl)-5-(isopropoxycarbonyl)-2,6-dimethyl-1,4-dihydropyridine -3-carboxylic acid) was reacted with [11C]CH3I in the presence of tetrabutylammonium hydroxide in DMF in an HPLC injector loop to produce the radiotracer in a good yield (6 ± 3% uncorrected radiochemical yield) and high specific activity (143 ± 90 GBq·µmol-1 at end-of-synthesis). PET imaging of normal rats revealed rapid brain uptake at baseline (0.37 ± 0.08% ID/cc (percent of injected dose per cubic centimeter) at peak, 15-60 s), which was followed by fast washout. After pretreatment with isradipine (2 mg·kg-1, i.p.), whole brain radioactivity uptake was diminished by 25%-40%. This preliminary study confirms that [11C]isradipine can be synthesized routinely for research studies and is brain penetrating. Further work on Ca2+-channel radiotracer development is planned.


Asunto(s)
Bloqueadores de los Canales de Calcio/farmacocinética , Hidrocarburos Yodados/química , Marcaje Isotópico/métodos , Isradipino/farmacocinética , Neuroimagen/métodos , Radiofármacos/farmacocinética , Animales , Encéfalo/metabolismo , Encéfalo/ultraestructura , Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/metabolismo , Canales de Calcio/metabolismo , Radioisótopos de Carbono , Dimetilformamida/química , Evaluación Preclínica de Medicamentos , Semivida , Isradipino/química , Isradipino/metabolismo , Masculino , Permeabilidad , Tomografía de Emisión de Positrones , Compuestos de Amonio Cuaternario/química , Radiofármacos/química , Radiofármacos/metabolismo , Ratas , Ratas Sprague-Dawley
2.
J Surg Res ; 188(2): 473-9, 2014 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-24582214

RESUMEN

BACKGROUND: Mitochondrial dysfunction has been closely related to many pathologic processes, such as cellular apoptosis. Alterations in organelle membrane potential are associated with mitochondrial dysfunction. A fluorine-18 labeled phosphonium compound: (18)F-triphenylphosphonium ((18)F-TPP) was prepared to determine its potential use as a mitochondria-targeting radiopharmaceutical to evaluate cellular apoptosis. METHODS: Studies were conducted in both ex vivo cell lines and in vivo using a burned animal model. Uptake of (18)F-TPP was assessed in PC-3 cells by gamma counting under the following conditions: graded levels of extracellular potassium concentrations, incubation with carbonyl cyanide m-chlorophenylhydrazone and staurosporine. Apoptosis was studied in a burn animal model using terminal deoxynucleotidyl transferase dUTP nick end labeling staining and simultaneous assessment of (18)F-TPP uptake by biodistribution. RESULTS: We found that stepwise membrane depolarization by potassium (K) resulted in a linear decrease in (18)F-TPP uptake, with a slope of 0.62 ± 0.08 and a correlation coefficient of 0.936 ± 0.11. Gradually increased concentrations of m-chlorophenylhydrazone lead to decreased uptake of (18)F-TPP. Staurosporine significantly decreased the uptake of (18)F-TPP in PC-3 cells from 14.2 ± 3.8% to 5.6 ± 1.3% (P < 0.001). Burn-induced significant apoptosis (sham: 4.4 ± 1.8% versus burn: 24.6 ± 6.7 %; P < 0.005) and a reduced uptake of tracer in the spleens of burn-injured animals as compared with sham burn controls (burn: 1.13 ± 0.24% versus sham: 3.28 ± 0.67%; P < 0.005). Biodistribution studies demonstrated that burn-induced significant reduction in (18)F-TPP uptake in spleen, heart, lung, and liver, which were associated with significantly increased apoptosis. CONCLUSIONS: (18)F-TPP is a promising new voltage sensor for detecting mitochondrial dysfunction and apoptosis in various tissues.


Asunto(s)
Apoptosis , Quemaduras/diagnóstico por imagen , Radioisótopos de Flúor , Potencial de la Membrana Mitocondrial , Compuestos Organofosforados/uso terapéutico , Animales , Carbonil Cianuro m-Clorofenil Hidrazona , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Humanos , Ratones , Ratones Endogámicos C57BL , Tomografía de Emisión de Positrones , Potasio , Bazo/diagnóstico por imagen , Estaurosporina , Valinomicina
3.
J Neuropsychiatry Clin Neurosci ; 24(2): 191-7, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22772667

RESUMEN

The serotonergic system is implicated in disordered emotional behavior. Autism is characterized by impaired processing of emotional information. The serotonergic (5-HT) system is also critically involved in brain development, and abnormal brain synthesis of serotonin is observed in autism. Furthermore, whole blood and platelet serotonin have been reported to be elevated in autism. The authors examined the CNS serotonin system in autism in vivo. 5-HT2 receptors were visualized by PET imaging of [18F]setoperone-binding in this pilot study of 6 high-functioning autistic adults and 10 matched-control participants. Autism subjects had less thalamic [18F]setoperone binding than controls, when covaried for age, but no difference reached significance in other areas. A negative relationship between thalamic binding and history of language impairment was also observed. Further studies will be needed to gain a clearer picture of the role of the 5-HT system in autism.


Asunto(s)
Trastorno Autístico/metabolismo , Radioisótopos de Flúor , Neuroimagen Funcional/psicología , Pirimidinonas , Receptores de Serotonina 5-HT2/metabolismo , Tálamo/metabolismo , Adulto , Trastorno Autístico/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Estudios de Casos y Controles , Femenino , Neuroimagen Funcional/métodos , Humanos , Trastornos del Lenguaje/complicaciones , Trastornos del Lenguaje/diagnóstico por imagen , Trastornos del Lenguaje/metabolismo , Masculino , Proyectos Piloto , Tomografía de Emisión de Positrones/métodos , Tomografía de Emisión de Positrones/psicología , Ensayo de Unión Radioligante/métodos , Ensayo de Unión Radioligante/psicología , Radiofármacos , Tálamo/diagnóstico por imagen
4.
Behav Brain Res ; 193(1): 63-8, 2008 Nov 03.
Artículo en Inglés | MEDLINE | ID: mdl-18562019

RESUMEN

Functional neuroimaging studies suggest that a lateral network in the brain is associated with the sensory aspects of pain perception while a medial network is associated with affective aspects. The highest concentration of opioid receptors is in the medial network. There is significant evidence that endogenous opioids are central to the experience of pain and analgesia. We applied an integrative multimodal imaging approach during acupuncture. We found functional magnetic resonance imaging signal changes in the orbitofrontal cortex, insula, and pons and [11C]diprenorphine positron emission tomography signal changes in the orbitofrontal cortex, medial prefrontal cortex, insula, thalamus, and anterior cingulate cortex. These findings include brain regions within both the lateral and medial pain networks.


Asunto(s)
Analgesia por Acupuntura/métodos , Diprenorfina , Imagen por Resonancia Magnética/métodos , Tomografía de Emisión de Positrones/métodos , Analgesia/métodos , Radioisótopos de Carbono , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/metabolismo , Diprenorfina/farmacocinética , Femenino , Lóbulo Frontal/diagnóstico por imagen , Lóbulo Frontal/metabolismo , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Vías Nerviosas/diagnóstico por imagen , Vías Nerviosas/metabolismo , Dimensión del Dolor/métodos , Puente/diagnóstico por imagen , Puente/metabolismo , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/metabolismo , Radiografía , Tálamo/diagnóstico por imagen , Tálamo/metabolismo
5.
J Nucl Med ; 46(2): 297-304, 2005 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-15695790

RESUMEN

UNLABELLED: This study describes the radiosynthesis and preliminary biologic evaluation of trans-9(RS)-(18)F-fluoro-3,4(RS,RS)-methyleneheptadecanoic acid ((18)F-FCPHA) as a new potential probe for assessing myocardial fatty acid metabolism by PET. This fatty acid, containing a cyclopropyl moiety in the beta,gamma-position, was designed to enter the myocardium by the same mechanism as natural fatty acids and to undergo partial metabolism before being trapped in the cell. METHODS: (18)F-FCPHA and the beta-methyl analog 8(RS)-(18)F-fluoro-3(RS)-methylheptadecanoic acid ((18)F-FBMHA) were prepared from their corresponding mesylate precursors by nucleophilic substitution. The precursors used for labeling were fully characterized, and the data were consistent with the proposed structures. Biodistribution studies of each tracer were performed with Sprague-Dawley rats at 5 and 60 min after injection. Sequential imaging of a rhesus monkey injected with 222 MBq of (18)F-FCPHA was performed by use of a microPET camera. RESULTS: At 5 and 60 min, heart uptake values measured as mean +/- SD percentage injected dose per gram (%ID/g) in rats for (18)F-FCPHA were 1.55 +/- 0.72 and 1.43 +/- 0.14, respectively. The heart-to-blood ratios at 5 and 60 min, an indication of target definition, were 25.8 and 20.4, respectively. The heart-to-lung ratios at 5 and 60 min were 3.3 and 4.6, respectively. Bone accumulation (%ID/g), an indication of defluorination, was 0.16 +/- 0.03 at 5 min and increased to 0.70 +/- 0.39 at 60 min. The heart-to-blood ratio obtained with (18)F-FBMHA was 2.6 at 5 min and did not change significantly at 60 min. Imaging of the monkey heart after injection of (18)F-FCPHA showed an initial spike of activity corresponding to blood flow followed by a plateau at 10 min. CONCLUSION: The cyclopropyl moiety in (18)F-FCPHA does have a significant influence on heart accumulation, as suggested by the high heart-to-blood ratio and the fast blood clearance in rats. These results, along with the remarkable quality of the PET images, indicate the potential of this new class of labeled fatty acids for use in studying heart disease by PET.


Asunto(s)
Ácidos Grasos/metabolismo , Ácidos Grasos/farmacocinética , Corazón/diagnóstico por imagen , Miocardio/metabolismo , Tomografía de Emisión de Positrones/métodos , Animales , Evaluación Preclínica de Medicamentos , Macaca mulatta , Masculino , Tasa de Depuración Metabólica , Especificidad de Órganos , Radiofármacos/farmacocinética , Ratas , Ratas Sprague-Dawley , Distribución Tisular
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