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J Surg Res ; 188(2): 473-9, 2014 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-24582214


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.

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
J Nucl Med ; 46(2): 297-304, 2005 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-15695790


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.

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