Preclinical evaluation of [(18)F]JNJ42259152 as a PET tracer for PDE10A.

Phosphodiesterase-10A (PDE10A) is implicated in several neuropsychiatric disorders involving basal ganglia neurotransmission, such as schizophrenia, obsessive-compulsive disorder and Huntington's disease. To confirm target engagement and exposure-occupancy relationships of clinical candidates for treatment, and to further explore the in vivo biology of PDE10A, non-invasive imaging using a specific PET ligand is warranted. Recently we have reported the in vivo evaluation of [(18)F]JNJ41510417 which showed specific binding to PDE10A in rat striatum, but with relatively slow kinetics. A chemically related derivative JNJ42259152 was found to have a similar in vivo occupancy, but lower lipophilicity and lower PDE10A in vitro inhibitory activity compared to JNJ41510417. (18)F-labeled JNJ42259152 was therefore evaluated as a potential PDE10A PET radiotracer. Baseline PET in rats and monkey showed specific retention in the PDE10A-rich striatum, and fast wash-out, with a good contrast to non-specific binding, in other brain regions. Pretreatment and chase experiments in rats with the selective PDE10A inhibitor MP-10 showed that tracer binding was specific and reversible. Absence of specific binding in PDE10A knock-out (KO) mice further confirmed PDE10A specificity. In vivo radiometabolite analysis using high performance liquid chromatography (HPLC) showed presence of polar radiometabolites in rat plasma and brain. In vivo imaging in rat and monkey further showed faster brain kinetics, and higher striatum-to-cerebellum ratios for [(18)F]JNJ42259152 compared to [(18)F]JNJ41510417. The arterial input function corrected for radiometabolites was determined in rats and basic kinetic modeling was established. For a 60-min acquisition time interval, striatal binding potential of the intact tracer referenced to the cerebellum showed good correlation with corresponding binding potential values of a Simplified Reference Tissue Model and referenced Logan Plot, the latter using a population averaged reference tissue-to-plasma clearance rate and offering the possibility to generate representative parametric binding potential images. In conclusion we can state that in vivo imaging in PDE10A KO mice, rats and monkey demonstrates that [(18)F]JNJ42259152 provides a PDE10A-specific signal in the striatum with good pharmacokinetic properties. Although presence of a polar radiometabolite in rat brain yielded a systematic but reproducible underestimation of the striatal BPND, a Logan reference tissue model approach using 60 min acquisition data is appropriate for quantification.

Reinfusión de sangre procedente del drenaje mediastínico en cirugía cardiaca / Autotransfunsion of shed mediastinal blood in cardiac surgery

El considerable incremento de intervenciones quirúrgicas, el desarrollo de técnicas complejas, edad media cada vez más elevada,y la mayor comorbilidad que acompaña a los pacientes intervenidos, ha motivado un mayor consumo de sangre homóloga.La cirugía cardiaca, por varios factores, fundamentalmente el empleo de la derivación cardiopulmonar o circulaciónextracorpórea, determina una utilización importante de sangre y hemoderivados. Esta situación de creciente demanda juntocon una oferta hospitalaria insuficiente a partir de las donaciones hace difícil mantener un balance adecuado entre demanday disponibilidad. En consecuencia se plantean y desarrollan diversas estrategias de ahorro de sangre en cirugía. La autotransfusiónprocedente del drenaje mediastínico, de uso habitual en algunas unidades de cirugía cardiaca, es un procedimientoaún sometido a debate con opiniones diversas y variadas en cuanto a su capacidad de ahorrar recursos sanguíneosy garantía en cuanto a problemas derivados de su uso. En el presente trabajo nos planteamos el análisis de la reinfusión postoperatoriade sangre como alternativa a la transfusión homóloga en cirugía cardiaca con los siguientes objetivos: Verificarque se trata de un método factible y de fácil aplicación, y en segundo lugar analizar y evaluar las alteraciones de la coagulación,en el paciente y en la sangre recogida, implícitas a la aplicación de esta técnica (AU)

The growing number of surgical interventions, the development of high complexity techniques, the higher comorbility and theincrease in the average age of patients, has lead to a greater spent of homologous blood. By means of many factors, especiallybecause of the cardiopulmonary bypass, undergoing cardiac surgery determines the use of an important amount ofblood and other by-products. This background of an increasing demand and an insufficient offer of blood from donations,makes it very difficult to maintain an adequate balance between demand and availability. In answer to this situation, newstrategies in blood saving are being developed. The autotransfusion of mediastinal shed blood is an usual technique in manycardiac surgery units, nevertheless there is still an ongoing debate regarding to it’s safety and capability to save blood-bankresources. In this study, we carried out the analysis of mediastinal shed blood transfusion in cardiac surgery as an alternativeto homologous blood transfusion with this aims: to verify that it is a feasible and easy to carry out method, and in secondplace, to analyze and evaluate the alterations of the coagulation in patients and in the recovered blood (AU)

Synthesis and antiviral evaluation of nucleosides of 5-methylimidazole-4-carboxamide.

Due to the antiviral activity of certain 5-substituted imidazole nucleosides related to ribavirin, 5-methylimidazole-4-carboxamide nucleosides having beta-D-ribofuranosyl, 2-deoxy-beta- and -alpha-D-ribofuranosyl, and (2-hydroxyethoxy)methyl moieties have been prepared and tested as antiviral agents. 1-beta-D-Ribofuranosyl-5-methylimidazole-4-carboxamide was obtained by deacetylation of the corresponding tri-O-acetyl nucleoside 11 or by deacetylation and ammonolysis of the blocked ethyl 5-methylimidazole-4-carboxylate nucleoside 10, which was prepared from the stannic chloride catalyzed condensation of the trimethylsilyl derivative of ethyl 4(5)-methylimidazole-5(4)-carboxylate. Glycosylation of 4(5)-methylimidazole-5(4)-carboxamide with 3,5-di-O-p-toluoyl-2-deoxy-D-erythro-pentofuranosyl chloride via mercuric cyanide method provided an anomeric mixture of the blocked 5-methylimidazole-4-carboxamide deoxynucleoside 14 along with an anomeric mixture of the 4-methyl 5-carboxamide isomer 15. Separation of compound 14 into the corresponding beta and alpha anomers was achieved by conversion to the 3',5'-di-O-acetyl derivatives 17 and 18, which after chromatographic separation were deacetylated to give 1-(2-deoxy-beta-D-erythro-pentofuranosyl)-5-methylimidazole-4-carboxa mid e and its alpha anomer 20. 1-[(2-Hydroxyethoxy)methyl]-5-methylimidazole-4-carboxamide was prepared by alkylation of the imidazole 13 with (2-acetoxyethoxy)methyl bromide followed by treatment with methanolic ammonia. All these imidazole nucleosides were tested in HeLa cell cultures against type 1 herpes simplex and vesicular stomatitis viruses. The ribofuranosyl derivative 12 showed a significant activity against type 1 herpes simplex virus.