Ru Supported on p-phthalic acid-Mn Derived from a Mn Metal-Organic Framework for Thermo- and Electrocatalytic Synthesis of Ethylene-D4 Glycol.

Deuterium-labeled polyols are one of the most extensive applied chemicals in biochemistry and biophysics. However, the deuteriation still is insufficient, exhibiting a low deuterated ratio and indistinct reaction mechanism. Herein, Ru supported on MnBCD (MnBDC, derived from Mn p-phthalic acid metal-organic framework) as nanocatalyst with an agglomerated sheet-type structure; this allows the possibility of achieving both thermo- and electrocatalytic hydrogen isotope exchange (HIE) reaction. Furthermore, XPS characterization confirmed that the specific structural changes in the electron density of Ru outer layers were modulated through the impregnation and reduction processes. According to the change of outer electronic structure, hydrogen spillover and electron-rich flow promote the reaction of the catalyst in thermo- and electrocatalytic systems, respectively. In addition, the results indicate that a high deuterated ratio of 97 % can be obtained, hence the catalytic technology has enormous potential for the synthesis of a broad variety of deuterium-labeled compounds.

Quantification of 13C, 15N labelled compounds with 13C, 15N edited 1H Nuclear Magnetic Resonance spectroscopy.

It was significant to detect isotope labelled compounds in biology and pharmacy. Based on a novel 1H Nuclear Magnetic Resonance (1H-NMR) technique, a simple, fast and green method has been successfully established to quantitatively detect 13C, 15N isotope labelled compounds. In this protocol, the couples between 1H and 13C, 15N nearby were removed, which greatly simplified the spectrum. At mean time, the multiple peaks led by 13C and 15N were combined into one peak, so the signal intensity was also significantly enhanced. Melamine was selected as the internal standard and five 13C, 15N isotope labelled compounds showed excellent linearity from 0.001 mM to 100 mM. A real polypeptide sample has quantitatively been detected.

Marcaje de arena sílice con 99mTc para la obtención de un radiotrazador sólido / Labeling of silica sand with 99mTc for obtaining a solid radiotracer

Resumen Para la obtención de radiotrazadores sólidos de 99mTc actualmente se necesitan nuevos soportes porosos. Estudios anteriores realizados por otros autores mostraron la posibilidad del marcaje con 99mTc de sedimentos de ríos con alto contenido de aluminosilicatos. En el presente trabajo se desarrolló una metodología para el marcaje de arena sílice con el 99mTcO4- para su uso como radiotrazador sólido. Se realizó el marcaje de la arena sílice previamente tratada y sin tratar empleando concentraciones variables de cloruro y fluoruro estañoso como agentes reductores y diferentes tiempos de marcaje. Se evaluó la influencia de la etapa de tratamiento previo de la arena en los rendimientos de retención del Tc obtenidos. Los cambios en la composición de la arena sílice luego de su tratamiento previo se pudieron constatar a partir de la Microscopía Electrónica de Barrido (SEM-EDS). Los resultados sugirieren el empleo de la arena sílice previamente tratada y de fluoruro estañoso como agente reductor, adicionalmente se propusieron modificaciones a la metodología inicial de tratamiento previo de la arena. Se pudo constatar a partir de la técnica SEM-EDS que el aumento del porciento de retención del Tc en la arena luego de su tratamiento, se debe fundamentalmente a los cambios observados en su composición química y en su estructura. Se logró la obtención de un radiotrazador sólido marcado con 99mTc en soporte de arena sílice con un tiempo de preparación estimado de 4 horas y un rendimiento de retención de 74%.

Abstract To obtain 99mTc solid radiotracers, new porous supports are currently needed. Previous studies carried out by other authors showed the possibility of 99mTc labeling of sediments from rivers with a high content of aluminosilicates. In the present work a methodology for labeling of silica sand with 99mTcO4- as a prospective solid radiotracer was developed. Labeling of the previously treated and untreated silica sand was carried out using variable concentrations of chloride and stannous fluoride as reducing agents and different labeling times. The influence of the pre-treatment stage of the sand on the obtained Tc retention yields was evaluated. The changes in the composition of the silica sand after its previous treatment could be verified from the Scanning Electron Microscopy (SEM-EDS). The results suggested the use of previously treated silica sand and stannous fluoride as a reducing agent, modifications were proposed to the initial methodology of previous treatment of the sand. It was possible to confirm from the SEM-EDS technique that the increase in the percentage of retention of Tc in the sand after its treatment is mainly due to the observed changes in its chemical composition and structure. It was possible to obtain a 99mTc solid radiotracer on support of silica sand with an estimated preparation time of 4 hours and a retention yield of 74%.

Centro de Isótopos: acciones en beneficio de la salud pública / Center of Isotope: actions for the benefit of public health

RESUMEN En tributo a los cinco siglos de ciudad el Centro de Isótopos hace recuento de su actividad. La obtención de compuestos marcados con radionucleidos y otros trabajos radioquímicos en el Instituto de Física Nuclear, inaugurado en 1969, estimularon las aplicaciones de las fuentes radiactivas abiertas, por lo que puede considerarse el antecedente organizado más palpable del centro. Posteriormente en los años 80, la Secretaria Ejecutiva para Asuntos Nucleares aceleró, diversificó y amplió las aplicaciones, desarrolló la formación de cuadros y especialistas y la colaboración internacional. La puesta en operación del Centro de Estudios Aplicados al Desarrollo de la Energía Nuclear coincidió con la consolidación de un grupo de instituciones de investigación y producción biotecnológica y con el auge de las aplicaciones en Medicina Nuclear. Pronto se reconoció que no era posible continuar el manejo de un inventario cada vez mayor de radionucleidos, por lo que se diseñó y construyó un centro especializado a ciclo completo: investigación-desarrollo, producción y comercialización, el CENTIS. Durante su integración en 1994 a la Agencia de Energía Nuclear, se concluyó la inversión y se establecieron las metodologías de producción de los más importantes radiofármacos. En más de 20 años de labor CENTIS se ha convertido en el principal soporte de la Medicina Nuclear del país. Con sus capacidades metrológicas en la magnitud radiactividad y sus investigaciones no clínicas y clínicas, se inserta de forma cada vez más estrecha en la vida socio-económica del país y su capital. En el trabajo se detallan los principales resultados de cada etapa en lo relacionado a la misión del centro y se hace una valoración técnica de hacia dónde se encaminan acciones en favor de sus sectores destino: salud e investigación biomédica. Lustros en favor de siglos.

ABSTRACT To commemorate the 500th anniversary of the city of Havana, the Isotope Center reviews its activity since its creation. The production of radionuclidemarked compounds and other radiochemical work at the Institute of Nuclear Physics, inaugurated in 1969, stimulated the applications of open radioactive sources, which can be considered as the most tangible organized antecedent of the center. Later in the 1980s, the Executive Secretary for Nuclear Affairs accelerated, diversified and expanded nuclear applications, developed the training of highly qualified staff and experts as well as international cooperation. The creation of the Center for Applied Nuclear Development Studies coincided with the consolidation of a group of biotechnological research and production institutions and with these applications gaining importance in Nuclear Medicine. It was soon recognized that it was not possible to continue managing a growing inventory of radionuclides. As a result, CENTIS, a specialized center with a complete cycle, was designed and built, which comprised not only research and development, but also production and marketing. When in 1994 CENTIS became part of the Nuclear Energy Agency, investment was concluded and the production methodologies of the most important radiopharmaceuticals were established. In more than 20 years of work CENTIS has become the main support of Nuclear Medicine in the country. With its metrological capabilities in the magnitude of radioactivity and its non-clinical and clinical research, it is increasingly part of the socio-economic life of the country and its capital. In this paper the main results of each stage are detailed in relation to the mission of the center and a technical assessment is made regarding the actions taken to favor their target sectors: health and biomedical research. Periods of five years in favor of centuries.

Aspectos regulatorios de las Investigaciones no Clínicas en el Centro de Isótopos (Centis) / Regulatory aspects of the non-clinical researches in the Isotope Center

En el control de calidad de los radiofármacos producidos en Centis y en los estudios de farmacocinética de nuevos fármacos se obtienen imágenes gammagráficas en animales. Esto permite observar la distribución y comportamiento dentro del organismo de estas moléculas radiomarcadas para su posterior empleo en los estudios clínicos en humanos con diferentes patologías. Además de seguir las regulaciones del Centro Nacional de Seguridad Nuclear para el trabajo con fuentes radiactivas abiertas, las áreas correspondientes del Laboratorio de Investigaciones No Clínicas se atienen a las regulaciones de Bioseguridad establecidas en el país, en particular, las del Centro para el Control Estatal de Medicamentos, Equipos y Dispositivos Médicos (Cecmed). La tendencia mundial de integración de los sistemas de gestión en los procesos de la organización hace necesaria la armonización de las Buenas Prácticas de Laboratorio, el cumplimiento de la Legislación de Seguridad Biológica y las Normas Internacionales con relación a la ética en este tipo de trabajo con animales de laboratorio. El mencionado laboratorio de Centis coordina sus servicios directamente con las instituciones que desarrollan fármacos en el país y con el departamento de calidad para el control de los productos de medicina nuclear que se producen en la entidad. En este trabajo se realiza una valoración de la legislación y las normativas aplicables a las áreas de Investigaciones No Clínicas para establecer acciones de mejora en la gestión integrada de bioseguridad, con vistas a la estructuración de un programa de seguridad

For the quality control of radiopharmaceuticals produced by Centis and in pharmacokinetic studies carried out in this institution, scintigraphic images of animals are obtained. This allows the assessment of the distribution and behavior of these radiolabeled molecules inside the organism in order to use them in clinical trials in people having different pathologies. Besides following the CNSN regulations involving work with open radioactive sources, non-clinical research laboratory areas are subject to Biosafety Regulations particularly those established by Cecmed. The world trend to integrate the management systems in the organization processes requires the harmonization of Good Laboratory Practices, the compliance with Biosafety Regulations and International Standards concerning the ethics, when working with laboratory animals. This kind of laboratory coordinates its services directly with institutions developing drugs and with the Department of Quality Control for Products used in Nuclear Medicine in Centis. The present work is aimed at assessing the legislation and regulations related with non-clinical research area to take actions intended to improve the integrated management of biosafety for structuring a safety program

Congener-specific determination of ultratrace levels of chlorinated and brominated polycyclic aromatic hydrocarbons in atmosphere and industrial stack gas by isotopic dilution gas chromatography/high resolution mass spectrometry method.

Isotopic dilution gas chromatography combined with high resolution mass spectrometry (GC/HRMS) has overwhelming advantages with respect to the accuracy of congener-specific ultratrace analysis of complex persistent organic pollutants (POPs) in environmental matrices. However, an isotopic dilution GC/HRMS method for analysis of chlorinated and brominated polycyclic aromatic hydrocarbons (Cl-PAHs and Br-PAHs) using 13C-labelled congeners as internal standards has not been established. In this study, a method for identification and quantification of 38 congeners of Cl-PAHs and Br-PAHs in atmosphere and stack gas samples from waste incinerators was developed using the isotopic dilution GC/HRMS technique. The instrumental detection limits of the GC/HRMS method ranged from 0.2pg to 1.8pg for Cl-PAH congeners, and 0.7pg to 2.7pg for Br-PAH congeners, which were about three orders of magnitude lower than those of the GC/quadrupole MS method. This new method developed was also the first to enable determination of Cl-PAH and Br-PAH homologs comprising congeners with the same molecular skeleton and chlorine or bromine substitution numbers. Among the detected congeners, seven Cl-PAH congeners and thirteen Br-PAH congeners that were abundant in the atmosphere and stack gases released from waste incinerators were firstly detected in real samples and reported using the established isotopic dilution GC/HRMS method. The developed isotopic dilution GC/HRMS is significant and needed for better studying the environmental behavior and health risk of Cl-PAHs and Br-PAHs.

Synthesis of [2H7]indatraline.

Deuterium-labelled indatraline was synthesized in high efficiency employing a Friedel-Crafts alkylation of [(2)H6]benzene with (E)-3-(3,4-dichlorophenyl)acrylic acid as a key step. The desired labelling of the final compound was ascertained in two ways, by incorporation of [(2)H6]benzene in the target molecule and additionally by deuterium transfer to the non-deuterated aryl moiety of the Friedel-Crafts alkylation product from [(2)H6]benzene, the latter thus serving as reagent and solvent.

Determination of the enrichment of isotopically labelled molecules by mass spectrometry.

A general method for the determination of the enrichment of isotopically labelled molecules by mass spectrometry (MS) is described. In contrast to other published procedures, the method described here takes into account and corrects for measurement errors such as the contribution at M - 1 due to loss of hydrogen or lack of spectral resolution and provides an uncertainty value for the determined enrichment. The general procedure requires the following steps: (1) evaluation of linearity in the mass spectrometer by injecting the natural abundance compound at different concentration levels, (2) determination of the purity of the mass cluster using the natural abundance analogue, (3) calculation of the theoretical isotope composition of the labelled compound using different tentative isotope enrichments, (4) calculation of 'convoluted' isotope distributions for the labelled compound taking into account the purity of the mass cluster determined with the natural abundance analogue and (5) comparison of the isotope distributions measured for the labelled compound with those calculated for different isotope enrichments using linear regression. The method was applied to a series of commercially available (13)C- and (2)H-labelled compounds and to a suite of singly (13)C-labelled ß2-agonist prepared in-house both by gas chromatography (GC)-MS, GC-tandem MS (MS/MS) and liquid chromatography-MS/MS with satisfactory results. It was observed that the main uncertainty source for the isotope enrichment was the uncertainty in the purity of the measured cluster as determined with the natural abundance compound.

Nuevo radioinmunoconjugado -dota-h-r3: Sintesis y radiomarcaje / New radioimmunoconjugate -dota-h-r3: synthesis and radiolabeling

El marcaje de anticuerpos monoclonales con metales radiactivos para diagnóstico y terapia generalmente involucra el uso de agentes quelatantes bifuncionales que contienen una función reactiva para conjugarse con las proteínas y un grupo capaz de enlazar fuertemente al metal formando complejos fisiológicamente estables. El objetivo del trabajo fue modificar el anticuerpo monoclonal humanizado (h-R3) con el ácido 1,4,7,10-tetraazaciclododecano-N,N´,N´´,N´´´-tetraacético (DOTA) en solución acuosa, realizar el marcaje de los conjugados obtenidos con y estudiar algunas de las variables que influyen en la reacción, así como la estabilidad del radioinmunoconjugado en presencia de otros agentes quelatantes.

Labelling of monoclonal antibodies with radioactive metals for cancer diagnosis and therapy has usually been accomplished by the use of bifunctional chelating agents, which contain both a reactive functionality for covalent attachment to proteins and a strong metal-binding group capable of forming a physiologically stable complex with the radionuclide. The objective of the present work was to modify the humanized monoclonal antibody (h-R3) with the 1,4,7,10-tetraaza-cyclododecane N,N´,N´´,N´´´-tetraacetic acid (DOTA) in aqueous solution, achieve the labelling of the obtained conjugates with and study some of the variables that influence in the labelling reaction, as well as the stability of the radioimmunoconjugate in presence of other chelating agents.

Proposing norms for clinical application of biological radiolabelled compunds. pharmacodynamic and toxicological recommendations for preclinical studies / Propuesta de normas para la aplicación clínica de compuestos biológicos radiomarcados. Recomendaciones farmacodinámicas y toxicológicas para los estudios preclínicos

En el mes de octubre de 2005 un pequeño grupo de investigadores de diferentes nacionalidades se reunieron en Viena, Austria, bajo los auspicios del Organismo Internacional de Energía Atómica con el objetivo de preparar un documento sencillo y útil para el personal involucrado en la preparación de productos biológicos radiomarcados como péptidos, proteínas y anticuerpos. Este documento debe incluir los aspectos prácticos, metodológicos y éticos relacionados con los productos radiomarcados anteriormente mencionados y debe esclarecer la ruta crítica que se debe seguir en esa área. Ese documento no cubre el uso de oligonucleótidos, células y otros productos antólogos radiomarcados y no ofrece protocolos técnicos sobre metodologías. En el trabajo presento recomendaciones farmacodinámicas y toxicológicas para los estudios preclínicos in vivo que deben seguir estos productos. Esta guía sólo representa mi forma actual de pensar sobre este tema.

In October of 2005 a small group of researchers from different Countries had a meeting at the International Atomic Energy Agency headquarter in Vienna, Austria; the aim was to prepare a tentative user-friendly document for personnel involved in preparation of radiopharmaceuticals based on peptides, proteins and antibodies for human use. This document should cover all practical, methodological and ethical concerns relating to radiolabelled products mentioned above and should clarify the complicated road-map that one has to follow in this area. This document does not cover the use of radiolabelled oligonucleotides, cells and other autologous products and does not provide technical protocols on actual methodologies. Herein, we will like to present you some pharmacodynamic and toxicological recommendations for in vivo preclinical studies. This guidance only represents my own current thinking in this topic.