Ultra-high pressure liquid chromatography apparatus to study the pharmacokinetics of small molecules

该建议旨在发展生物介质中低水平循环分子的定量能力。它旨在支持nserc资助的三个研究小组的研究，这些小组在药物化学（Marsault），分子成像（Lepage）和干细胞研究（Bentzinger）方面具有互补的专业知识。******Marsault的研究旨在确定大环细胞渗透性的结构决定因素，这类分子在药物发现中引起了越来越多的兴趣。为此，他对大环肽进行了修饰，以了解细微的修饰如何影响它们的渗透性，这对进一步将它们用作口服药物很重要。同样重要的是能够确定这些分子的代谢命运。******Bentzinger的研究旨在描述肌肉干细胞如何与环境反应和相互作用。在这方面，他已经确定了环境的一些关键因素，这些因素对干细胞的命运很重要。他现在正在鉴定影响干细胞命运的小分子，这些小分子需要在体内进行量化。******Lepage的研究旨在为正电子发射断层扫描和磁共振成像中使用的成像探针开发更好的药代动力学建模方法。在这方面，为了量化成像探针在体内与目标相互作用的能力，他需要使用能够量化低水平示踪剂的分析设备。******所需的仪器是配备UV检测器和馏分收集器的超高效液相色谱（UPLC），将与现有的串联质谱/质谱仪耦合。这两种仪器的结合将提供分析生物流体中极低含量化合物所需的高灵敏度。这种能力对于支持三个共同申请者的项目以及与学术和工业团体的额外合作至关重要。在生物科学更多地依赖并严重依赖高性能分析能力的背景下，这种专门知识对于培养高素质人员也至关重要。

This proposal aims at developing a capacity for the quantification of low-level circulating molecules in biological media. It is intended to support the research of three NSERC-funded research groups with complementary expertise in medicinal chemistry (Marsault), molecular imaging (Lepage) and stem cell research (Bentzinger).******Marsault's research aims at identifying the structural determinants of cellular permeability of macrocycles, a class of molecules that is drawing increasing levels of interest in drug discovery. Toward this end, he modifies macrocyclic peptides to understand how subtle modifications influence their permeability, which is important to further use them as oral drugs. It is equally important to be able to determine the metabolic fate of these molecules.******Bentzinger's research aims at characterizing how muscle stem cells respond and interact with their environment. In that respect, he has identified some key elements of the environment that are important for stem cells fate. He is now in the process of identifying small molecules that influence stem cell fate that will need to be quantified in vivo.******Lepage's research aims to develop better methods for pharmacokinetic modeling of imaging probes used in positron emission tomography and magnetic resonance imaging. In that respect, in order to quantify in vivo the ability of imaging probes to interact with their target, he needs access to an analytical equipment able to quantify low levels of tracers.******The required instrument, a UltraHigh Performance Liquid Chromatography (UPLC) equipped with a UV detector and a fraction collector, will be coupled to an existing tandem MS/MS instrument. The combination of these two instruments will provide the high level of sensibility required to analyze very low levels of compounds in biological fluids. This capacity is critical to support the programs of the three co-applicants, as well as additional collaborations with academic and industrial groups. This expertise is also critical for the training of highly qualified personnel in a context where biological sciences rely more and are heavily on high performance analytical capacities.