Giron M C, Portolan S, Bin A, Mazzi U, Cutler C S
Department of Pharmacology and Anesthesiology, University of Padua, Padua, Italy.
Q J Nucl Med Mol Imaging. 2008 Sep;52(3):254-66. Epub 2008 May 13.
Positron emission tomography (PET) is a powerful non-invasive probe to investigate human physiology. A large number of radiotracers have been studied as imaging agents, but only a few have found clinical applications in pharmacology. A potential radiopharmaceutical is designed with very specific physiochemical characteristics, but, generally, less attention is paid to its adsorption, distribution, metabolism, and excretion properties, especially metabolism. Understanding the metabolic fate of radiopharmaceutical probes is essential for an accurate analysis and interpretation of PET measurements. The inherent inability of PET to differentiate between a parent compound and its metabolites confounds the interpretation of images and may impact the identification of the pathologically induced biochemical changes under investigation. Cytochrome P450 plays a major role in mammalian xenobiotic biotransformation and many in vitro methods are available to study and predict drug metabolism. The purpose of this review is to highlight the existing in vitro techniques available to investigate the biotransformation of xenobiotics in a fashion analogous to small molecule drug discovery. The aim is to facilitate the development and validation phases of PET tracers during preclinical evaluation. Emphasis is placed also on describing how cross species comparisons are essential in establishing appropriate translational pharmacology. Procedures of analysis (tandem liquid chromatography-mass spectrometry), typically used for studying the metabolism of drugs, are proposed as quick and accurate tools for the determination of a radiopharmaceutical's metabolic stability at the tracer level.
正电子发射断层扫描(PET)是一种用于研究人体生理学的强大非侵入性探针。大量放射性示踪剂已作为成像剂进行研究,但只有少数在药理学中得到临床应用。一种潜在的放射性药物是根据非常特定的物理化学特性设计的,但一般来说,人们较少关注其吸附、分布、代谢和排泄特性,尤其是代谢。了解放射性药物探针的代谢命运对于准确分析和解释PET测量结果至关重要。PET无法区分母体化合物及其代谢物的固有能力混淆了图像的解释,并可能影响对所研究的病理诱导生化变化的识别。细胞色素P450在哺乳动物的外源性生物转化中起主要作用,并且有许多体外方法可用于研究和预测药物代谢。本综述的目的是强调现有的体外技术,这些技术可用于以类似于小分子药物发现的方式研究外源性物质的生物转化。目的是在临床前评估期间促进PET示踪剂的开发和验证阶段。还强调了描述跨物种比较在建立适当的转化药理学中的重要性。通常用于研究药物代谢的分析程序(串联液相色谱 - 质谱法)被提议作为在示踪剂水平测定放射性药物代谢稳定性的快速准确工具。