Institute of Pharmaceutical Sciences Department of Chemistry and Applied Biosciences, ETH Zürich, Vladimir-Prelog-Weg 4, 8093, Zürich, Switzerland.
Department of Nuclear Medicine, University Hospital Zürich, Rämistrasse 100, 8091, Zürich, Switzerland.
ChemMedChem. 2020 Jun 17;15(12):1040-1043. doi: 10.1002/cmdc.202000085. Epub 2020 May 5.
[ F]Flurpiridaz is a recently developed positron emission tomography tracer that is currently being investigated in phase III clinical trials to measure myocardial blood flow. The relatively long physical half-life of fluorine-18 alongside the high spatial resolution and outstanding myocardium-to-background ratio fuels its potential to be the next gold standard for the early detection of coronary artery disease. Notwithstanding the expected widespread use of [ F]flurpiridaz, the reported multistep synthesis of its precursor for radiofluorination involves a hazardous alkylation step using carcinogenic ethylene oxide, and a low overall chemical yield of 7 %. In this work, we have improved the overall yield more than fivefold and concurrently replaced the hazardous step. Specificity of binding of [ F]flurpiridaz to mitochondrial complex 1 was demonstrated by in vitro autoradiography on mouse heart tissue sections. These results thus pave the way for assessing myocardial blood flow and coronary flow reserve in mouse models of cardiovascular disease.
氟[F]比拉达扎是一种最近开发的正电子发射断层扫描示踪剂，目前正在进行 III 期临床试验，以测量心肌血流。氟-18 的物理半衰期相对较长，空间分辨率高，心肌与背景的比值优异，这使其有可能成为早期发现冠状动脉疾病的下一个金标准。尽管预计氟[F]比拉达扎将被广泛使用，但报告的其放射性氟化前体的多步合成涉及使用致癌性环氧乙烷的危险烷基化步骤，以及总体化学收率仅为 7%。在这项工作中，我们将总收率提高了五倍以上，并同时取代了危险步骤。通过对小鼠心脏组织切片的体外放射自显影，证明了[F]氟比拉扎与线粒体复合物 1 的特异性结合。这些结果为评估心血管疾病小鼠模型中的心肌血流和冠状动脉储备铺平了道路。
