Identifying novel radiotracers for PET imaging of the brain: application of LC-MS/MS to tracer identification.
Nuclear medicine imaging biomarker applications are limited by the radiotracers available. Radiotracers enable the measurement of target engagement, or occupancy in relation to plasma exposure. These tracers can also be used as pharmacodynamic biomarkers to demonstrate functional consequences of binding a target. More recently, radiotracers have also been used for patient tailoring in Alzheimer's disease seen with amyloid imaging. Radiotracers for the central nervous system (CNS) are challenging to identify, as they require a unique intersection of multiple properties. Recent advances in tangential technologies, along with the use of iterative learning for the purposes of deriving in silico models, have opened up additional opportunities to identify radiotracers. Mass spectral technologies and in silico modeling have made it possible to measure and predict in vivo characteristics of molecules to indicate potential tracer performance. By analyzing these data alongside other measures, it is possible to delineate guidelines to increase the likelihood of selecting compounds that can perform as radiotracers or serve as the best starting point to develop a radiotracer following additional structural modification. The application of mass spectrometry based technologies is an efficient way to evaluate compounds as tracers in vivo, but more importantly enables the testing of potential tracers that have either no label site or complex labeling chemistry which may deter assessment by traditional means; therefore, use of this technology allows for more rapid iterative learning. The ability to differentially distribute toward target rich tissues versus tissue with no/less target present is a unique defining feature of a tracer. By testing nonlabeled compounds in vivo and analyzing tissue levels by LC-MS/MS, rapid assessment of a compound's ability to differentially distribute in a manner consistent with target expression biology guides the focus of chemistry resources for both designing and labeling tracer candidates. LC-MS/MS has only recently been used for de novo tracer identification; however, this connection of mass spectral technology to imaging has initiated engagement from a wider community that brings diverse backgrounds into the tracer discovery arena.
Eli Lilly and Co., Lilly Research Laboratories, Indianapolis, Indiana 46285, United States.
Vanessa
V
Barth
Anne
A
Need
D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging*; D002853:Chromatography, Liquid; D006801:Humans; D049268:Positron-Emission Tomography; D011849:Radioactive Tracers; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution
D011849:Radioactive Tracers; D019275:Radiopharmaceuticals
Positron emission tomography (PET); biomarker; lipophilicity; liquid chromatography coupled to mass spectrometry (LC-MS/MS); physicochemical properties; small molecule; tracer