A rapid vesicle electrokinetic chromatography method for the in vitro prediction of non-specific binding for potential PET ligands.
High non-specific binding (NSB) is one of the most common reasons for candidate failure in potential positron emission tomography (PET) radiotracer development. It is of interest to develop high throughput in vitro methods for predicting non-specific binding prior to radiolabeling, which would help guide radiotracer candidate selection and assist decision making in new radiotracer discovery. We evaluated several electrokinetic chromatographic (EKC) systems to help identify PET ligands with low non-specific binding characteristics by mimicking the ligand-brain tissue interaction. The measured retention factors of tracers in clinical use or terminated candidates within AOT vesicle EKC systems were compared with literature in vitro or in vivo NSB data. We conclude that there is a statistical correlation between the chromatographic retention parameters of tested drugs and their NSB. The AOT vesicle EKC method can provide NSB in vitro trend analysis for a large number of drug candidates early in the novel radiotracer discovery process with minimal resources.
Novartis Institutes for Biomedical Research, Global Discovery Chemistry, Wimblehurst Road, Horsham, West Sussex, UK.
Zhengjin
Z
Jiang
John
J
Reilly
Brian
B
Everatt
Emmanuelle
E
Briard
D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D020374:Chromatography, Micellar Electrokinetic Capillary; D055808:Drug Discovery / Q000191:economics / Q000379:methods*; D057166:High-Throughput Screening Assays; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008081:Liposomes / Q000737:chemistry*; D008954:Models, Biological; D049268:Positron-Emission Tomography; D011849:Radioactive Tracers; D019275:Radiopharmaceuticals / Q000737:chemistry* / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D013501:Surface-Active Agents / Q000737:chemistry*; D013997:Time Factors
D008024:Ligands; D008081:Liposomes; D011849:Radioactive Tracers; D019275:Radiopharmaceuticals; D013501:Surface-Active Agents