Radiotracer properties determined by high performance liquid chromatography: a potential tool for brain radiotracer discovery

Tavares, A.A.S., Lewsey, J. , Dewar, D. and Pimlott, S.L. (2012) Radiotracer properties determined by high performance liquid chromatography: a potential tool for brain radiotracer discovery. Nuclear Medicine and Biology, 39(1), pp. 127-135. (doi: 10.1016/j.nucmedbio.2011.06.011)

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Publisher's URL: http://dx.doi.org/10.1016/j.nucmedbio.2011.06.011

Abstract

Introduction Previously, development of novel brain radiotracers has largely relied on simple screening tools. Improved selection methods at the early stages of radiotracer discovery and an increased understanding of the relationships between in vitro physicochemical and in vivo radiotracer properties are needed. We investigated if high performance liquid chromatography (HPLC) methodologies could provide criteria for lead candidate selection by comparing HPLC measurements with radiotracer properties in humans. Methods Ten molecules, previously used as radiotracers in humans, were analysed to obtain the following measures: partition coefficient (Log P); permeability (Pm); percentage of plasma protein binding (%PPB); and membrane partition coefficient (Km). Relationships between brain entry measurements (Log P, Pm and %PPB) and in vivo brain percentage injected dose (%ID); and Km and specific binding in vivo (BPND) were investigated. Log P values obtained using in silico packages and flask methods were compared with Log P values obtained using HPLC. Results The modelled associations with %ID were stronger for %PPB (r2=0.65) and Pm (r2=0.77) than for Log P (r2=0.47) while 86% of BPND variance was explained by Km. Log P values were variable dependant on the methodology used. Conclusions Log P should not be relied upon as a predictor of blood-brain barrier penetration during brain radiotracer discovery. HPLC measurements of permeability, %PPB and membrane interactions may be potentially useful in predicting in vivo performance and hence allow evaluation and ranking of compound libraries for the selection of lead radiotracer candidates at early stages of radiotracer discovery

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Pimlott, Dr Sally and Dewar, Dr Deborah and Lewsey, Professor Jim
Authors: Tavares, A.A.S., Lewsey, J., Dewar, D., and Pimlott, S.L.
Subjects:R Medicine > R Medicine (General)
College/School:College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Health Economics and Health Technology Assessment
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing > Centre for Population and Health Sciences
Journal Name:Nuclear Medicine and Biology
ISSN:0969-8051

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