title: Radiotracer properties determined by high performance liquid chromatography: a potential tool for brain radiotracer discovery.
abstract: BACKGROUND
  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 (P(m)); percentage of plasma protein binding (%PPB); and membrane partition coefficient (K(m)). Relationships between brain entry measurements (Log P, P(m) and %PPB) and in vivo brain percentage injected dose (%ID); and K(m) and specific binding in vivo (BP(ND)) 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 (r(2)=0.65) and P(m) (r(2)=0.77) than for Log P (r(2)=0.47) while 86% of BP(ND) variance was explained by K(m). 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.
authors.affiliation: Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, G12 8QQ, UK. a.tavares.1@research.gla.ac.uk
authors.forename: Adriana Alexandre S
authors.initials: AA
authors.lastname: Tavares
authors.forename: James
authors.initials: J
authors.lastname: Lewsey
authors.forename: Deborah
authors.initials: D
authors.lastname: Dewar
authors.forename: Sally L
authors.initials: SL
authors.lastname: Pimlott
mesh_terms: D001798:Blood Proteins / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D010539:Permeability; D049268:Positron-Emission Tomography / Q000379:methods*; D011485:Protein Binding; D011868:Radioisotopes / Q000737:chemistry / Q000378:metabolism; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*
chemical_list: D001798:Blood Proteins; D011868:Radioisotopes