18F]FDG-6-P as a novel in vivo tool for imaging staphylococcal infections

Bethany Mills,Jeni Luckett,Alan C Perkins,Dave Turton,Philip J Hill,Ramla O Awais,Paul Williams

doi:10.1186/s13550-015-0095-1

Bethany Mills, Jeni Luckett + Show 5 more

Open Access

https://doi.org/10.1186/s13550-015-0095-1

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Abstract

BackgroundManagement of infection is a major clinical problem. Staphylococcus aureus is a Gram-positive bacterium which colonises approximately one third of the adult human population. Staphylococcal infections can be life-threatening and are frequently complicated by multi-antibiotic resistant strains including methicillin-resistant S. aureus (MRSA). Fluorodeoxyglucose ([18F]FDG) imaging has been used to identify infection sites; however, it is unable to distinguish between sterile inflammation and bacterial load. We have modified [18F]FDG by phosphorylation, producing [18F]FDG-6-P to facilitate specific uptake and accumulation by S. aureus through hexose phosphate transporters, which are not present in mammalian cell membranes. This approach leads to the specific uptake of the radiopharmaceutical into the bacteria and not the sites of sterile inflammation.Methods[18F]FDG-6-P was synthesised from [18F]FDG. Yield, purity and stability were confirmed by RP-HPLC and iTLC. The specificity of [18F]FDG-6-P for the bacterial universal hexose phosphate transporter (UHPT) was confirmed with S. aureus and mammalian cell assays in vitro. Whole body biodistribution and accumulation of [18F]FDG-6-P at the sites of bioluminescent staphylococcal infection were established in a murine foreign body infection model.ResultsIn vitro validation assays demonstrated that [18F]FDG-6-P was stable and specifically transported into S. aureus but not mammalian cells. [18F]FDG-6-P was elevated at the sites of S. aureus infection in vivo compared to uninfected controls; however, the increase in signal was not significant and unexpectedly, the whole-body biodistribution of [18F]FDG-6-P was similar to that of [18F]FDG.ConclusionsDespite conclusive in vitro validation, [18F]FDG-6-P did not behave as predicted in vivo. However at the site of known infection, [18F]FDG-6-P levels were elevated compared with uninfected controls, providing a higher signal-to-noise ratio. The bacterial UHPT can transport hexose phosphates other than glucose, and therefore alternative sugars may show differential biodistribution and provide a means for specific bacterial detection.

Highlights

Management of infection is a major clinical problem
The clinical imaging agents currently employed for this purpose (such as radiolabelled leukocytes [1,2,3,4] or [18F]FDG (2-fluoro-2-deoxy-D-glucose) [5,6,7,8,9]) are non-specific and as such may accumulate at sites of sterile inflammation or other lesions, resulting in a high rate of false positive results [9,10,11,12,13,14,15]
The purity of the [18F]FDG-6-P product was determined by reverse-phase high-performance liquid chromatography (RP-HPLC) on an Agilent 1260 Series LC

Summary

Introduction

Management of infection is a major clinical problem. Staphylococcus aureus is a Gram-positive bacterium which colonises approximately one third of the adult human population. We have modified [18F]FDG by phosphorylation, producing [18F]FDG-6-P to facilitate specific uptake and accumulation by S. aureus through hexose phosphate transporters, which are not present in mammalian cell membranes This approach leads to the specific uptake of the radiopharmaceutical into the bacteria and not the sites of sterile inflammation. Mills et al EJNMMI Research (2015) 5:13 most common multi-drug resistant (MDR) bacteria isolated from European hospitals [18,19,20,21] It causes a wide range of infections including skin and soft tissue (such as impetigo or abscesses), deep bone and foreign body infections that can lead to sepsis and pneumonia [22]. Developing new radiopharmaceuticals that enable rapid diagnosis of staphylococcal infections is imperative

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