Infection Imaging With 18F-FDS and First-in-Human Evaluation☆
Introduction
Despite advances in the field of antibiotics, bacterial infections are still the predominant cause of mortality and morbidity worldwide. The Centers for Disease Control and Prevention (CDC) estimates that roughly 1.7 million hospital-associated infections (nosocomial infections) cause approximately 99,000 deaths each year, with an annual cost that exceeds $4.5 billion [1]. The Gram-negative bacterium E. coli is commonly associated with life-threatening drug-resistant infections in patients [2], [3].
Diagnosis of bacterial infections in vivo is currently a challenge in medicine, and the gold standard is still culturing of the infectious agent from suspected sites (tissue biopsies or blood samples) [4], [5], [6]. However, this method suffers from many limitations, such as it is invasive, unable to determine the spread of infection, and delays in getting results [7]. Computed tomography (CT) and magnetic resonance imaging (MRI) have also been employed for the imaging and location of unknown infections involving structural abnormalities. However, anatomical abnormalities are not always obvious until the late stage of diseases, which is still a challenge for the evaluation and treatment of patients [8].
Currently, PET/CT has been widely used for the noninvasive imaging of bacterial infections (often caused inflammation) using the approved radiotracer 18F-FDG, as it is taken up by inflammatory cells. However, the utility of FDG in bacterial imaging is limited by two aspects of the tracer: low selectivity and inability to distinguish sterile infection from inflammation caused by infection [9], [10]. As a result, there is an unmet clinical need for novel PET probes with high specificity and sensitivity for the early diagnosis of noninvasive bacterial infections in vivo.
18F-FDS is an analog of sorbitol and was first reported in 2008 by Li for the possible diagnosis of brain tumors [11]. Sorbitol is a metabolic substrate that is uniquely utilized by Enterobacteriaceae and the metabolic pathway does not exist in mammalian cells [12]. Based on this theory, Weinstein hypothesized and showed 18F-FDS to be a promising probe capable of distinguishing E. coli infection from general inflammation as well as from infection with Gram-positive bacteria, such as Staphylococcus aureus[2]. In this study, we present a valid fully automatic synthesis of 18F-FDS from 18F ion using a multifunctional synthesis module and microPET imaging of E. coli infection in an animal model. 18F-FDS was employed for the evaluation of antibiotic efficacy in animals infected with drug-susceptible E. coli. In addition, pilot PET scan of 18F-FDS in healthy human volunteers are also included.
Section snippets
General
All chemicals obtained commercially were of analytical grade (Sigma-Aldrich, USA) and used without further purification otherwise stated. 19F-FDG (2-Fluoro-2-deoxy-D-glucose) standard was also purchased from Sigma-Aldrich. Sep-Pak light QMA, Sep-Pak plus Alumina B (N) and Sep-Pak plus C18 cartridges were obtained from Waters (Milford, USA) and IC-H Maxi-Clean cartridge was purchased from Altech (Illinois, USA). Sep-Pak light QMA cartridges were pre-conditioned with 8.4% NaHCO3 (8 mL) and water
Radiosynthesis
After detection, the synthesis of 18F-FDG was completed in 28 min with a yield of 50 ± 5% [15]. The overall uncorrected radiochemical yield of 18F-FDS was 40 ± 4% (n = 8) from 18F− with a total synthesis time of 45 min. The specific activity was greater than 29.6 ± 6.5 GBq/μmol (n = 8) based on the intermediate 18F-FDG. Radiochemical purity was greater than 99% as analyzed by radio-TLC (Fig. 4a&b). The Rf values for 18F-FDG (Fig. 4a) and 18F-FDS (Fig. 4b) were 0.58 and 0.40, respectively (CH3CN:H20 80:20).
Discussion
Herein, we have described the fully automated radiosynthesis of 18F-FDS and its standard. The preparation procedure was finished in three steps with the yield of 40 ± 4% (n = 8) from 18F ions. The FDS standard was synthesized in a similar reduction process.
Like the most widely used radiolabelled tracer 18F-FDG, which is used for the imaging of disease related to abnormal glucose uptake [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], 18F-FDS showed high
Conclusion
In this study, we have successfully prepared the diagnostic tool 18F-FDS with high purity and yield from 18F-FDG, the most widely used PET probe worldwide, and examined its potential application in the imaging of an E. coli infections in mice. The first human PET study of this compound provided us with positive results for low background and fast clearance in vivo. On the basis of preliminary results, we hope in the future, 18F-FDS might provide a rapid, noninvasive diagnostic test for the
Conflict of interest
The authors declare that they have no conflict of interest.
Acknowledgement
We thank Junling Zhan, Chuan Qin and Chao Ren for technical help and assistance to this study.
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The trial was registered in Clinicaltrial.gov and the registration number is: NCT02450942. The authors confirm that all ongoing and related trials for this drug/intervention are registered.
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These authors (Shaobo Yao and Haiqun Xing) contributed equally.