Infection Imaging With 18F-FDS and First-in-Human Evaluation

https://doi.org/10.1016/j.nucmedbio.2015.11.008Get rights and content

Abstract

Purpose

The noninvasive imaging of bacterial infections is critical in order to reduce mortality and morbidity caused by these diseases. The recently reported 18F-FDS (18F-2-fluorodeoxy sorbitol) as a PET (positron emission tomography) tracer can be used to image Enterobacteriaceae-specific infections and provides a potential alternative to this problem compared with other probes for imaging infections. In this study, automatic synthesis, validation of 18F-FDS and a first-in-human study were performed and discussed.

Methods

A multifunctional synthesis module was employed for the radiosynthesis of 18F-FDG (18F-2-fluorodeoxy glucose) and 18F-FDS starting from 18F ion using two-pot three-step fully automated reactions. The behavior of 18F-FDS as an in vivo imaging probe for infections was evaluated in an Escherichia coli mouse infection model. The first detailed pharmacokinetic and biodistribution parameters were obtained from healthy human volunteers.

Results

The uptake of 18F-FDS in an E. coli mouse-myositis infection model was easily differentiated from other organs and normal muscle. Intensive lesion uptake declined after antibiotic treatment. In the pilot human study, no adverse effects due to 18F-FDS were observed up to 24 h post-injection. The radiotracer was rapidly cleared from the circulation and excreted mainly through the urinary system.

Conclusion

We conclude that 18F-FDS PET holds great potential for appropriate and effective for the imaging of bacterial infections in vivo. These preliminary results indicate that further clinical studies are warranted.

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.

References (39)

  • X.J. Wang et al.

    Bacterial imaging comes of age

    Sci Transl Med

    (2014)
  • A.W.J.M. Glaudemans et al.

    The use of 18F-FDG-PET/CT for diagnosis and treatment monitoring of inflammatory and infectious diseases

    Clin Dev Immunol

    (2013)
  • Z.B. Li et al.

    The synthesis of 18F-FDS and its potential application in molecular imaging

    Mol Imaging Biol

    (2008)
  • G.H. Tang et al.

    High efficient automated synthesis of 2-[18F] fluoro-2-deoxy-D-glucose

    Nucl Technol

    (2006)
  • M.L.V. Ogtrop et al.

    Comparative study of the effects of four Cephalosporins against Escherichia coli in vitro and in vivo.

    Antimicrob Agents Chemother

    (1990)
  • F. Fuchner et al.

    Basic hydrolysis of 2-[18F]Fluoro-1,3,4,6 -tetra-O-acetyl-D-glucose in the preparation of 2-[18F]Fluoro-2-deoxy-D-glucose

    Appl Radiat Isot

    (1996)
  • S.S. Gambhir et al.

    A tabulated summary of the FDG PET literature

    J Nucl Med

    (2001)
  • M. Ghesani et al.

    Role of 18F-FDG positron emission tomography (PET) in the assessment of myocardial viability

    Echocardiography

    (2005)
  • O.S. AAssar et al.

    Metastatic head and neck cancer: role and usefulness of FDG PET in locating occult primary tumors

    Radiology

    (1999)
  • Cited by (0)

    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.

    1

    These authors (Shaobo Yao and Haiqun Xing) contributed equally.

    View full text