Investigation of 6-[18F]-Fluoromaltose as a Novel PET Tracer for Imaging Bacterial Infection

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Abstract

Despite advances in the field of nuclear medicine, the imaging of bacterial infections has remained a challenge. The existing reagents suffer from poor sensitivity and specificity. In this study we investigate the potential of a novel PET (positron emission tomography) tracer that overcomes these limitations.

Methods

6-[ ¹⁸F]-fluoromaltose was synthesized. Its behavior in vitro was evaluated in bacterial and mammalian cultures. Detailed pharmacokinetic and biodistribution profiles for the tracer were obtained from a murine model.

Results

6-[ ¹⁸F]-fluoromaltose is taken up by multiple strains of pathogenic bacteria. It is not taken up by mammalian cancer cell lines. 6-[ ¹⁸F]-fluoromaltose is retained in infected muscles in a murine model of bacterial myositis. It does not accumulate in inflamed tissue.

Conclusion

We have shown that 6-[ ¹⁸F]-fluoromaltose can be used to image bacterial infection in vivo with high specificity. We believe that this class of agents will have a significant impact on the clinical management of patients.

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Most cited references 20

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A molecular imaging primer: modalities, imaging agents, and applications.

Michelle L James, Sanjiv Gambhir (2012)

Molecular imaging is revolutionizing the way we study the inner workings of the human body, diagnose diseases, approach drug design, and assess therapies. The field as a whole is making possible the visualization of complex biochemical processes involved in normal physiology and disease states, in real time, in living cells, tissues, and intact subjects. In this review, we focus specifically on molecular imaging of intact living subjects. We provide a basic primer for those who are new to molecular imaging, and a resource for those involved in the field. We begin by describing classical molecular imaging techniques together with their key strengths and limitations, after which we introduce some of the latest emerging imaging modalities. We provide an overview of the main classes of molecular imaging agents (i.e., small molecules, peptides, aptamers, engineered proteins, and nanoparticles) and cite examples of how molecular imaging is being applied in oncology, neuroscience, cardiology, gene therapy, cell tracking, and theranostics (therapy combined with diagnostics). A step-by-step guide to answering biological and/or clinical questions using the tools of molecular imaging is also provided. We conclude by discussing the grand challenges of the field, its future directions, and enormous potential for further impacting how we approach research and medicine.

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Real-time in vivo imaging of invasive- and biomaterial-associated bacterial infections using fluorescently labelled vancomycin.

Tina Schäfer, Eleni Tsompanidou, Ed Lim … (2012)

Invasive and biomaterial-associated infections in humans are often difficult to diagnose and treat. Here, guided by recent advances in clinically relevant optical imaging technologies, we explore the use of fluorescently labelled vancomycin (vanco-800CW) to specifically target and detect infections caused by Gram-positive bacteria. The application potential of vanco-800CW for real-time in vivo imaging of bacterial infections is assessed in a mouse myositis model and a human post-mortem implant model. We show that vanco-800CW can specifically detect Gram-positive bacterial infections in our mouse myositis model, discriminate bacterial infections from sterile inflammation in vivo and detect biomaterial-associated infections in the lower leg of a human cadaver. We conclude that vanco-800CW has a high potential for enhanced non-invasive diagnosis of infections with Gram-positive bacteria and is a promising candidate for early-phase clinical trials.

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Maltodextrin-based imaging probes detect bacteria in vivo with high sensitivity and specificity.

Xinghai Ning, Eric Gilbert, Seungjun Lee … (2011)

The diagnosis of bacterial infections remains a major challenge in medicine. Although numerous contrast agents have been developed to image bacteria, their clinical impact has been minimal because they are unable to detect small numbers of bacteria in vivo, and cannot distinguish infections from other pathologies such as cancer and inflammation. Here, we present a family of contrast agents, termed maltodextrin-based imaging probes (MDPs), which can detect bacteria in vivo with a sensitivity two orders of magnitude higher than previously reported, and can detect bacteria using a bacteria-specific mechanism that is independent of host response and secondary pathologies. MDPs are composed of a fluorescent dye conjugated to maltohexaose, and are rapidly internalized through the bacteria-specific maltodextrin transport pathway, endowing the MDPs with a unique combination of high sensitivity and specificity for bacteria. Here, we show that MDPs selectively accumulate within bacteria at millimolar concentrations, and are a thousand-fold more specific for bacteria than mammalian cells. Furthermore, we demonstrate that MDPs can image as few as 10(5) colony-forming units in vivo and can discriminate between active bacteria and inflammation induced by either lipopolysaccharides or metabolically inactive bacteria.

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Author and article information

Contributors

Kewei Chen: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2014

Publication date (Electronic): 22 September 2014

Volume: 9

Issue: 9

Electronic Location Identifier: e107951

Affiliations

[1 ]Department of Radiology, Stanford University School of Medicine, Stanford, California, United States of America

[2 ]Sanofi R&D, Sanofi, Paris, France

[3 ]Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America

[4 ]Department of Bioengineering, Stanford University School of Medicine, Stanford, California, United States of America

Banner Alzheimer's Institute, United States of America

Author notes

* E-mail: gayatrig@ 123456stanford.edu

Competing Interests: The authors have a patent on the imaging probe described in the manuscript. Patent title: PROBES AND METHODS OF IMAGING A BACTERIAL INFECTION. Serial No. 14/204,402. Filed: March 11, 2014. Docket No. 221907-1950. One of the authors, Dr. Erwan Jouannot, is an employee of Sanofi Inc. This does not alter the authors' adherence to PLOS ONE editorial policies and criteria. Sanjiv Sam Gambhir is on the editorial board for PLOS ONE. This does not alter the authors' adherence to PLOS ONE editorial policies and criteria.

Conceived and designed the experiments: GG SSG. Performed the experiments: GG MN EBJ RR AH. Analyzed the data: GG. Contributed reagents/materials/analysis tools: JH. Wrote the paper: GG AH SSG.

Article

Publisher ID: PONE-D-14-25942

DOI: 10.1371/journal.pone.0107951

PMC ID: 4171493

PubMed ID: 25243851

SO-VID: 04665815-b4cd-4693-ba42-f99b567b8b35

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 12 June 2014

Date accepted : 17 August 2014

Page count

Pages: 6

Funding

The authors received no specific funding for this work.

Custom metadata

Data Availability The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting information files.