Harnessing the power of PET to diagnose infectious disease

A child and their caregiver arrive at a pediatric hospital. The child, who has sickle cell disease, is in pain. But what is causing it? It is up to their physicians to determine whether the cause is a vaso-occlusive crisis – when blood flow in small vessels becomes blocked by sickled red blood cells – or a case of osteomyelitis – a bone infection caused by bacteria. But tracking down the source of the pain to treat it properly is anything but straightforward.  

Amanda Green, MD, St. Jude Department of Infectious Diseases, explains that while biopsies (either from tissue or blood) remain a gold standard in infection detection, difficult-to-detect infections often require noninvasive imaging techniques. These techniques can include computed tomography (CT) or magnetic resonance imaging (MRI) to assess changes in the body’s anatomical landscape and tissue structure. However, when viewed anatomically, inflammation originating from disease processes can often look like changes caused by bacterial infection. 

“In this subset of patients, it is difficult to tell if you’re dealing with the underlying disease or a new infection,” says Green. It is a diagnostic dilemma that carries significant clinical weight as infectious diseases remain a leading cause of morbidity and mortality around the globe. This dilemma is also felt by a physician trying to decide on the correct treatment for a patient in pain. “The patient might get an invasive biopsy that may not offer much more information, or we may decide to go ahead and treat for both suspected conditions. Ideally, we want to avoid these invasive tests and unnecessary treatment,” she says.

Green and her St. Jude colleagues are working on a solution to this problem that leverages their expertise in imaging technologies and infectious diseases. If successful, the approach could make accurately diagnosing infections easier in people with sickle cell disease.  

Expanding the specificity of imaging technology 

The key to diagnosing deep-seated infections lies beyond anatomical appearances. Positron emission tomography (PET) offers the ability to visualize the function of organs and tissues, not just their shape and location. With PET technology housed in a scanner along with a CT component, hybrid PET/CT medical devices offer imaging capabilities that allow physicians to see what is happening in the body and where. 

The CT aspect of a PET/CT scanner visualizes anatomy by generating cross-sectional images of the body using X-rays. Meanwhile, the PET component visualizes metabolic processes within the body by detecting signals emitted by radioactive tracers (radiotracers) after they are injected into the body. The power of PET lies not only in the hybrid scanning capability but also in a chosen radiotracer’s specificity. 

Radiotracers target and bind to specific molecular qualities exhibited by different areas or processes of interest in the body – leading to high accumulation or “uptake” of the tracers in these areas. This is how radiotracers make PET a disease-specific – or even pathogen-specific – imaging technique.

Kiel Neumann, PhD, St. Jude Department of Radiology, and his team developed a new radiotracer that contains mannitol – a sugar many kinds of bacteria use as a source of nutrition. Now, a team of investigators at St. Jude is working to conduct a first-in-human study to assess the safety of the novel radiotracer in a PET/CT study in healthy adults. PAKMANN, the phase 0 investigational new drug (IND) trial, is a first step in introducing a new diagnostic imaging technique to address a persistent diagnostic dilemma. 

Developing an imaging solution to a diagnostic dilemma

Neumann’s interest in developing a novel PET radiotracer for pathogenic bacteria was sparked by combat veterans experiencing suspected bacterial infections. At the time, he was Director of Radiochemistry and an assistant professor at the University of Virginia.  

“As a chemist, this area of study was interesting because antibiotics are often given prophylactically because of unclear diagnostic test results,” he says. “Yet, you wouldn’t give chemotherapy prophylactically to a patient with suspected cancer without very specific results. Why was this happening in the infectious disease space, and what could we do about it?”

In 2020, Neumann began developing a PET radiotracer designed to detect and bind to common pathogenic bacteria responsible for healthcare-associated infections in the U.S., namely Staphylococcus aureus, Escherichia coli and Acinetobacter baumannii. When used in PET imaging of preclinical models, the tracer, [18F]fluoromannitol, showed accumulation in gram-positive and gram-negative bacteria but not in mammalian or cancer cells.  [18F]fluoromannitol’s ability to accumulate only in bacteria indicated it to be a sensitive bacterial imaging agent worthy of further investigation.

When Neumann joined St. Jude as a faculty member in 2022, he brought the research around [18F]fluoromannitol with him. Upon his arrival in Memphis, he began seeking infectious disease clinicians at St. Jude willing to collaborate on possible clinical applications. With promising preclinical data published in 2023 in the Journal of Nuclear Medicine, Neumann saw the potential to move further investigations of [18F]fluoromannitol from the lab into humans.

So did Green.

A diagnostic dilemma leads to scientific serendipity

Green recalls first hearing about Neumann’s new tracer. “He had this great data in some kinds of bacteria, but then he sent out an inquiry to clinicians asking what species of bacteria are most clinically relevant in the different populations at St. Jude. Because I’m the sickle cell disease liaison, I gave him my input for what proves difficult to diagnose and treat in the patient population I’m responsible for. It’s about figuring out what we can use this for in terms of clinically relevant bacteria,” she says.

In a spark of serendipity, the bacteria that most concerned Green were compatible with [18F]fluoromannitol. Green asked Neumann if he wanted to bring the tracer into humans. Such a translational pipeline is an investigator’s dream, and Neumann emphasizes that Green “has been the perfect collaborator. She is very involved; she even wrote the protocol herself. Our development of this study has never felt territorial in any way; it’s been a true collaboration.”

However, the collaborative nature of the study has not been limited to Green and Neumann. To build a bridge between lab development and clinical use, a dedicated molecular imaging resource at St. Jude played a vital role in developing this first-in-human PET study.

A core resource for molecular imaging research at St. Jude

Amy Vavere, PhD, Department of Radiology, serves as Director of the Molecular Imaging Core at St. Jude. The core functions as a departmental and institutional resource to produce radiotracers for PET imaging research and specific clinical use cases, and also supports PET imaging clinical trials. 

“We do a little bit of everything,” says Vavere. “If it gets to a point where an investigator is interested in doing a clinical trial, the molecular imaging core will do all the testing required for approval and prepare all the documentation needed around tracer manufacturing and quality controls.”

Showing the radiotracer production process and safety controls are a major aspect of the clinical trial submission process required by the Food and Drug Administration (FDA). This is especially true for a novel tracer being evaluated as an investigational new drug. For Vavere’s group, PAKMANN marks the first phase 0, first-in-human PET trial they have supported. 

“The plan was, as Kiel’s lab optimized the chemistry of fluoromannitol, our molecular imaging core team would translate it into a system to automate the radiochemistry,” she says. “It was our job to take this made-by-hand radiotracer he developed in his lab into an automated radiochemistry production system that we could further optimize, document and submit to the FDA as part of this first-in-human study.”

While this is the first phase 0 trial for the group, they followed the standard FDA submission process, which Vavere explains is not easy but familiar. She further explains her group is bolstered by the molecular imaging community. 

“I’m connected with a network of molecular imaging facility core directors around the country: it’s a pretty small field, so we’re a tiny community, but we’re in touch all the time. We are constantly helping each other out with best practices for tracer production and tips for successful FDA submission,” she says. 

Harnessing the power of PET in a first-in-human study and beyond

Newly open to recruitment, the investigators and clinicians remain hopeful about what this trial could mean for infectious disease detection and management. 

Vavere emphasizes that “a lot of investigators and clinicians don’t know that PET scans don’t have to be conducted with the same tracer every time. A lot of my work is in educating people that we they can select a specific tracer to follow a process in the body and then image it with a PET/CT scanner; that’s the power of PET.”

Expanding the knowledge of when and how to harness the power of PET/CT with the utilization of a disease- or pathogen-specific radiotracer is a goal shared by Green, Neumann and Vavere. When the phase 0 trial concludes, thereby establishing requisite safety and quality standards for the novel radiotracer in healthy adults, Green and Neumann hope to open a trial that uses [18F]fluoromannitol to detect bacterial infections in pediatric patients with sickle cell disease. 

“This will really serve the patients,” says Green. “We aren’t trying to replace other imaging modalities that are useful for standard diagnostic situations. The use of PET in this instance is for those diagnostic dilemmas, and we imagine it will save a lot of unnecessary care.” 

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