Researchers in the U.S. and U.K. have developed what they say is a more accurate way to scan for tuberculosis (TB) using positron emission tomography (PET) to detect the causative Mycobacterium tuberculosis (Mtb) bacterium.
The team, from the Rosalind Franklin Institute, the Universities of Oxford and Pittsburgh, and the National Institutes of Health, developed a new PET radiotracer, called FDT ([18F]FDT), that is taken up by live TB bacteria in the body. (Radiotracers are radioactive compounds which give off radiation that can be detected by scanners and turned into a 3D image.) Development of the new Mtb-specific radiotracer means that PET can be used for the first time to accurately pinpoint where and when there is active disease in a patient’s lungs.
The researchers reported on studies evaluating the radiotracer in multiple preclinical models with no adverse effects, and say it is now ready to progress into early clinical studies in humans.
Clifton Barry III, PhD, from the National Institute of Allergy and Infectious Diseases, said: “FDT will enable us to assess in real time whether the TB bacteria remains viable in patients who are receiving treatment, rather than having to wait to see whether or not they relapse with active disease. This means FDT could add significant value to clinical trials of new drugs, transforming the way they are tested for use in the clinic.”
Barry is co-corresponding author of the team’s published paper in Nature Communications, titled “Distributable, metabolic PET reporting of tuberculosis,” in which they say that the combined results of their preclinical assessment and other evaluations “… now suggest [18F]FDT as a new, viable radiotracer for TB, suitable for Phase I trials.”
Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a serious global health challenge causing an estimated 1.3 million deaths worldwide in 2022, the authors wrote. “Prompt, short-term diagnoses of TB are crucial for public health infection control measures, as well as for ensuring appropriate treatment for infected patients and controls.”
Professor Ben Davis, PhD, science director of the Franklin’s Next Generation Chemistry group, led the research. He explained, “Finding an accurate way to identify when TB is still active in the body is not only important for initial diagnosis, but to ensure patients are receiving antibiotics long enough to kill the disease, and no longer.”
Two methods currently exist for TB diagnosis, either testing for the TB bacteria in a patient’s sputum, or carrying out a PET scan to look for signs of inflammation in the lung, using the common radiotracer FDG ([18F]FDG).
However, a sputum test can show a negative long before the disease has been fully treated in the lungs, which could result in patients finishing treatment too early. And while scanning for inflammation can be helpful in seeing the extent of the disease, the current radiotracer is not specific to TB, and inflammation can be caused by other conditions. Inflammation can also persist in the lung after the TB bacteria has been eliminated, leading to treatment continuing longer than necessary.
“Existing detection methods rely almost exclusively on bacterial culture from sputum which limits sampling to organisms on the pulmonary surface,” the team noted. And while advances in monitoring tuberculous lesions have utilized the common glucoside [18F]FDG, these methods also lack specificity to the causative pathogen Mycobacterium tuberculosis so do not directly correlate with pathogen viability. “… [18F]FDG is also taken up and retained by any metabolically active tissue and so, as a generic marker of more active metabolism, has a limitation in its lack of specificity and inability to clearly distinguish granulomatous TB disease from other inflammatory conditions, including cancer,” the investigators stated.
Other radiotracers have been developed, the authors further pointed out, but their specificity and sensitivity may be only similar, or even worse than that of FDG, and they can be complex to produce. Their new approach is more specific as its focus is on a carbohydrate, trehalose, that is only processed by the TB bacteria. “The lack of naturally occurring trehalose in mammalian hosts as well as the uptake of exogenous trehalose by Mtb has suggested that trehalose-based probes could function as both highly specific and sensitive reporters,” they stated noted.
The new radiotracer, [18F]FDT, is what they described as one of the simplest 18F-analogs of trehalose. It is created from FDG using a relatively simple process involving enzymes developed by the research team. This means it can be produced without specialist expertise or laboratories and so would be a viable option in low- and middle-income countries with less developed healthcare systems. These countries currently see over 80% of global TB cases and deaths from the disease. “… we show that one of the simplest 18F-analogs of trehalose, 2-[18F]fluoro-2-deoxytrehalose [18F]FDT can be generated as an in vivo TB-reporter using one-pot, automatable, pyrogen-free, chemoenzymatic synthesis from readily-available [18F]FDG in a validated manner that does not require specialist expertise,” they wrote.
In their published paper the team reported on tests with the PET radiotracer in multiple preclinical models, including non-human primates. “Toxicological and preclinical testing in diverse species shows that this now creates access to a safe probe that is effective and selective in multiple preclinical models both to visualize TB lesions and to monitor their treatment non-invasively,” they stated.
A key advantage of the new approach is that it only requires a hospital to have standard radiation control and PET scanners, which are becoming more widely available throughout the world. Davis further commented, “The common radiotracer FDG and the enzymes we’ve developed to turn it into FDT can all be sent by post. With a minimum of additional training, this effective diagnostic in essence could be rolled out into most healthcare systems around the world—and most importantly, in the places where this disease is still taking its greatest toll.”
The authors concluded, “We anticipate that this distributable technology to generate clinical-grade [18F]FDT directly from the widely-available clinical reagent [18F]FDG, without need for either custom-made radioisotope generation or specialist chemical methods and/or facilities, could now usher in global, democratized access to a TB-specific PET tracer … Together therefore our results suggest that disease-selectivity demonstrated by [18F]FDT will allow effective monitoring of disease and its treatment. This is likely to be invaluable for clinical evaluation of not only effectiveness in the development of new therapies but also in longitudinal monitoring and hence compliance.”
