Folate-Targeted PET Enters Human Testing for Vascular Inflammation in Atherosclerosis
A new clinical study is taking aim at one of cardiology’s most persistent blind spots: inflammatory activity inside atherosclerotic plaque. In coronary artery disease and after myocardial infarction, plaque burden alone does not capture the full biological risk. Macrophage-driven inflammation can destabilize lesions long before luminal narrowing becomes severe, and the ATHERO-FOL study is built around that premise.
The trial will evaluate 18F-AlF-NOTA-Folate, a PET tracer designed to bind folate receptor beta on activated macrophages. Because those immune cells are central to plaque inflammation, the tracer is intended to reveal where inflammatory activity is concentrated across the arterial tree. The study is observational and diagnostic, not therapeutic, but its premise is clinically direct: if the tracer can map inflammatory burden in living patients, it may offer a way to study atherosclerosis with far greater biological specificity than standard anatomy-based imaging alone.
Coronary Disease, Recent Infarction, and a Whole-Body Inflammatory Readout
Investigators plan to enroll about 90 adults. One cohort will include approximately 80 patients with suspected or stable coronary artery disease who have already undergone coronary CT angiography and are being referred for cardiac 15O-water PET myocardial perfusion imaging for clinical reasons. The second cohort will include about 10 patients with a recent myocardial infarction.
This design matters because it captures two clinically important settings: chronic disease, where plaque inflammation may be ongoing but smoldering, and the post-infarction period, where arterial biology can be abruptly altered. Whole-body imaging is a particularly strong feature of the protocol. Rather than limiting analysis to the coronaries, the scan will extend from the neck to the inguinal region and will assess the carotid arteries, aorta, renal arteries, and iliac arteries as well as the coronary circulation. Inflammation rarely respects a single vascular bed. A systemic arterial scan is better aligned with the biology of atherosclerosis than a narrow coronary-only view.
Participants will also provide blood samples, allowing exploratory comparison between imaging findings and circulating markers of inflammation. The study will further examine inflammatory uptake in the bone marrow and spleen, two hematopoietic organs that may reflect systemic immune activation and myeloid cell trafficking. In practical terms, the protocol is trying to connect three layers of disease biology at once: vessel wall inflammation, plaque structure, and the systemic immune response.
Why Macrophage Imaging Could Change the Way Plaque Is Studied
Atherosclerosis is not simply a disorder of cholesterol deposition. It is an inflammatory disease in which immune cells accumulate within the vessel wall, alter plaque composition, and contribute to rupture risk. Activated macrophages are central to that process, which is why FR-β has become an attractive target. The tracer’s promise lies in its specificity: instead of measuring anatomy alone, it seeks a cellular marker of active inflammation.
Previous experimental work showed that folate receptor beta-targeted radiotracers can accumulate in macrophage-rich atherosclerotic lesions. Human experience with a related FR-β tracer in rheumatoid arthritis also suggested uptake in inflamed joints and a favorable safety profile. This study extends that concept into cardiovascular medicine, where the challenge is more difficult. Coronary arteries move, are small, and sit close to structures that complicate PET interpretation. Any signal must be robust enough to survive those technical constraints if the approach is to become clinically useful.
For that reason, the protocol includes external ECG recording and, when appropriate, respiratory motion information so cardiac PET data can be gated. Motion correction is not a minor technical detail here. Coronary inflammation imaging will depend on it.
Imaging, Quantification, and the Search for a Coronary Inflammatory Metric
The imaging sequence is carefully staged. At the first visit, participants in the stable coronary artery disease group will undergo additional resting total-body 15O-water PET perfusion imaging beyond their clinically indicated stress PET scan. At the second visit, all participants will undergo whole-body PET with 18F-AlF-NOTA-Folate plus contrast-enhanced CT angiography. Group B will also receive coronary CT angiography as part of the same contrast-enhanced examination.
About 150 MBq of tracer will be administered intravenously. The first five participants will undergo dynamic PET for roughly 120 minutes, while the remaining participants will undergo a static scan approximately 60 to 90 minutes after injection. That split reflects a methodical attempt to characterize tracer behavior early in the study before moving to a more streamlined imaging approach.
Coronary CT angiography will be analyzed quantitatively for vessel narrowing, plaque burden, plaque volume, vessel and lumen volumes, remodeling, and plaque type. The protocol also specifies an artificial intelligence-based quantitative CT analysis method for the coronary images. On the PET side, coronary uptake will be assessed using standardized uptake values and target-to-background ratios. Investigators will also explore a new coronary inflammatory activity measure intended to represent the overall inflammatory burden in the coronary tree.
That effort is ambitious because coronary inflammation is not a single lesion problem. A patient can carry multiple plaques with different biologic behavior, and a single narrowed segment may not tell the whole story. A global inflammatory measure could become useful if it captures cumulative plaque activity rather than only the hottest spot on the scan.
Longitudinal Follow-Up Will Tie Imaging to Events
The study is not stopping at imaging. Participants will be followed through hospital and registry records for up to five years to assess whether the PET and CT findings are associated with later cardiovascular events. This is the point at which a diagnostic tracer becomes more than an imaging curiosity. If inflammatory uptake tracks with subsequent outcomes, the signal may eventually help define which atherosclerotic lesions are biologically active enough to merit closer attention.
Exclusion criteria are strict and reflect the complexity of the imaging protocol. Patients with unstable angina, previous myocardial infarction in the stable-disease cohort, prior coronary bypass surgery or percutaneous coronary intervention, severe pulmonary disease, significant valvular disease, uncontrolled hypertension, severe hypotension, severe renal failure, pregnancy, certain conduction abnormalities, contrast allergy, known inflammatory or autoimmune disease, infection, anti-inflammatory medication use, folate antagonists such as corticosteroids or methotrexate, and known cancer are excluded. Those restrictions narrow the population, but they also reduce confounding from conditions that could distort tracer uptake or blur interpretation.
What this study will not answer is just as important as what it may reveal. It will not test treatment, and it will not establish a management algorithm. It is a diagnostic probe into plaque immunobiology, with outcome linkage planned over years rather than months. If the tracer proves technically workable, the harder question will be whether a map of arterial inflammation can change care at the bedside for patients with stable coronary disease or after infarction.