Fluciclovine PET baseline maps normal head uptake for glioma diagnosis

When a radiologist scans the head of a patient with a suspected brain tumor using an amino acid positron emission tomography tracer, the question is never simply whether the tracer accumulates somewhere. It is whether that accumulation is abnormal. Tumor cells avidly import amino acids, but so do many healthy tissues, and a bright signal in the parotid gland or the nasal cavity can be entirely physiological. A team at Nagoya University Graduate School of Medicine has now published the first comprehensive map of where the tracer 18F-fluciclovine settles in normal-appearing head tissues, intracranial and extracranial alike, in patients being evaluated for suspected malignant glioma. The work, described in Frontiers in Nuclear Medicine, provides a quantitative baseline that could sharpen the interpretation of one of the most technically demanding PET studies in neuro-oncology.

18F-fluciclovine, chemically anti-1-amino-3-[18F]fluorocyclobutane-1-carboxylic acid, is a synthetic amino acid analogue designed to exploit the amino acid transporters that tumor cells overexpress. It crosses the blood-brain barrier and is taken up primarily through the sodium-dependent alanine-serine-cysteine transporter 2, known as ASCT2, with a supporting role for the sodium-independent L-type amino acid transporter 1, LAT1. Crucially, unlike natural amino acids, fluciclovine is not metabolized inside cells and is not incorporated into protein synthesis, so the signal it generates reflects transporter-dependent accumulation rather than metabolic processing. That property makes it attractive for imaging glioma, but it also means the tracer lingers in the bloodstream longer than tracers that are rapidly cleared into protein, which can contaminate measurements in blood-rich structures.

The researchers retrospectively analyzed 18F-fluciclovine PET/CT images from 20 consecutive patients scanned at Nagoya University Hospital between July 2024 and June 2025. All were treatment-naïve, with no history of neurosurgical resection, radiotherapy, or chemotherapy, and none were taking corticosteroids, sedatives, or antiepileptic drugs at the time of imaging. The cohort had a mean age of 49.6 years, ranging from 6 to 77, and included 14 patients with glioma and 2 with primary central nervous system lymphoma. Tracer was administered intravenously at a mean dose of about 231 MBq, and PET acquisition began 10 minutes after injection, running in list mode for 20 minutes with dynamic images reconstructed every 2 minutes alongside a static acquisition on a Biograph 16 Horizon scanner.

Two board-certified nuclear medicine physicians measured standardized uptake values in 24 predefined head regions, 12 intracerebral and 12 extracerebral. The intracerebral set covered the four cortical lobes, white matter, thalamus, basal ganglia, midbrain, pons, medulla oblongata, cerebellum, and cerebellar vermis. The extracerebral set spanned the pituitary and pineal glands, choroid plexus, venous and cavernous sinuses, lacrimal and parotid glands, pharynx, nasal cavity, skeletal muscle, bone marrow, and skin. Volumes of interest were placed as spherical regions on axial images with CT for anatomical reference, and cortical measurements were taken in tumor-free contralateral gray matter, a standardized approach borrowed from 11C-methionine PET studies to minimize measurement error and improve comparability across subjects.

The headline finding is that fluciclovine uptake in the brain is remarkably low and remarkably uniform. White matter showed the lowest SUVmean of any region, 0.15 ± 0.04, while the cerebral cortex averaged 0.28 ± 0.06, with no significant differences among the frontal, parietal, temporal, and occipital lobes. The cortex-to-cerebellum ratio stayed between 0.67 and 0.71 across lobes, a consistency that matters because it suggests minimal nonspecific accumulation anywhere in the cerebral hemispheres. Among the deeper brain structures, the cerebellar vermis led with an SUVmean of 0.46 ± 0.09, followed by the pons, cerebellum, thalamus, basal ganglia, midbrain, and medulla, all clustered between roughly 0.35 and 0.43.

Dynamic time-activity curves, available in 15 patients, showed that brain uptake crept upward only slightly during the 2-to-20-minute window, with absolute SUV changes of 0.05 to 0.08 in the cortex and no more than 0.15 anywhere in the parenchyma. That stability carries a practical implication: SUV measurements are unlikely to be substantially distorted by minor timing variations within this interval. The picture outside the brain was entirely different. The pituitary gland and parotid gland peaked at the first 2-minute frame and then washed out markedly, declining 41.9 percent and 35.1 percent respectively over the acquisition period, while the choroid plexus, nasal cavity, lacrimal gland, venous sinus, bone marrow, and cavernous sinus showed moderate declines of 22.6 to 31.2 percent.

The extracerebral biodistribution is where the baseline becomes genuinely useful for diagnosis. The parotid gland showed the highest SUVmean of any head region, 3.39 ± 0.82, roughly twelve times the cortical value, followed by the pharynx at 2.51, the pituitary gland at 2.32, the nasal cavity at 2.30, skeletal muscle at 2.23, bone marrow at 1.99, and skin at 1.88. Uptake in muscle, marrow, and skin was heterogeneous: the posterior neck, lateral pterygoid, and extraocular muscles lit up, as did the marrow of the clivus and occipital bone and the skin of the vertex. These hot spots likely reflect high ASCT2 expression in metabolically active cell populations, abundant regional blood flow, and, in the marrow, hematopoietic activity concentrated where red marrow persists in adults.

Eight patients also underwent 11C-methionine PET/CT within three weeks, allowing a direct head-to-head comparison of the two amino acid tracers. Methionine showed significantly higher uptake in every brain region, all p ≤ 0.004, and cortical SUVpeak values of 1.15 to 1.32 against fluciclovine’s 0.30 to 0.31. No significant correlations between the two tracers were observed in the brain, which the authors attribute to differences in transporter distribution: methionine rides mainly on LAT1 and LAT2, while fluciclovine depends chiefly on ASCT2, whose expression in brain endothelial cells is lower than LAT1’s. Outside the brain, the relationship reversed in places. Fluciclovine was significantly higher in the venous sinuses, skeletal muscle, and nasal cavity, possibly because it is not incorporated into protein synthesis and remains in the blood pool, whereas methionine is rapidly cleared from the bloodstream.

Age left its fingerprints on the extracerebral map. Pineal gland and bone marrow uptake both declined significantly with age, with correlation coefficients of −0.64 and −0.63 respectively, likely reflecting the progressive calcification of the pineal gland and the physiological shrinkage of hematopoietic red marrow. Cavernous sinus uptake, by contrast, rose with age. Intracerebral uptake showed no significant age-related changes, with correlation coefficients between −0.16 and 0.20. Incidental findings reinforced the caution needed in interpretation: a subcutaneous neurofibroma in a patient with neurofibromatosis reached an SUVmax of 3.37, and mild uptake appeared in the mucosal thickening of three cases of maxillary sinusitis, with a mean SUVmax of 1.10. Fluciclovine uptake is not tumor-specific, and benign lesions with high cellular proliferation or metabolic activity can light up.

The authors acknowledge the limits of their study. The participants were scanned for clinical indications rather than being healthy volunteers, so subtle metabolic alterations in normal-appearing tissue cannot be excluded, and the small, heterogeneous cohort with incomplete histological confirmation limits generalizability. Fasting conditions were not standardized, dynamic imaging began only at 10 minutes post-injection so early kinetics were not captured, and manual volume-of-interest placement introduces observer variability that was not formally assessed. Still, the contralateral measurements broadly matched previous reports, supporting the validity of the findings. For clinicians, the payoff is concrete: the very low, uniform brain uptake should enhance contrast with tumor tissue and aid preoperative margin delineation, while awareness of the hot physiological zones, particularly the venous sinuses and bone marrow near the skull base and tentorium, should help avoid false-positive readings where such uptake can mimic tumor. The team calls for multicenter validation in larger cohorts with standardized protocols, but the baseline they have drawn gives interpreters of fluciclovine head PET a reference framework they have never had before.

Subject of Research: Physiological biodistribution of 18F-fluciclovine PET in the head: as a baseline for interpretation in patients with suspected glioma

Article Title: Physiological biodistribution of 18F-fluciclovine PET in the head: as a baseline for interpretation in patients with suspected glioma

Article References: Abe, Y., Minamimoto, R., Fujita, N., Higashi, M., Ito, R., Kato, K., Deguchi, S., Ohka, F., Saito, R., & Naganawa, S. (2026). Physiological biodistribution of 18F-fluciclovine PET in the head: as a baseline for interpretation in patients with suspected glioma. Frontiers in Nuclear Medicine, 6, Article 1850254. https://doi.org/10.3389/fnume.2026.1850254

Image Credits: AI Generated

DOI: 10.3389/fnume.2026.1850254

Keywords: Physiological, biodistribution, F-fluciclovine, head, baseline, interpretation, patients, suspected, glioma, scientific research