Glioblastoma is the most aggressive type of primary brain tumor in adults, with median survival typically under two years. Radiolabeled amino acids, including O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET), are crucial for diagnosing gliomas and assessing treatment response using positron emission tomography (PET). However, the fact that [18F]FET PET is negative in about 10–30% of glioma paitients, highlights the need for alternative radiotracers. We previously showed that 6-[18F]fluoronicotinic acid ([18F]FNA) PET can distinctly visualize and delineate human glioblastoma in intracranial xenograft mouse model, with tumor uptake mediated by monocarboxylate transporters 1 and 2 (MCT1/2). In this study, we assessed the potential clinical value of [18F]FNA by comparing its PET imaging performance to that of established clinical amino acid tracers, [18F]FET and [11C]methionine ([11C]MET).

Orthotopic human glioblastoma xenograft models were made in immunocompromised mice for radiotracer comparisons and MCT blocking studies. Dynamic PET imaging, ex vivo biodistribution, brain tissue autoradiography, and histological staining were performed.

In the same mice, PET imaging with [18F]FNA clearly delineated the tumor, whereas [18F]FET did not yield detectable tumor signals. This was despite [18F]FET having a similar brain uptake (SUVmean = 0.40 ± 0.08) as [18F]FNA (SUVmean = 0.40 ± 0.09, P = 0.486). Although [18F]FET PET did not detect the tumor, imaging with [11C]MET was positive. In vivo blocking experiments indicated that MCT1, MCT2, and MCT4 are important transporters but may contribute in unequal measures to [18F]FNA tissue uptake. In vivo blocking with AZD3965, a dual inhibitor of MCT1 and MCT2, reduced [18F]FNA tumor uptake by 68─77%, while blocking MCT4 reduced uptake by 23%.

We could not visualize the human glioblastoma xenografts in mice by [18F]FET PET; However, tumor uptake was clearly observed with [18F]FNA and [11C]MET PET. MCT1, MCT2, and MCT4 contribute substantially to [18F]FNA uptake in glioblastoma and other tissues. Thus, given its distinct biological uptake mechanism relative to current clinical tracers, [18F]FNA could be an alternative approach for clinical PET imaging of glioblastoma.

The authors thank Lu Bai and Johan Rajander for their kind contributions and InFLAMES Research Flagship for research and travel support