Glioblastoma is the most malignant brain tumor in adults, and its prognosis remains dismal. The blood-brain barrier impedes the effectiveness of many drugs, which are otherwise effective for cancer treatment. Monocarboxylate transporter 1 (MCT1) is expressed on endothelial and glioblastoma cells. Our approach aims to leverage MCT1 to transport theranostic agents across the blood-brain barrier. In this context, we present herein the application of fluorine-18-labeled nicotinic acid (denoted as [18F]FNA) for glioblastoma imaging using positron emission tomography (PET). An intracranial mouse model of human glioblastoma was prepared by using patient-derived BT12 cells. PET imaging, ex vivo biodistribution, brain tissue autoradiography, and tumor and tissue uptake kinetic analyses were performed. Additionally, the ligand-target interaction was studied using in silico modeling. The xenografted glioblastomas were distinctly visualized in all 18 mice with a mean standardized uptake value of 0.92 ± 0.11 and tumor-to-brain ratio of 1.66 ± 0.17. The tumor uptake of intravenously administered [18F]FNA decreased by 76% on average when MCT1 was inhibited, whereas preadministration of 60 mg/kg niacin significantly enhanced [18F]FNA tumor uptake. The G protein-coupled receptor GPR109A is a high-affinity receptor for niacin (nicotinic acid). In silico simulations indicated that both niacin and fluorinated nicotinic acid (FNA) interact with the GPR109A receptor in a similar manner. In the presence of a GPR109A inhibitor in in vivo experiments, the tumor residence of [18F]FNA was extended. [18F]FNA has demonstrated its potential for PET imaging in a clinically relevant orthotopic glioblastoma model, and MCT1 plays a crucial role in [18F]FNA transport. The results pave the way for the development of niacin-derived theranostics for glioblastoma care.
Keywords: G protein-coupled receptor GPR109A; fluorine-18; glioblastoma; monocarboxylate transporter 1; niacin; nicotinic acid.