Distribution of glutamate and glutamine in tumor microenvironments of brain metastasis: Insights from biochemical analysis and molecular imaging

Cancer neuroscience has implicated peritumoral neurons in facilitating breast-to-brain metastasis (BrBM) progression via the N-methyl-D-aspartate receptor (NMDAR), a glutamate (Glu) receptor. The Glu-glutamine (Gln) cycle converts Glu into Gln, forming the combined Glx pool. This study investigated the spatial distribution of phosphorylated GluN2B (pGluN2B), an NMDAR subunit, and Glx in BrBM. <i>Ex vivo</i> analysis revealed elevated pGluN2B expression in BrBM, particularly in tumor cores, while Glx levels were paradoxically reduced. In mouse models, glutamine-based positron emission tomography (Gln-PET) imaging revealed higher tracer uptake in BrBM than that in paired breast tumors, with uptake values correlated positively with Glx concentration and pGluN2B expression. Strong Gln-PET uptake in BrBM noninvasively indicated elevated Glx metabolism in a BrBM patient, confirmed by <i>ex vivo</i> staining. This study highlighted the regional distribution of NMDAR and Glx, underscoring their potential as diagnostic biomarkers for BrBM. Glutamine-based molecular imaging can noninvasively visualize the tumor microenvironment relevant to cancer neuroscience.