Multi-tracer and multiparametric PET imaging to detect the IDH mutation in glioma: a preclinical translational in vitro, in vivo, and ex vivo study

Background: This translational study explores multi-tracer PET imaging for the non-invasive detection of the IDH1 mutation which is a positive prognostic factor in glioma. Methods: U87 human high-grade glioma (HGG) isogenic cell lines with or without the IDH1 mutation (CRISP/Cas9 method) were stereotactically grafted into rat brains, and examined, in vitro, in vivo and ex vivo. PET imaging sessions, with radiotracers specific for glycolytic metabolism ([¹⁸F]FDG), amino acid metabolism ([¹⁸F]FDopa), and inflammation ([¹⁸F]DPA-714), were performed sequentially during 3–4 days. The in vitro radiotracer uptake was expressed as percent per million cells. For each radiotracer examined in vivo, static analyses included the maximal and mean tumor-to-background ratio (TBR_max and TBR_mean) and metabolic tumor volume (MTV). Dynamic analyses included the distribution volume ratio (DVR) and the relative residence time (RRT) extracted from a reference Logan model. Ex vivo analyses consisted of immunological analyses. Results: In vitro, IDH1+ cells (i.e. cells expressing the IDH1 mutation) showed lower levels of [¹⁸F]DPA-714 uptake compared to IDH1- cells (p < 0.01). These results were confirmed in vivo with lower [¹⁸F]DPA-714 uptake in IDH+ tumors (3.90 versus 5.52 for TBR_max, p = 0.03). Different values of [¹⁸F]DPA-714 and [¹⁸F] FDopa RRT (respectively 11.07 versus 22.33 and 2.69 versus − 1.81 for IDH+ and IDH- tumors, p < 0.02) were also observed between the two types of tumors. RRT [¹⁸F]DPA-714 provided the best diagnostic performance to discriminate between the two cell lines (AUC of 100%, p < 0.01). Immuno-histological analyses revealed lower expression of Iba-1 and TSPO antibodies in IDH1+ tumors. Conclusions: [18F]DPA-714 and [18F] FDopa both correlate with the presence of the IDH1 mutation in HGG. These radiotracers are therefore good candidates for translational studies investigating their clinical applications in patients.