The tumor microenvironment is highly heterogeneous. For gliomas, the tumor-associated inflammatory response is pivotal to support growth and invasion. Factors of glioma growth, inflammation, and invasion, such as the translocator protein (TSPO) and matrix metalloproteinases (MMP), may serve as specific imaging biomarkers of the glioma microenvironment. In this study, noninvasive imaging by PET with [ 18 F]DPA-714 (TSPO) and [ 18 F]BR-351 (MMP) was used for the assessment of localization and quantification of the expression of TSPO and MMP. Imaging was performed in addition to established clinical imaging biomarker of active tumor volume ([ 18 F]FET) in conjunction with MRI. We hypothesized that each imaging biomarker revealed distinct areas of the heterogeneous glioma tissue in a mouse model of human glioma. Tracers were found to be increased 1.4-to 1.7-fold, with [ 18 F]FET showing the biggest volume as depicted by a thresholding-based, volumes of interest analysis. Tumor areas, which could not be detected by a single tracer and/or MRI parameter alone, were measured. Specific compartments of [ 18 F]DPA-714 (14%) and [ 18 F]BR-351 (11%) volumes along the tumor rim could be identified. [ 18 F]DPA-714 (TSPO) and [ 18 F]BR-351 (MMP) matched with histology. Glioma-associated microglia/macrophages (GAM) were identified as TSPO and MMP sources. Multitracer and multimodal molecular imaging approaches may allow us to gain important insights into glioma-associated inflammation (GAM, MMP). Moreover, this noninvasive technique enables characterization of the glioma microenvironment with respect to the disease-driving cellular compartments at the various disease stages. Cancer Res; 77(8); 1831-41. Ó2017 AACR.

TSPO-PET and diffusion-weighted MRI for imaging a mouse model of infiltrative human glioma

<p>Supplementary Figure Legends 1-5</p>

<p>(A) T/B ratios, (B-D) tracer volumes, (E-J) areas of unique tracer uptake and overlapping regions. No significant effect on volumetric data was observed based on the order of imaging experiments.</p>

<p>(A) An elliptical VOI (yellow) was drawn in the striatum. (B) Another elliptical VOI (green) was placed over the affected hemisphere. (C) After application of a thresholding based on the control VOI. The same original VOIs (left and middle) were used for all animals for individual thresholding.</p>

<p>Gli36dEGFR cells were implanted. Thereafter, two imaging sequences were conducted: In sequence 1, T2w MRI and PET with [¹⁸F]DPA-714 was performed, while [¹⁸F]BR-351 PET and [¹⁸F]FET PET were conducted at day 13 and 14, respectively. In imaging sequence 2, T2w MRI and [¹⁸F]FET PET were conducted at day 12, followed by [¹⁸F]BR-351 and [¹⁸F]DPA-714 at day 13 and 14, respectively. After the last imaging experiment, mice were sacrificed and the brains immediately harvested for further analysis.</p>

<div>Abstract<p>The tumor microenvironment is highly heterogeneous. For gliomas, the tumor-associated inflammatory response is pivotal to support growth and invasion. Factors of glioma growth, inflammation, and invasion, such as the translocator protein (TSPO) and matrix metalloproteinases (MMP), may serve as specific imaging biomarkers of the glioma microenvironment. In this study, noninvasive imaging by PET with [¹⁸F]DPA-714 (TSPO) and [¹⁸F]BR-351 (MMP) was used for the assessment of localization and quantification of the expression of TSPO and MMP. Imaging was performed in addition to established clinical imaging biomarker of active tumor volume ([¹⁸F]FET) in conjunction with MRI. We hypothesized that each imaging biomarker revealed distinct areas of the heterogeneous glioma tissue in a mouse model of human glioma. Tracers were found to be increased 1.4- to 1.7-fold, with [¹⁸F]FET showing the biggest volume as depicted by a thresholding-based, volumes of interest analysis. Tumor areas, which could not be detected by a single tracer and/or MRI parameter alone, were measured. Specific compartments of [¹⁸F]DPA-714 (14%) and [¹⁸F]BR-351 (11%) volumes along the tumor rim could be identified. [¹⁸F]DPA-714 (TSPO) and [¹⁸F]BR-351 (MMP) matched with histology. Glioma-associated microglia/macrophages (GAM) were identified as TSPO and MMP sources. Multitracer and multimodal molecular imaging approaches may allow us to gain important insights into glioma-associated inflammation (GAM, MMP). Moreover, this noninvasive technique enables characterization of the glioma microenvironment with respect to the disease-driving cellular compartments at the various disease stages. <i>Cancer Res; 77(8); 1831–41. ©2017 AACR</i>.</p></div>

<p>Supplementary Figure Legends 1-5</p>