# Immuno-PET for Glioma Imaging: An Update
## 4 Targets for Immuno-PET
### Vegf  
The vascular endothelial growth factor receptor 2 (VEGF-2/Flk-1/KDR) is a biomarker that is overexpressed in tumor neo-vasculature and several types of malignancies [38]. Angiogenesis has identified important players as targets, including vascular endothelial growth factors (VEGF), VEGF receptors (VEGFRs), integrins (particularly v3), and matrix metalloproteinases (MMPs). These targets are used to produce both imaging and therapeutic medicines. Several specialized imaging agents, such as HuMV833, VG76e, and bevacizumab, have been developed using radiolabeled VEGF or monoclonal antibodies against VEGF. Furthermore, [^18F]-fluciclatide, a radioisotope-labeled short cyclic peptide comprising the arginyl-glygly-aspartic acid (RGD) tripeptide with great binding affinity to v3 integrins, has shown promise for imaging angiogenesis. Reduced [^18F]-fluciclatide absorption was associated with the decreased expressions of three integrins and an early response to antiangiogenic targeted therapies in both experimental and clinical studies. Furthermore, in a preclinical MMP study, ^18F-labeled marimastat, an MMP inhibitor, and MMP2/9 substrates were observed to accumulate in tumor locations. As a result, radiolabeling therapeutic antiangiogenic drugs has become a well-established practice in scientific literature [39]. Beyond the mentioned angiogenesis indicators, researchers have identified a minimum of 46 potential therapeutic targets residing on the endothelial cells of tumor blood vessels. These specific markers on tumor endothelial cells, referred to as TEMs (Tumor Endothelial Markers), constitute a cluster of genes participating in angiogenesis regulation. Among these TEMs, TEM8 stands out as it has been observed to exhibit increased expression in tumor vasculature across various tumor types in both human patientsand mouse models bearing tumors. Importantly, this upregulation is not observed in the context of normal reparative angiogenesis during processes such as wound healing or ovulation [40]. Bevacizumab is a humanized monoclonal antibody with a distinct capacity to bind exclusively to vascular endothelial growth factor A (VEGF-A). VEGF-A is an overexpressed biomarker in cervical cancer, where it plays a critical role in the beginning and maintenance of tumor-associated neo-angiogenesis, or the development of new blood vessels to support tumor growth. However, the effectiveness of the VEGF-targeted mAb bevacizumab in treating diffuse intrinsic pontine glioma (DIPG) remains uncertain. [PERSON] et al. investigated how bevacizumab labeled with zirconium-89 (\({}^{89}\)Zr) behaves in DIPG mouse models regarding biodistribution and uptake [41]. Human E98-FM, U251-FM glioma cells, and HSJD-DIPG-007-FLUC primary DIPG cells were injected into nude mice through subcutaneous, pons, or striatum injection. Tumor development was tracked via bioluminescence imaging and observed using MRI. PET scans were performed 72 to 96 h post [89 Zr]-bevacizumab administration, and biodistribution was assessed through ex vivo analysis. The researchers verified elevated VEGF expression in human DIPG using publicly available mRNA data. However, no significant uptake of [89 Zr]-bevacizumab was identified in the brain or brain tumors at any disease stage, although significant uptake was observed in subcutaneous tumors. VEGF expression was definitely detectable in the perinecrotic areas of subcutaneous E98-FM tumors, despite the absence of VEGF expression in cerebral tumors via in situ hybridization. The low absorption of [89 Zr]-bevacizumab in brain-based xenografts shows that bevacizumab targeting VEGF may be ineffective in treating diffuse infiltrative portions of glial brain tumors in mice. Extrapolating these results to clinical scenarios implies that administering bevacizumab to DIPG patients should only be considered after confirming VEGF targeting through [89 Zr]-bevacizumab immuno-PET.