# Immuno-PET for Glioma Imaging: An Update
## 5 Discussion  
Despite advances in the field of diagnosis and therapy, primary brain tumors, of which gliomas represent the most common category, remain a diagnostic and therapeutic challenge. In particular, the prognosis for high-grade gliomas is still grim, with a median survival of around 13 months [53]. In addition, the introduction of new therapeutic approaches, such as the combination of radiotherapy with temozolomide, has led to the emergence of atypical patterns in MRI and CT, such as pseudoprogression [54; 55]. The latter, which occurs more frequently in the first 3 months after the completion of combined radiotherapy and chemotherapy, is predominantly associated with edema, increased capillary permeability, and inflammatory components. In this context, molecular imaging with PET can provide an important contribution through the use of radiopharmaceuticals targeted towards specific metabolic pathways characteristic of tumors, such as radiolabeled amino acids [56]. The utilization of amino acid radiopharmaceuticals in PET imaging shows promise for diagnosing and grading gliomas. It can serve as a valuable tool for guiding biopsies and planning surgical and radiotherapy procedures. Specifically, integrating PET imaging into the resection process and radiotherapy planning may offer more insightful information compared to standard MRI, potentially leading to improved survival outcomes for patients with gliomas [57]. However, PET with radiolabeled amino-acids exploits a non-specific metabolic mechanism. In the era of personalized medicine, it is imperative to identify biomarkers associated with gliomas that can be used for molecular imaging and potential targeted therapy. In this context, our review of the existing literature has prompted several considerations. First, although several attempts have been made in the field, none among the examined potential targets (i.e., EGFR, VEGF, CD146, CD11b, PSMA) have emerged as predominantly effective in the field, since their expression has been found to be not homogeneous, and strictly depending on the tumor grade and type (i.e., DIPG, GBM, oligodendroglioma etc.). Secondly, other relevant considerations should be made on the various radionuclides and ligands employed for immuno-PET. One of the most challenging aspects of immuno-PET is its reliance on mAbs, or sometimes antibody fragments. Despite their high specificity, these agents are characterized by slow clearance, necessitating delayed imaging (e.g., 48 h p.i.) to achieve an adequate target-to-background ratio [58]. Notably, certain radionuclides traditionally used in clinical practice, such as \({}^{68}\)Ga and \({}^{18}\)F, have a too-short physical half-life, rendering them unsuitable for delayed imaging. In contrast, \({}^{89}\)Zr has shown more promising results due to its longer physical half-life [59]. In this context, it is crucial to emphasize that specific radiochemical approaches merit exploration to facilitate the labeling of mAbs with [\({}^{68}\)Ga] or [\({}^{18}\)F], particularly those involving in vivo bio-orthogonal reactions [60]. Initial steps in investigating this methodology were taken by [PERSON] et al. in 2012 [61]. The researchers conjugated anti-CD45 mAbs with TransCyloCOctyne (TCO) and administered them intravenously to mice 24 h prior to in vivo click chemistry. They employed polymer-modified tetrazine (PMT) as a pivotal facilitator. Subsequent to the reaction between TCO and tetrazine, [\({}^{18}\)F]-PMT was successfully utilized for whole-body PET imaging. This approach holds significant implications and warrants further exploration in the realm of glioma-targeted immuno-PET. Although humanized mAbs have been recently integrated for immuno-PET imaging, careful consideration is warranted for potential host immuno-mediated adverse reactions [62]. Furthermore, the application of mAb in CNS tumors is constrained by the BBB, which impedes the delivery of both small-molecule drugs and therapeutic proteins.