Abstract Theranostics refers to the combination of a radioactive drug to identify (diagnose) and another radioactive drug to deliver therapy to cancer. In adult cancer several radiopharmaceuticals with specificity for receptors like cx-chemokine-receptor type 4 (CXCR-4), prostate-membrane specific antigen (PSMA), and somatostatine receptor (SSTR2a) are used. Especially PSMA for prostate cancer and SSTR2a ligands for neuro-endocrine tumors have proven their value. Moreover, novel promising targets like B7-H3 are upcoming. In children the potential of such theranostic drugs have been minimally explored. AIM of this study is to explore the expression of theranostic markers CXCR-4, PSMA, SSTR2a and B7-H3 in a broad cohort of high-grade pediatric CNS tumors to determine the potential of these imaging ligands in this cohort. METHODS The expression of CXCR-4, PSMA, SSTR2a and B7-H3 were examined both by RNA (by bulk RNAsequencing) and protein level (by immunohistochemistry (IHC)) (RNA n=161/IHC n=52) in pediatric high-grade CNS tumors: ependymomas (n=33/11), atypical teratoid rhabdoid tumors (ATRT) (n=9/7), medulloblastomas (n=51/11), diffuse midline gliomas H3K27-altered (n=27/9) and other high-grade gliomas (n=41/15). RESULTS mRNA expression of CXCR-4 was present but low in most tumor types, with the highest expression in medulloblastoma. Immunohistochemistry showed variable CXCR-4 expression, with the highest expression in some medulloblastomas, ependymomas and ATRTs. PSMA (FOLH1) mRNA and protein expression was generally very low. As expected SSTR2a showed a very high mRNA and protein expression only in medulloblastoma samples. Remarkably, B7-H3 (CD276) showed a relatively high expression in all high-grade pediatric CNS tumor types, both on RNA and protein level. CONCLUSION Of the four potential theranostic targets tested, SSTR2a is an interesting antigen in medulloblastoma. CXCR-4 could be of interest for individual patients with medulloblastoma, ATRT or ependymoma. Finally, B7-H3 is widely but variably expressed on all different tumor types, and seems a promising novel target for theranostics in pediatric CNS tumors.