18 F-Labeled brain-penetrant EGFR tyrosine kinase inhibitors for PET imaging of glioblastoma

Significant evidence suggests that the failure of clinically tested epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors ( erlotinib, lapatinib, gefitinib) in glioblastoma (GBM) patients is primarily attributed to insufficient brain penetration, resulting in inadequate exposure to the...

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Bibliographic Details
Published inChemical science (Cambridge) Vol. 14; no. 47; pp. 13825 - 13831
Main Authors Narayanam, Maruthi Kumar, Tsang, Jonathan E, Xu, Shili, Nathanson, David A, Murphy, Jennifer M
Format Journal Article
LanguageEnglish
Published England 06.12.2023
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Summary:Significant evidence suggests that the failure of clinically tested epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors ( erlotinib, lapatinib, gefitinib) in glioblastoma (GBM) patients is primarily attributed to insufficient brain penetration, resulting in inadequate exposure to the targeted cells. Molecular imaging tools can facilitate GBM drug development by visualizing drug biodistribution and confirming target expression and localization. To assess brain exposure PET molecular imaging, we synthesized fluorine-18 isotopologues of two brain-penetrant EGFR tyrosine kinase inhibitors developed specifically for GBM. Adapting our recently reported radiofluorination of -arylsydnones, we constructed an -disubstituted [ F]fluoroarene as the key intermediate. The radiotracers were produced on an automated synthesis module in 7-8% activity yield with high molar activity. PET imaging revealed rapid brain uptake in rodents and tumor accumulation in an EGFR-driven orthotopic GBM xenograft model.
ISSN:2041-6520
2041-6539
DOI:10.1039/D3SC04424F