⁶⁸Ga/²¹¹At-Labeled Specific NPY1R Peptide-Based Molecular Probe for Glioma-Targeted Imaging and Alpha Therapy

Neuropeptide Y receptor Y1 (NPY1R) is an excellent potential target in glioma. This study aims to prepare ⁶⁸Ga/²¹¹At-labeled NPY1R-targeting peptide as radiopharmaceuticals for glioma-targeted imaging and therapy. Molecular operating environment (MOE) was used for mutation scanning and design peptide sequences. The peptide KINWKFRLRY (KINW) showed low cytotoxicity and efficient tumor targeting. ⁶⁸Ga-labeled KINW demonstrated the enhanced uptake in U87-MG cell xenograft models, confirming the potential imaging for glioma. KINW-conjugated N-succinimidyl-3-(trimethylstannyl) benzoate (m-MeATE) with ²¹¹At labeling (²¹¹At-ATE-KINW) exhibited a better stability and higher cellular than free ²¹¹At. ²¹¹At-ATE-KINW suppressed Akt/GSK3β/β-catenin signaling, reducing invasion, migration, and proliferation in U87-MG cells. Biodistribution revealed minimal normal tissue retention of ²¹¹At-ATE-KINW. Moreover, ²¹¹At-ATE-KINW had better tumor growth inhibition and significantly prolonged survival in U87-MG cell xenograft models compared to free ²¹¹At. Thus, a novel specific NPY1R peptide has potential to be applied in development of ⁶⁸Ga/ ²¹¹At-labeled radiopharmaceuticals for glioma-targeted imaging and therapy.