⁶⁸Ga/¹⁷⁷Lu-Labeled Bivalent Agents for Targeting Hypoxia and PSMA-Binding in Prostate Cancer

Prostate-specific membrane antigen (PSMA) is an excellent target for cancer detection and therapy. Hypoxia is prevalent in solid tumors, and various nitroimidazole (NI) radioligands can be trapped inside hypoxic cells for diagnosis and therapy. To enhance tumor uptake and retention, we designed bivalent agents (compounds 1-8) incorporating a hypoxia-sensitive NI-moiety and a PSMA-targeting group. Ligands 1-8 were successfully prepared and labeled with ⁶⁸Ga or ¹⁷⁷Lu. Among them, [⁶⁸Ga]Ga-8 ([⁶⁸Ga]Ga-AAZTA-NI-PSMA-093) demonstrated significantly higher cellular accumulation under hypoxic conditions than under normoxic conditions, suggesting hypoxia-selective trapping by the introduction of NI group. PET/CT imaging at 60 min postinjection of [⁶⁸Ga]Ga-8 revealed high tumor uptake (SUV_max: 10.68%ID/mL) in the tumor-bearing mice model. SPECT/CT imaging of [¹⁷⁷Lu]Lu-8 at 24 and 48 h postinjection demonstrated excellent accumulation and retention. Preliminary studies indicate that [⁶⁸Ga]Ga/[¹⁷⁷Lu]Lu-8 may be promising bivalent agents targeting hypoxia and PSMA binding for diagnosis and radiotherapy.