Development and Preclinical Evaluation of Six-Transmembrane Epithelial Antigen of Prostate 2 Targeted PET Probes: A Case of Drug Repurposing Based on Molecular Docking

Six-transmembrane epithelial antigen of prostate 2 (STEAP2) is overexpressed in prostate cancer, yet no STEAP2-targeted imaging probes exist. Using molecular docking, we screened triptorelin and leuprorelin by radioiodine labeling and identified triptorelin as a high-affinity, selective ligand. To enhance in vivo stability and pharmacokinetics, triptorelin underwent acetylation, PEG extension, and 4-iodophenylbutyric acid conjugation, yielding five DOTA-conjugated analogs radiolabeled with 68Ga. In 22Rv1 xenografts, 68Ga-Trip-5 exhibited moderate but specific tumor uptake (SUVmax 1.8) with favorable tumor-to-background contrast. In vivo stability, biodistribution, pharmacokinetics, and human radiation dosimetry (effective dose 0.00345 mSv/MBq) demonstrated favorable safety. Autoradiography on human prostate cancer specimens showed probe accumulation correlating with endogenous STEAP2 expression. This represents the first STEAP2-targeted PET probe developed via molecular docking-guided drug repurposing. Cellular, biochemical, and imaging data provide supportive evidence of STEAP2-mediated targeting. Preclinical performance supports clinical translation of 68Ga-Trip-5, with definitive target validation