[⁶⁸Ga]Ga-HM or [⁶⁸Ga]Ga-PM: Which Is Superior for PET/CT Imaging of HMGB1-Positive Tumors?

High mobility group box 1 (HMGB1) is highly expressed in various malignancies and has been considered as a promising molecular target for cancer diagnosis and therapy. In this study, two novel peptide-based radiotracers targeting HMGB1 were synthesized, each achieving high radiochemical purity (>95%). Of these tracers, [⁶⁸Ga]Ga-HM possessed superior characteristics with a high binding affinity for the PC3 cell line (K_d = 46.11 ± 0.97 nM). Micro-PET imaging and biodistribution investigation in PC3 tumor-bearing mice revealed significant tumor uptake (SUV_max = 1.52 ± 0.10) and an excellent tumor-to-muscle ratio (6.96 ± 0.64) at 30 min post-injection. Moreover, robust imaging performance and favorable biodistribution profiles were consistently observed for [⁶⁸Ga]Ga-HM across multiple distinct HMGB1-positive tumor models. These findings demonstrate that [⁶⁸Ga]Ga-HM could serve as a diagnostic tracer to identify tumors with high HMGB1 expression, enabling personalized cancer treatment through the selection and monitoring of targeted therapeutic approaches.