Preclinical Evaluation on the Radiohybrid Tandem [18F]La- and [225Ac]Ac-rhPSMA-10.1 for Targeted α-Therapy of Prostate Cancer.

Prostate-specific membrane antigen (PSMA)-targeted α-therapy holds promise for the treatment of prostate cancer but has increased side effects compared with therapy using β-emitting PSMA ligands. This emphasizes the need for precise imaging of the biodistribution of 225Ac-labeled ligands for patient selection and dosimetry. However, imaging of [225Ac]Ac-PSMA ligands remains technically challenging, and no radioactive actinium isotopes with favorable imaging characteristics exist. In this study, we therefore developed radiohybrid ligands that can be labeled with 225Ac for therapy and 18F for imaging. Methods: We developed the radiohybrid ligand pair [225Ac]Ac-rhPSMA-10.1 and [18F]La-rhPSMA-10.1. Lanthanum was used for the diagnostic agent because no stable actinium isotopes exist, and the ionic chemistry of lanthanum and actinium is similar. The PSMA binding affinity, cellular internalization, and externalization of the ligands were determined. Biodistribution studies of [18F]La-rhPSMA-10.1 and [225Ac]Ac-rhPSMA-10.1 versus the reference [225Ac]Ac-PSMA I&T were performed in LNCaP tumor-bearing mice. For evaluation of the efficacy, LNCaP tumor-bearing mice (n = 6 per group) received a single dose of [225Ac]Ac-rhPSMA-10.1 or [225Ac]Ac-PSMA I&T or no treatment. Results: [225Ac]Ac-rhPSMA-10.1 and [18F]La-rhPSMA-10.1 showed similar cellular uptake parameters and a similar biodistribution. Compared with [225Ac]Ac-PSMA I&T, tumor uptake of [225Ac]Ac-rhPSMA-10.1 was 2.2-fold and 3.5-fold higher at 1 h and 24 h postinjection, respectively, with a similar biodistribution in healthy tissues. In the efficacy study, median survival was 12 d in the control group and more than 50 d for animals treated with [225Ac]Ac-rhPSMA-10.1 or [225Ac]Ac-PSMA I&T. Tumor growth was similarly inhibited by [225Ac]Ac-rhPSMA-10.1 or [225Ac]Ac-PSMA I&T. Conclusion: [225Ac]Ac-rhPSMA-10.1/[18F]La-rhPSMA-10.1 represents a promising theranostic pair that may improve patient selection and dosimetry of α-therapy for prostate cancer.