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

Abstract

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.