Trithiol ligand provides tumor-targeting 191Pt-complexes with high molar activity and promising in vivo properties

Abstract

Purpose

The Auger electron-emitting radionuclide ¹⁹¹Pt is a promising candidate for radiopharmaceutical therapy. Herein, we explored novel labeling methods for ¹⁹¹Pt using thiol-containing ligands to improve the in vivo stability and targeting ability of ¹⁹¹Pt-labeled complexes.

Methods

We synthesized dithiol-containing N₂S₂ and NS₂ ligands, and a trithiol ligand, and then compared their radiochemical reactivity with ¹⁹¹Pt. [¹⁹¹Pt]Pt-trithiol was synthesized and its biodistribution was evaluated in mice and compared with free ¹⁹¹Pt. Finally, a ¹⁹¹Pt-trithiol complex targeting prostate-specific membrane antigen (PSMA): [¹⁹¹Pt]Pt-trithiol-PSMA was developed and evaluated in mice bearing tumor xenografts and compared with a ¹⁹¹Pt-complex labeled via monothiol-containing Cys ([¹⁹¹Pt]Pt-Cys-PSMA).

Results

A comparison of N₂S₂, NS₂, and trithiol showed that the trithiol ligand is the best for producing ¹⁹¹Pt-labeled compounds in high yield and as a single peak in preparative HPLC. Notably, the trithiol ligand made ¹⁹¹Pt-labeled compounds and precursors separatable, achieving ¹⁹¹Pt-labeled products with a high molar activity: 200–400 mCi/μmol (7.4–14.8 GBq/μmol) at EOS. Additionally, [¹⁹¹Pt]Pt-trithiol and [¹⁹¹Pt]Pt-trithiol-PSMA were stable in vivo with rapid clearance compared with free ¹⁹¹Pt and [¹⁹¹Pt]Pt-Cys-PSMA. [¹⁹¹Pt]Pt-trithiol-PSMA resulted in a low uptake in most normal organs and a high uptake in the kidneys and prostate cancer with PSMA expression.

Conclusions

This study demonstrated that a labeling method with trithiol for Pt radionuclides achieves ¹⁹¹Pt-labeled products with high molar activity. ¹⁹¹Pt-trithiol-PSMA showed promising in vivo stability and tumor-targeting specificity, which should facilitate the pharmaceutical development of Pt radionuclides for radiopharmaceutical therapy, especially Auger electron cancer therapy.