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

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.