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

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

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

[RESULTS] A comparison of NS, NS, and trithiol showed that the trithiol ligand is the best for producing Pt-labeled compounds in high yield and as a single peak in preparative HPLC. Notably, the trithiol ligand made Pt-labeled compounds and precursors separatable, achieving Pt-labeled products with a high molar activity: 200-400 mCi/μmol (7.4-14.8 GBq/μmol) at EOS. Additionally, [Pt]Pt-trithiol and [Pt]Pt-trithiol-PSMA were stable in vivo with rapid clearance compared with free Pt and [Pt]Pt-Cys-PSMA. [Pt]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 Pt-labeled products with high molar activity. Pt-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.