Receptor-Targeted Peptide Conjugates Based on Diphosphines Enable Preparation of Tc and Re Theranostic Agents for Prostate Cancer.

Benchtop Mo/Tc and W/Re generators enable economical production of molecular theranostic Tc and Re radiopharmaceuticals, provided that simple, kit-based chemistry exists to radiolabel targeting vectors with these radionuclides. We have previously described a diphosphine platform that efficiently incorporates Tc into receptor-targeted peptides. Here, we report its application to label a prostate-specific membrane antigen (PSMA)-targeted peptide with Tc and Re for diagnostic imaging and systemic radiotherapy of prostate cancer. Two diphosphine-dipeptide bioconjugates, DP1-PSMAt and DP2-PSMAt, were formulated into kits for radiolabeling with Tc and Re. The resulting radiotracers were studied in vitro, in prostate cancer cells, and in vivo in mouse xenograft models, to assess similarity of uptake and biodistribution for each Tc/Re pair of agents. Both DP1-PSMAt and DP2-PSMAt could be efficiently radiolabeled with Tc and Re using kit-based methods to furnish the isostructural compounds M-DP1-PSMAt and M-DP2-PSMAt (M = [Tc]Tc, [Re]Re). All Tc/Re radiotracers demonstrated specific uptake in PSMA-expressing prostate cancer cells, with negligible uptake in prostate cancer cells that did not express PSMA or in which PSMA uptake was blocked. M-DP1-PSMAt and M-DP2-PSMAt also exhibited high tumor uptake (18-30 percentage injected dose per gram at 2 h after injection), low retention in nontarget organs, fast blood clearance, and excretion predominantly via a renal pathway. Importantly, each pair of Tc/Re radiotracers showed near-identical biologic behavior in these experiments. We have prepared and developed novel pairs of isostructural PSMA-targeting Tc/Re theranostic agents. These generator-based theranostic agents have potential to provide access to the benefits of PSMA-targeted diagnostic imaging and systemic radiotherapy in health care settings that do not routinely have access to either reactor-produced Lu radiopharmaceuticals or PET/CT infrastructure.