Receptor-Targeted Peptide Conjugates Based on Diphosphines Enable Preparation of ^99mTc and ¹⁸⁸Re Theranostic Agents...

Benchtop ⁹⁹Mo/^99mTc and ¹⁸⁸W/¹⁸⁸Re generators enable economical production of molecular theranostic ^99mTc and ¹⁸⁸Re 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 ^99mTc into receptor-targeted peptides. Here, we report its application to label a prostate-specific membrane antigen (PSMA)-targeted peptide with ^99mTc and ¹⁸⁸Re for diagnostic imaging and systemic radiotherapy of prostate cancer. Methods: Two diphosphine-dipeptide bioconjugates, DP1-PSMAt and DP2-PSMAt, were formulated into kits for radiolabeling with ^99mTc and ¹⁸⁸Re. 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 ^99mTc/¹⁸⁸Re pair of agents. Results: Both DP1-PSMAt and DP2-PSMAt could be efficiently radiolabeled with ^99mTc and ¹⁸⁸Re using kit-based methods to furnish the isostructural compounds M-DP1-PSMAt and M-DP2-PSMAt (M = [^99mTc]Tc, [¹⁸⁸Re]Re). All ^99mTc/¹⁸⁸Re 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 ^99mTc/¹⁸⁸Re radiotracers showed near-identical biologic behavior in these experiments. Conclusion: We have prepared and developed novel pairs of isostructural PSMA-targeting ^99mTc/¹⁸⁸Re 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 ¹⁷⁷Lu radiopharmaceuticals or PET/CT infrastructure.