Maleic anhydride derived diphosphines: adaptable chelators for receptor-targeted ^99mTc, ⁶⁴Cu and ¹⁸⁸Re radiotracers

The diagnostic imaging radionuclide, ^99mTc, used in Single Photon Emission Computed Tomography (SPECT), has extraordinary potential for enabling economical molecular receptor imaging in oncology, provided suitable chelators are available to enable kit-based radiolabelling. We report the development of two new bis(phosphino)maleic anhydrides, DP^An and DP^MEP, that exhibit increased electron donor capacity and concomitant increased radiochemical yields compared to their first-generation diphosphine analogues. Both DP^An and DP^MEP can be reacted with a wide range of biological targeting vectors, including receptor-targeted peptides, carbohydrates, vitamins and small-molecule inhibitors. Exemplar diphosphine-peptide bioconjugates, DP^An-PSMAt and DP^MEP-PSMAt (which target the prostate-specific membrane antigen, PSMA), can be formulated into kits to enable near-quantitative, one-pot radiosynthesis of new ^99mTc radiotracers, <i>cis</i>/<i>trans</i>-[^99mTcO₂(DP^An-PSMAt)₂]⁺ and <i>cis</i>/<i>trans</i>-[^99mTcO₂(DP^MEP-PSMAt)₂]⁺, respectively. We demonstrate that the two exemplar ^99mTc radiotracers, <i>cis</i>/<i>trans</i>-[^99mTcO₂(DP^An-PSMAt)₂]⁺ and <i>cis</i>/<i>trans</i>-[^99mTcO₂(DP^MEP-PSMAt)₂]⁺, display favourable SPECT imaging properties in murine prostate cancer models, including high tumour uptake, fast clearance from circulation, excretion <i>via</i> a renal pathway and high metabolic stability. The same diphosphine-peptide bioconjugates can also be radiolabelled with the Positron Emission Tomography (PET) isotope, ⁶⁴Cu, and the radiotherapeutic β^--emitting isotope, ¹⁸⁸Re, in high radiochemical yields. The new DP^An and DP^MEP chelator platforms thus enable development of novel molecular imaging radiopharmaceuticals for ^99mTc SPECT, ⁶⁴Cu PET and ¹⁸⁸Re systemic radiotherapy.