Maleic anhydride derived diphosphines: adaptable chelators for receptor-targeted 99m Tc, 64 Cu and 188 Re 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, DPAn and DPMEP, that exhibit increased electron donor capacity and concomitant increased radiochemical yields compared to their first-generation diphosphine analogues. Both DPAn and DPMEP 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, DPAn-PSMAt and DPMEP-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, cis/trans-[99mTcO2(DPAn-PSMAt)2]+ and cis/trans-[99mTcO2(DPMEP-PSMAt)2]+, respectively. We demonstrate that the two exemplar 99mTc radiotracers, cis/trans-[99mTcO2(DPAn-PSMAt)2]+ and cis/trans-[99mTcO2(DPMEP-PSMAt)2]+, display favourable SPECT imaging properties in murine prostate cancer models, including high tumour uptake, fast clearance from circulation, excretion via 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 DPAn and DPMEP chelator platforms thus enable development of novel molecular imaging radiopharmaceuticals for 99mTc SPECT, 64Cu PET and 188Re systemic radiotherapy.