Synthesis of 64CuII–Bis(dithiocarbamatebisphosphonate) and Its Conjugation with Superparamagnetic Iron Oxide Nanoparticles: In Vivo Evaluation as Dual-Modality PET–MRI Agent**

The synergistic combination of positron emission tomography (PET) and magnetic resonance imaging (MRI) is likely to become the next generation of dual-modality scanners in medical imaging. These instruments will provide us with accurate diagnoses thanks to the sensitive and quantifiable signal of PET and the high soft-tissue resolution of MRI. Furthermore, patients will receive less radiation dose and spend less time in the procedure relative to current dualmodality scanners (e.g. PET–computed tomography (CT)). As a consequence, there has been increasing interest recently in the development of dual-modality PET–MRI agents. The majority of the PET–MRI agents reported to date are based on the combination of PET isotopes with superparamagnetic iron oxide (SPIO) nanoparticles. These magnetic nanoparticles are ideal for the purpose, having a proven record of biocompatibility and a track record of extensive use in the clinic as MRI contrast agents for imaging the reticuloendothelial and lymphatic systems. The radiolabeling of SPIOs has been done to date by often complicated chemical conjugation with their coatings, which are commonly biocompatible polymers such as dextran that provide them with colloidal stability. The polymeric coatings are typically bound relatively weakly to the surface of the SPIOs, which results in a lack of stability over time. One solution to this problem is to cross-link the polymer units at the surface of the nanoparticles. However, there are concerns for the translatability of these compounds due to toxic chemicals used in the synthesis. An alternative to radiolabeling the coatings of SPIO particles is to label their inorganic surface directly with a molecule that binds to both a PET isotope and the nanoparticle, leaving the polymeric coating unaffected. In this regard, we have recently reported that bisphosphonates (BPs; Figure 1) radiolabeled with a suitable isotope (Tc) for