A new bisphosphonate-containing (99m)Tc(I) tricarbonyl complex potentially useful as bone-seeking agent: synthesis and biological evaluation.

Aiming to develop new bone-seeking radiotracers based on the organometallic core fac-(99m)Tc(CO)(3) with improved radiochemical and biological properties, we have prepared new conjugates with phosphonate pendant groups. The conjugates comprise a chelating unit for metal coordination, which corresponds to a pyrazolyl-containing backbone (pz) with a N,N,N donor-atom set, and a pendant diethyl phosphonate (pz-MPOEt), phosphonic acid (pz-MPOH) or a bisphosphonic acid (pz-BPOH) group for bone targeting. Reactions of the conjugates with the precursor (99m)Tc(H(2)O)(3)(CO)(3) yielded (mote than 95%) the single and well-defined radioactive species (99m)Tc(CO)(3)(kappa(3)-pz-MPOEt) (1a), (99m)Tc(CO)(3)(kappa(3)-pz-MPOH (2a) and (99m)Tc(CO)(3)(kappa(3)-pz-BPOH) (3a), which were characterized by reversed-phase high-performance liquid chromatography . The corresponding Re surrogates (1-3), characterized by the usual analytical techniques, including X-ray diffraction analysis in the case of 1, allowed for macroscopic identification of the radioactive conjugates. These radioactive complexes revealed high stability both in vitro (phosphate-buffered saline solution and human plasma) and in vivo, without any measurable decomposition. Biodistribution studies of the complexes in mice indicated a fast rate of blood clearance and high rate of total radioactivity excretion, occurring primarily through the renal-urinary pathway in the case of complex 3a. Despite presenting moderate bone uptake (3.04 +/- 0.47% injected dose per gram of organ, 4 h after injection), the high stability presented by 3a and its adequate in vivo pharmacokinetics encourages the search for new ligands with the same chelating unit and different bisphosphonic acid pendant arms.