Synthesis and evaluation of [2 + 1] re(i) and 99mtc(i) complexes: new synthons for the preparation of isostructural optical and nuclear probes

The synthesis, stability, photophysical properties and/or in vivo biodistribution of [2 + 1] Re(I) and Tc(I) complexes derived from bipyridine (bipy) type ligands and a series of imidazole derivatives were investigated as a new class of targeted isostructural optical/nuclear molecular imaging probes. Preparation of the Re(I) and Tc(I) complexes was achieved using microwave assisted methods where the latter could be prepared in high radiochemical yield using a convenient pH mediated one-pot reaction. Incubation of the Tc(I) complexes in saline and plasma, and amino acid challenge experiments showed that N-substituted imidazole derivatives, bearing electron donating groups, exhibited superior stability to analogous metal complexes derived from less basic ligands. Imaging studies in mice revealed that with the appropriate choice of monodentate ligand, it is possible to prepare robust [2 + 1] Tc complexes that can be used as the basis for preparing targeted isostructural optical and nuclear probes. Complexes containing the water soluble ligand, bathophenanthroline disulfonate (BPS), showed particularly attractive chemical and biological properties. As a result, [2 + 1] complexes of BPS containing a tetrazine were prepared so that bioorthogonal chemistry could be used to prepare targeted imaging probes. Measurement of the kinetics of the reaction between the tetrazine-Tc complex and trans-cycloocteneol showed a second rate order constant of 8.6 × 103 M-1S-1 at 37 °C, which is suitable for use in vivo. Biodistribution studies in normal mice treated with a bisphosphonate conjugate of trans-cyclooctene (TCO-BP) showed high activity concentrations in the knee (9.3  0.3% ID/g) and shoulder (5.3  0.7% ID/g). The chelate complex in the absence of the TCO-BP showed no bone uptake demonstrating that in vivo coupling between the two bioorthogonal reagents was successful. Details on the chemistry, biology and potential future applications in medical imaging will be presented.

کلیدواژه ها:

Imaging Probes