Biological assessment of novel bisphosphonate-containing 99mTc/Re-organometallic complexes

Bone-seeking radiopharmaceuticals such as radiolabeled bisphosphonates (BPs) bind to bone matrix in areas of increased bone turnover, characteristic of metastization sites, delivering selectively γ radiation or β− particles for bone imaging or bone-pain palliation, respectively. Recent preclinical studies suggest that nitrogen-containing BPs may have also a direct anti-tumor activity. We have recently introduced a set of 99mTc-organometallic complexes that allow the simultaneous delivery of γ radiation and BPs to bone tissue. Aimed at finding complexes of the same family with improved bone-seeking properties and adequate tumor cell uptake profile, we have synthesized novel complexes of the type fac-[M(CO)3(k3-L)]+ (M = 99mTc/Re, Tc3/Re3–Tc5/Re5) stabilized by bifunctional chelators with different molecular weight, overall charge, (lipo)hydrophilic nature and different positions of BP attachment. Biodistribution studies in normal mice have shown that Tc3, where the BP unit (alendronate) is at position 4 of the pyrazolyl ring, presents the most favorable pharmacokinetic profile with fast blood clearance, high bone uptake (17.1 ± 3.6% I.A./g at 1 h p.i.), and higher bone-to-blood and bone-to-muscle ratios than the gold standard 99mTc-MDP. Cellular uptake studies in the MDAMB231 metastatic breast cancer cells showed a maximal uptake of 4–6% at 6 h incubation for all complexes. Interestingly, cell fragmentation studies have shown that Tc3 presents the highest accumulation in the cytosol (35%). The promising biological profile of the BP-containing complex Tc3 encourages further research towards evaluation of 188Re congeners for potential therapeutic applications.