Control of biodistribution of Rhenium-186-MAG3-conjugated bisphosphonate using a competitive inhibitor of protein binding

Ogawa, Kazuma*; Mukai, Takahiro*; Kawai, Keiichi*; Takamura, Norito*; Hanaoka, Hirofumi*; Hashimoto, Kazuyuki; Saji, Hideo*

Previously, based on the concept of bifunctional radiopharmaceuticals, we developed a highly stableRe-MAG3 complex conjugated bisphosphonate (Re-MAG3-HBP) for treatment of the painful bone metastases. We assumed that competitive inhibitors of protein binding might be useful forRe-MAG3-HBP because it has been reported that the concurrent administration between Tc-MAG3 and drugs with high protein binding affinity produced competitive displacement at the specific binding sites and enhanced total clearance and tissue distribution. In this study, the displacement effect between Re-MAG3-HBP and several protein binding inhibitors were investigated. Effects of each competitive protein binding inhibitor were examined in in vitro human serum. Bucolome, ceftriaxione and cefazolin as displacers of human serum albumin (HSA) binding site I, and ibuprofen as a displacer of HSA binding site II were added to each serum before addition of Re-MAG3-HBP. As a result of in vitro study, the free fraction rate of Re-MAG3-HBP was significantly increased by the addition of ceftriaxone. In biodistribution studies, the loading ceftriaxone enhanced the clearance of radioactivity of Re-MAG3-HBP in blood and non-target tissues without the reduction of the bone accumulation. These findings suggested that the use of a protein binding competitive inhibitor would be effective for lowering the side effects of Re-MAG3-HBP.