Usefulness of competitive inhibitors of protein binding for improving the pharmacokinetics of Re-MAG3-conjugated bisphosphonate (Re-MAG3-HBP), an agent for treatment of painful bone metastases

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

European Journal of Nuclear Medicine and Molecular Imaging, 36(1), p.115 - 121, 2009/01

https://doi.org/10.1007/s00259-008-0925-8

We have developed a Re-MAG3 complex-conjugated bisphosphonate (Re-MAG3-HBP) for the treatment of painful bone metastases. We assumed competitive inhibitors of protein binding to be useful for procuring a favorable biodistribution of Re-MAG3-HBP because it has been reported that the concurrent administration of Tc-MAG3 and drugs with high affinity for serum protein enhanced total clearance and tissue distribution. The protein binding of Re-MAG3-HBP in a human serum albumin solution was significantly decreased by the addition of ceftriaxone. In the biodistribution experiments, pretreatment with ceftriaxone enhanced the clearance of the radioactivity of Re-MAG3-HBP in blood and nontarget tissues but had no effect on accumulation in bone. The findings suggested that the use of protein-binding competitive inhibitors would be effective in improving the pharmacokinetics of radiopharmaceuticals with high affinity for serum protein.

Rhemium-186-monoaminemonoamidedithiol-conjugated bisphosphonate derivatives for bone pain palliation

Ogawa, Kazuma*; Mukai, Takahiro*; Arano, Yasushi*; Otaka, Akira*; Ueda, Masashi*; Uehara, Tomoya*; Magata, Yasuhiro*; Hashimoto, Kazuyuki; Saji, Hideo*

Nuclear Medicine and Biology, 33(4), p.513 - 520, 2006/05

https://doi.org/10.1016/j.nucmedbio.2006.03.006

To develop a radiopharmaceutical for the palliation of painful bone metastases based on the concept of bifunctional radiopharmaceuticals, we synthesized a bisphosphonate derivative labeled with rhenium-186 (Re) that contains a hydroxyl group at the central carbon of its bisphosphonate structure and attached a stable Re-MAMA chelate to the amino group of a 4-amino-butylidene-bisphosphonate derivative, Re-MAMA-HBP, and investigated the effect of a hydroxyl group at the central carbon of its bisphosphonate structure on the affinity for hydroxyapatite and biodistribution by conducting a comparative study with Re-MAMA-BP. Re-MAMA-HBP was prepared by a reaction with ReO and SnCl in citrate buffer after the deprotection of trityl groups of Tr-MAMA-HBP. After reversed phase HPLC, Re-MAMA-HBP had a radiochemical purity of over 95 %. Compared with Re-MAMA-BP, Re-MAMA-HBP showed a greater affinity for hydroxyapatite beads in vitro and accumulated a significantly higher level in the femur in vivo. Thus, the introduction of a hydroxyl group into Re complex-conjugated bisphosphonates would be effective in enhancing accumulation in bone. These findings provide useful information on the design of bone-seeking therapeutic radiopharmaceuticals.

Design of a radiopharmaceutical for the palliation of painful bone metastases; Rhenium-186-labeled bisphosphonate derivative

Ogawa, Kazuma*; Mukai, Takahiro*; Arano, Yasushi*; Hanaoka, Hirofumi*; Hashimoto, Kazuyuki; Nishimura, Hiroshi*; Saji, Hideo*

Journal of Labelled Compounds and Radiopharmaceuticals, 47(11), p.753 - 761, 2004/11

https://doi.org/10.1002/jlcr.864

no abstracts in English

None

Sato, Shinya*; Mukai, Kazuyuki*

JNC TJ7440 2000-030, 110 Pages, 2000/11

JNC-TJ7440-2000-030.pdf:5.1MB

no abstracts in English

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*

no journal, , 

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 for Re-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.