Assessment of Re-186 chelate-conjugated bisphosphonate for the development of new radiopharmaceuticals for bones

作者：Uehara Tomoya; Jin Zhe Long; Ogawa Kazuma; Akizawa Hiromichi; Hashimoto KazuyukI; Nakayama Morio; Arano Yasushi^*

来源：Nuclear Medicine and Biology, 2007, 34(1): 79-87.

DOI：10.1016/j.nucmedbio.2006.10.001

• rhenium
• bisphosphonate
• bone scintigraphy
• palliative treatment
• bone pain

Introduction: The preferable pharmacokinetics of rhenium-186 (Re-186)-monoaminemonoamidedithiol-conjugated or Re-186-mercaptoacetyl-triglycine-conjugated bisphosphonates (Bps) suggested that the molecular design would be applicable to other radionuclides such as Ga-68, (TC)-T-99m, Sm-153 and Lu-177. In this study, a key factor affecting the pharmacokinetics of a chelate-conjugated BP was investigated to estimate the validity and the applicability of molecular design.
Methods: Chemically inert and well-characterized tricarbony][Re-186][(cyclopentadienylcarbonyl amino)-acetic acid]rhenium ([Re-186]CpTR-Gly) was conjugated with 3-amino-l-hydroxypropylidene-l, l-bisphosphonate and purified by high-performance liquid chromatography (HPLC) to prepare [Re-186](1-{3-[tricarbonyl(cyclopentadienylcarbonyl amino)-acetylamido]-l-hydroxy-l-phosphono-propyl}-phosphonic acid)rhenium ([Re-186]CpTR-Gly-APD). Plasma stability, plasma protein binding, hydroxyapatite (HA) binding and the pharmacokinetics of [Re-186]CpTR-Gly-APD were compared with those of Re-186 l-hydroxyethylidene-l,l-diphosphonate (HEDP). The effect of HEDP coadministration and preadministration on the pharmacokinetics of [ 116 Re]CpTR-Gly-APD was also determined.
Results: The HPLC-purified [186 Re]CpTR-Gly-APD showed higher plasma stability, higher HA binding, higher bone accumulation and lower plasma protein binding than did Re-186-HEDP. However, HA binding of [Re-186]CpTR-Gly-APD decreased to levels slightly higher than that of Re-186-HEDP at similar HEDP concentrations. Bone accumulation of [Re-186]CpTR-Gly-APD also decreased to levels similar to that of Re-186-HEDP when [Re-186]CpTR-Gly-APD was coinjected with HEDP equivalent to that in Re-186-HEDP. In contrast, HEDP pretreatment did not impair bone accumulation of the two Re-186-labeled compounds. However, a delay in blood clearance and an increase in renal radioactivity levels were observed particularly with Re-186-HEDP.
Conclusions: Although Re-186-HEDP possessed HA binding and bone accumulation similar to those of [Re-186]CpTR-Gly-APD, the specific activity of Re-186-labeled BPs was found to play a crucial role in bone accumulation and blood clearance. Thus, the molecular design of chelate-conjugated BP would be useful for the development of bone-seeking radiopharmaceuticals with a variety of radionuclides by selecting chelating molecules that provide high specific activities.

• 出版日期2007-1