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

ABSTRACT
INTRODUCTION: The preferable pharmacokinetics of rhenium-186 (¹⁸⁶Re)-monoaminemonoamidedithiol-conjugated or ¹⁸⁶Re-mercaptoacetyltriglycine-conjugated bisphosphonates (BPs) suggested that the molecular design would be applicable to other radionuclides such as ⁶⁸Ga, ^99mTc, ¹⁵³Sm and ¹⁷⁷Lu. 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 tricarbonyl[¹⁸⁶Re][(cyclopentadienylcarbonyl amino)-acetic acid]rhenium ([¹⁸⁶Re]CpTR-Gly) was conjugated with 3-amino-1-hydroxypropylidene-1,1-bisphosphonate and purified by high-performance liquid chromatography (HPLC) to prepare [¹⁸⁶Re](1-{3-[tricarbonyl(cyclopentadienylcarbonyl amino)-acetylamido]-1-hydroxy-1-phosphono-propyl}-phosphonic acid)rhenium ([¹⁸⁶Re]CpTR-Gly-APD). Plasma stability, plasma protein binding, hydroxyapatite (HA) binding and the pharmacokinetics of [¹⁸⁶Re]CpTR-Gly-APD were compared with those of ¹⁸⁶Re 1-hydroxyethylidene-1,1-diphosphonate (HEDP). The effect of HEDP coadministration and preadministration on the pharmacokinetics of [¹⁸⁶Re]CpTR-Gly-APD was also determined.
RESULTS: The HPLC-purified [¹⁸⁶Re]CpTR-Gly-APD showed higher plasma stability, higher HA binding, higher bone accumulation and lower plasma protein binding than did ¹⁸⁶Re-HEDP. However, HA binding of [¹⁸⁶Re]CpTR-Gly-APD decreased to levels slightly higher than that of ¹⁸⁶Re-HEDP at similar HEDP concentrations. Bone accumulation of [¹⁸⁶Re]CpTR-Gly-APD also decreased to levels similar to that of ¹⁸⁶Re-HEDP when [¹⁸⁶Re]CpTR-Gly-APD was coinjected with HEDP equivalent to that in ¹⁸⁶Re-HEDP. In contrast, HEDP pretreatment did not impair bone accumulation of the two ¹⁸⁶Re-labeled compounds. However, a delay in blood clearance and an increase in renal radioactivity levels were observed particularly with ¹⁸⁶Re-HEDP.
CONCLUSIONS: Although ¹⁸⁶Re-HEDP possessed HA binding and bone accumulation similar to those of [¹⁸⁶Re]CpTR-Gly-APD, the specific activity of ¹⁸⁶Re-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.