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

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