title: Assessment of 186Re chelate-conjugated bisphosphonate for the development of new radiopharmaceuticals for bones.
abstract: BACKGROUND
  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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba 260-8675, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Uehara
authors.forename: Zhe Long
authors.initials: ZL
authors.lastname: Jin
authors.forename: Kazuma
authors.initials: K
authors.lastname: Ogawa
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Akizawa
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Morio
authors.initials: M
authors.lastname: Nakayama
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Arano
mesh_terms: D000818:Animals; D002614:Chelating Agents / Q000737:chemistry; D004164:Diphosphonates / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D008657:Metabolic Clearance Rate; D051379:Mice; D009928:Organ Specificity; D011868:Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use; D012211:Rhenium / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014018:Tissue Distribution
chemical_list: D002614:Chelating Agents; D004164:Diphosphonates; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D012211:Rhenium