Complexation of Re-188-phosphonates: in vitro and in vivo studies

Abstract

MDP (methylenediphosphonate) and HEDP (hydroxyethylidene diphosphonate), both diphosphonates, and EDTMP (ethylenediamine tetramethylene phosphonic acid), a tetraphosphonate ligand, have been previously labeled with Re-188 for use in metastatic bone-pain palliation. the aim of this study was a comparison between the three complexes Re-188-MDP, Re-188-HEDP and Re-188-EDTMP concerning the complexation conditions, in order to achieve maximum yield, stability and bone uptake. Methods: MDP was dissolved in water and HEDP and EDTMP were dissolved in NaOH 1 N followed by reduction of pH with HCl 1 N. To all mixtures stannous chloride and (ReO4-)-Re-188 were added in a nitrogen atmosphere. the preparations were heated in boiling water bath for 15 min. Yield as well as radiochemical stability was estimated by ITLC. Different concentrations of phosphonates and stannous chloride were evaluated. Biodistribution studies in Swiss mice were done for the three Re-188-phosphonates that presented the best radiochemical yield. the optimal ligand concentration for maximum complexation was 85.2 mM for MDP, 72.8 mM for HEDP and 45.8 mM for EDTMP. the best amount of SnCl2-2H(2)O was 1.5 mg/mL for Re-188-HEDP and 1 mg/mL for both Re-188-MDP and Re-188-EDTMP. in these conditons the three complexes showed a complexation rate above 95%. Reasonable radiochemical stability for 24 hours was achieved by Re-188-EDTMP when employing ascorbic acid. All products showed a great uptake by the kidneys. Re-188-EDTMP had the greatest uptake by femur (3.1 +/- 0.2% ID/g) followed by Re-188-MDP (1.2 +/- 0.1% ID/g) and Re-188-HEDP (1.0 +/- 0.1% ID/g), 4 hours post injection. Re-188-EDTMP displayed a femur bone/muscle ratio of 28.5, Re-188-MDP 4.9 and Re-188-HEDP 4.9. in conclusion Re-188-EDTMP demonstrated the best potential as a radiopharmaceutical for bone cancer pain relief, encouraging further dosimetric studies and clinical trials.