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

Abstract

Summary MDP (methylenediphosphonate) and HEDP (hydroxyethylidene diphosphonate), both diphosphonates, and EDTMP (ethylenediamine tetramethylene phosphonic acid), a tetraphosphonate ligand, have been previously labeled with 188Re for use in metastatic bone-pain palliation. The aim of this study was a comparison between the three complexes 188Re-MDP, 188Re-HEDP and 188Re-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 1N followed by reduction of pH with HCl 1N. To all mixtures stannous chloride and 188Re4 - were added in a nitrogen atmosphere. The preparations were heated in boiling water bath for 15min. 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 188Re-phosphonates that presented the best radiochemical yield. The optimal ligand concentration for maximum complexation was 85.2mM for MDP, 72.8mM for HEDP and 45.8mM for EDTMP. The best amount of SnCl2·2H2O} was 1.5mg/mL for 188Re-HEDP and 1mg/mL for both 188Re-MDP and 188Re-EDTMP. In these conditons the three complexes showed a complexation rate above 95. Reasonable radiochemical stability for 24 hours was achieved by 188Re-EDTMP when employing ascorbic acid. All products showed a great uptake by the kidneys. 188Re-EDTMP had the greatest uptake by femur (3.1±0.2 ID/g) followed by 188Re-MDP (1.2±0.1 ID/g) and 188Re-HEDP (1.0±0.1 ID/g), 4 hours post injection. 188Re-EDTMP displayed a femur bone/muscle ratio of 28.5, 188Re-MDP 4.9 and 188Re-HEDP 4.9. In conclusion 188Re-EDTMP demonstrated the best potential as a radiopharmaceutical for bone cancer pain relief, encouraging further dosimetric studies and clinical trials.