Is 177Lu-DOTMP a better alternative to 177Lu-EDTMP for palliative radiotherapy of skeletal metastasis? A systematic investigation

Abstract

Aim: 177Lu is presently being considered as an excellent radionuclide for developing bone pain palliation agents owing to its suitable nuclear decay characteristics [T1/2 = 6.73 d, Eβ(max) = 497 keV, Eγ =113 keV (6.4%) and 208 keV (11%)] and large scale production feasibility with adequate specific activity using moderate flux research reactors. Among the multidentate polyaminophosphonic acids proven to be desirable carrier molecules in designing agents for palliative radiotherapy of bone pain, ethylenediaminetetramethylene phosphonic acid (EDTMP) is one of the most widely used ligands and is presently being used as 153Sm-EDTMP (Quadramet®). The macrocyclic analog of EDTMP, viz. 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene phosphonic acid (DOTMP) could be chosen as yet another efficacious ligand. This is based on the well-documented phenomenon that macrocyclic chelators form complexes with enhanced stability and kinetic inertness with lanthanides compared to their acyclic analogs. The present paper describes a comparison between 177Lu complexes of two potential polyaminophosphonic acid ligands namely, EDTMP and DOTMP with respect to their radiochemical and in-vivo biological characteristics. Materials and Methods: 177Lu was produced by irradiation of natural (2.6% 176Lu) Lu2O3 target in DHRUVA reactor for 21 d at a thermal neutron flux of 6×1013 n/cm2.s. 177Lu-EDTMP and 177Lu-DOTMP complexes were prepared at room temperature by incubating the ligands with 177LuCl3 in NaHCO3 buffer at pH ∼7. Comparative in vitro stability of the complexes were ascertained in saline (pH ∼7), 0.1 M HCl solution as well as in human serum. Comparative biological evaluation of 177Lu-phosphonate complexes were carried out by biodistribution and scintigraphic imaging studies in Wistar rats as well as by imaging studies in New Zealand white rabbits. Results: 177Lu was produced with a specific activity of ∼12 GBq/ mg and radionuclidic purity of 99.98%. Both the 177Lu-phosphonate complexes were obtained in near-quantitative yields (98.5±0.3% for 177Lu-EDTMP and 99.1±0.2% for 177Lu-DOTMP) under optimized reaction conditions (ligand:metal ratio of 10:1). 177Lu-DOTMP complex could be prepared with very high complexation yield (98.2±0.3%) even when a ligand:metal ratio as low as 2:1 was used. Both the phosphonate complexes showed excellent stabilities at room temperature as both retained >97% radiochemical purity in saline upto 30 d post-preparation in saline. However, when the complexes were stored in 0.1 M HCl medium to assess their stabilities in presence of a large excess of H+, it was found that 177Lu-DOTMP complex underwent decomposition to a lesser extent compared to 177Lu- EDTMP indicating superior kinetic inertness of 177Lu-DOTMP over 177Lu-EDTMP. Biodistribution studies in Wistar rats showed favorable and comparable features such as, rapid and selective skeletal uptake, fast clearance from blood and almost no uptake in any of the major organs/tissue for both the complexes. 177Lu-EDTMP showed slightly higher skeletal uptake compared to 177Lu-DOTMP (46.25±3.48 and 40.23±8.45% injected activity in skeleton at 24 h p.i., respectively) and marginally higher retention in liver and kidneys. Scintigraphic studies carried out in normal Wistar rats and New Zealand white rabbits also demonstrated favorable characteristics similar to those observed in biodistribution studies. Conclusion: The present studies indicate that both 177Lu-EDTMP and 177Lu-DOTMP have promising features and could be taken up for further detailed investigations. Though both the agents exhibited almost similar characteristics, the comparative efficacy of the agents in providing the palliative care could only be conclusively decided after extensive human clinical studies.