Studies on 177Lu-labeled methylene diphosphonate as potential bone-seeking radiopharmaceutical for bone pain palliation

Objective99mTc-MDP (technetium-99m-labeled methylene diphosphonate) has been widely used as a radiopharmaceutical for bone scintigraphy in cases of metastatic bone disease. 177Lu is presently considered as an excellent radionuclide for developing bone pain palliation agents. No study on preparing a complex of 177Lu with MDP has been reported yet. Based on these facts, it was hypothesized that a bone-seeking 177Lu–MDP (lutetium-177-labeled MDP) radiopharmaceutical could be developed as an agent for palliative radiotherapy of bone pain due to skeletal metastases. Biodistribution studies after intravenous injection of 177Lu–MDP complex in rats may yield important information to assess its potential for clinical use as a bone pain palliation agent for the treatment of bone metastases.Methods177Lu was produced by irradiating natural Lu2O3 (10 mg) target at a thermal flux ∼8.0×1013 n/cm2 per second for 12 h in the swimming pool-type reactor.177Lu was labeled with MDP by adding nearly 37 MBq (1.0 mCi) of 177LuCl3 to a vial containing 10 mg MDP. The radiochemical purity and labeling efficiencies were determined by thin layer chromatography. Labeling of 177Lu with MDP was optimized, and one sample was subjected to high-performance liquid chromatography (HPLC) analysis. Twelve Sprague-Dawley rats were injected with 18.5 MBq (0.5 mCi). 177Lu–MDP in a volume of 0.1 ml was injected intravenously and then sacrificed at 2 min, 1 h, 2 h and 22 h (three rats at each time point) after injection. Samples of various organs were separated, weighed and measured for radioactivity and expressed as percent uptake of injected dose per gram. Bioevaluation studies with rats under gamma-camera were also performed to verify the results.ResultsThe quality control using thin layer chromatography has shown >99% radiochemical purity of 177Lu–MDP complex. Chromatography with Whatman 3MM paper showed maximum labeling at pH=6, incubation time=30 min, and ligand/metal ratio=60:1. HPLC analysis showed 1.35±0.05 min retention time of 177Lu–MDP complex. No decrease in labeling was observed at higher temperatures, and the stability of the complex was found adequate. Biodistribution studies of 177Lu–MDP revealed high skeletal uptake, i.e., 31.29±1.27% of the injected dose at 22 h post injection. Gamma-camera images of 177Lu–MDP in Sprague-Dawley rats also showed high skeletal uptake and verified the results.ConclusionThe study demonstrated that MDP could be labeled with 177Lu with high radiochemical yields (>99%). The in vitro stability of the complex was found adequate. Biodistribution studies in Sprague-Dawley rats indicated selective bone accumulation, relatively low uptake in soft tissue (except liver) and higher skeletal uptake, suggesting that it may be useful as a bone pain palliation agent for the treatment of bone metastases.