Formulation of 'ready-to-use' human clinical doses of ${}^{177}$Lu-labeled bisphosphonate amide of DOTA using moderate specific activity ${}^{177}$Lu and its preliminary evaluation in human patient

Radiolabeled macrocyclic bisphosphonate ligands have recently been demonstrated to be highly efficacious in treatment of patients with painful bone metastases. Herein, we report a robust protocol for formulation of therapeutically relevant doses of ${}^{177}$Lu-labeled bisphosphonate amide of DOTA (BPAMD) using moderate specific activity ${}^{177}$Lu produced by direct (n,γ) route and its preliminary investigation in human patients. Doses (2.8 ± 0.2 GBq) were formulated with high radiochemical purity (98.3 ± 0.4 %) using a protocol optimized after extensive radiochemical studies. In vitro binding studies with mineralized osteosarcoma cells demonstrated specific binding of the radiotracer. Biodistribution studies in healthy Wistar rats demonstrated rapid skeletal accumulation with fast clearance from the non-target organs. In a patient administered with 555 MBq dose of ${}^{177}$Lu-BPAMD, intense radiotracer uptake was observed in the metastatic skeletal lesions with insignificant uptake in any other major non-targeted organs. Preliminary clinical investigations carried out after administration of 2.6 GBq of ${}^{177}$Lu-BPAMD revealed significant reduction in pain after 1 week without any adverse effects. The developed protocol for formulation of ${}^{177}$Lu-BPAMD doses using moderate specific activity carrier added ${}^{177}$Lu has been found to be effective and warrants wider investigations in patients with painful skeletal metastases.