177Lu-BPAMD - From bone imaging to therapy with a macrocycle-bisphosphonate ligand

Objectives 68Ga-BPAMD (BPAMD = (4-{[bis-(phosphonomethyl))carbamoyl]methyl}-7,10-bis(carboxy methyl)-1,4,7,10-tetraazacyclododec-1-yl)acetic acid) was used in a first human in vivo study for diagnosis of osteoblastic bone metastases. The DOTA-based bisphosphonate ligand BPAMD may also be suitable for complexation with therapeutic radionuclides such as 177Lu. The same ligand thus may be used for diagnosis, dosimetry calculation, therapy and therapy control via PET/CT.

Methods 177Lu was provided in 0.04 M HCl via the 176Yb(n,γ)177Yb→177Lu production process. Labelling was studied using different amounts of ligand in acetate buffer at pH 4-5 and different temperatures. For quality control different TLC systems and HPLC were used. Stability of 177Lu-BPAMD was investigated over one week.

Results BPAMD can be labelled in almost quantitative radiochemical yield and high specific activity in less than 30 min in acetate buffer. 177Lu-BPAMD shows radiolysis under high activity concentrations (15 GBq/mL). By dilution directly after labelling this decomposition can be suppressed. These findings result in a protocol for human application and therapy with 177Lu-BPAMD. The first human therapy using 5 GBq 177Lu-BPAMD monitored by SPECT over 24 h showed significant enrichment on bone lesions.

Conclusions BPAMD exhibits the potential to be used for diagnosis and therapy monitoring (by means of PET with 68Ga) and radionuclide therapy itself (with 177Lu). The uptake is reflecting the farnesyl diphosphate synthase enzyme dynamics in the HMG-CoA reductase pathway. Since this pathway is mainly responsible for the osteoclastic bone destruction, BPAMD is a promising ligand for 177Lu therapy of bone lesions