Preclinical development of Meta-[²¹¹At]astatobenzylguanidine ([²¹¹At]MABG) as an alpha particle emitting systemic targeted radiotherapeutic for neuroblastoma (NB).

Objectives NB is a radiosensitive childhood malignancy that frequently shows robust expression of the norepinephrine transporter (NET) on the tumor cell surface. NET-ligand therapy with [¹³¹I]MIBG is inefficient in tumor microclusters because of the relatively long path-length of β-particles. Targeted radiotherapy with the α-particle emitting NET-ligand [²¹¹At]MABG has the potential to deliver lethal radiation doses to sites of minimal residual disease because of the higher linear energy transfer and short path length of α-particles.

Methods ²¹¹At was produced at the UPenn cyclotron facility with dry distillation to isolate ²¹¹At. Solid-phase radiosynthesis of [²¹¹At]MABG utilized Ultratrace resin. [²¹¹At]MABG uptake assays as well as biodistribution experiments were performed using NET transfected NB cell lines. In vivo dose escalation studies with [²¹¹At]MABG to determine radiotoxicology are ongoing. Finally, clonogenic assays and therapeutic trials in mouse models with [²¹¹At]MABG are also ongoing.

Results We synthesized [²¹¹At]MABG (radiochemical yield of 50-60%, radiochemical purity > 95%) and showed NET-specific uptake. NET-overexpressing lines demonstrated tumor-specific [²¹¹At]MABG uptake in vivo with tumor-muscle ratios of 7.37. Toxicity studies have shown that doses of 10 and 25 uCi of [²¹¹At]MABG were well tolerated. Clonogenic assays show [²¹¹At]MABG to be potently cytotoxic and murine efficacy studies are ongoing.

Conclusions We have synthesized ²¹¹At-MABG in quantities sufficient for our preclinical experiments and are scaling production for clinical trials. [²¹¹At]MABG biodistribution and toxicity parameters are similar to the currently used radiotherapeutic [¹³¹I]MIBG. Our preliminary in-vitro data suggests that [²¹¹At]MABG may be an effective agent for salvage therapy for children with refractory/relapsed NB.

Research Support Department of Defense (DoD) PRMRP Grant PressOn Foundation Progenics Pharmaceuticals