META-[(211)AT]ASTATOBENZYLGUANIDINE - FURTHER EVALUATION OF A POTENTIAL THERAPEUTIC AGENT

Meta-[At-211]astatobenzylguanidine ([At-211]MABG) is an astatinated analogue of meta-iodobenzylguanidine (MIBG) that could be of value for therapeutic applications. The initial goal of this study was to determine whether [At-211]MABG is taken up, like MIBG, by a specific uptake-I mechanism. Norepinephrine and desipramine (DMI) decreased [At-211]MABG uptake in SK-N-SH human neuroblastoma cells. This uptake was found to be energy-dependent: In mice, pre-treatment with DMI reduced uptake of [At-211]MABG at 1 hr post-injection in the adrenal and in the heart. Tetrabenazine at a dose of 40 mg/kg reduced uptake of [At-211]MABG in the mouse heart in vivo (69% of control) whereas up to 100 mu M of tetrabenazine did not affect the in vitro uptake of [At-211]MABG in SK-N-SH cells. In SKN-SH cells, 53% and 38%, respectively, of the initial uptake of [At-211]MABG was retained at 4 hr and 6 hr. For no-carrier-added (n.c.a.) [I-131]MIBG these values were similar, 60% and 48%. The ability of SK-N-SH cells to incorporate [H-3]thymidine was reduced to less than 50% of control values when treated with as little as 3.2 nCi of [At-211]MABG. In contrast, no significant reduction in the thymidine uptake was observed, even with 80 nCi of n.c.a. MIBG. (C) 1994 Wiley-Liss, Inc.