Synthesis and preliminary characterization of a high-affinity novel radioligand for the dopamine transporter

In our effort to develop a novel radioligand selective for the dopamine tra nsporter, compound Ib (O-972) was designed and characterized. The compound Ib was characterized for its binding both in monkey and rat striatum tissue , which demonstrated its high selectivity for the dopamine transporter (DAT ) when its binding was compared with that at the serotonin transporter (SER T). The compound 5, which is a precursor for the tritiated radiolabel ligan d [H-3]O-972, was synthesized and biologically characterized. The prelimina ry characterization of this novel radioligand revealed its strong binding a ffinity for the DAT. Thus, the pharmacological profile of [H-3]O-972 indica ted that DAT inhibitors, which include GBR 12909, mazindol, CFT, and cocain e, could potently displace this novel radioligand from monkey brain striatu m tissue. On the other hand, compounds known to be not selective for and po tent at the DAT were very weak to do so. Initial binding results also indic ate that [H-3]O-972 may interact with the DAT in a manner that is not ident ical to that for GBR 12909 and tropane analogs. (C) 2001 Wiley-Liss, Inc.