Single-photon emission tomographic (SPET) imaging with the radiotracer [I-123] 2 beta-carbomethoxy-3 beta(4-iodophenyl)tropane ([I-123]beta-CIT) has been reported to be a useful in vivo measure of dopamine (DA) transporters. However, in addition to its high DA transporter affinity, beta-CIT also binds with high affinity to serotonin (5-HT) transporters. 2 beta-Carboisopropoxy-3 beta-(4-iodophenyl)tropane (IPCIT) has been demonstrated by in vitro studies to have higher selectivity for the DA transporter. We compared [I-123]beta-CIT and [I-123]IPCIT SPET imaging and plasma metabolite analyses in baboons to evaluate the potential advantages of [I-123]IPCIT for quantitative in vivo measurements of DA transporter densities. Both tracers had low levels (2% of total plasma I-123 activity) of lipophilic radiolabeled metabolites at 420 min. [I-123]IPCIT had significantly higher binding to plasma proteins. The average percent free (nonprotein bound) [I-123]beta-CIT and [I-123]IPCIT were 52%+/-7% and 14%+/-6%, respectively. Region of interest uptake data were normalized by injected dose and body weight. Consistent with the high density of 5-HT transporters in the midbrain and the lower 5-HT transporter affinity of IPCIT, the normalized peak specific midbrain uptake of [I-123]beta-CIT (1.7+/-0.5) was higher than that of [I-123]IPCIT (0.4+/-0.2). Consistent with its greater lipophilicity, [I-123]IPCIT had higher nonspecific uptake, such that normalized cerebellar uptake of [I-123]IPCIT was about twice that of [123]beta-CIT. The ratio of specific to nonspecific uptake in striatum was greater for [I-123]beta-CIT compared to [I-123]IPCIT; however, striatal binding potentials and distribution volumes were not significantly different. In conclusion, [I-123]IPCIT demonstrated in vivo a higher DA transporter selectivity and higher level of nonspecific uptake.