SPECT IMAGING OF DOPAMINE AND SEROTONIN TRANSPORTERS WITH [I-123] BETA-CIT - PHARMACOLOGICAL CHARACTERIZATION OF BRAIN UPTAKE IN NONHUMAN-PRIMATES

Single photon emission computed tomography (SPECT) studies of regional kinetic uptake and pharmacological speCifiCity of [I-123]methyl 3beta-(4-iodophenyl) tropane-2beta-carboxylate ([I-123]beta-CIT) were performed in nonhuman primates (n = 41). In control experiments, activity was concentrated in striatum and in hypothalamic/midbrain regions. Striatal uptake increased for 140-180 min and displayed stable levels thereafter. Striatal to cerebellar activity ratios were 7.3 +/- 0.9 (mean +/- SEM) at 300 min. About 75% of striatal uptake was displaceable by injection of nonradioactive beta-CIT. Hypothalamic/midbrain activity reached maximal levels at approximately 45 min. A slow washout phase followed this peak activity. Activities in frontal, occipital, and cerebellar regions were characterized by an early peak (20-30 min), followed by rapid washout. Displacement studies demonstrated that striatal uptake was associated with dopamine (DA) transporters, as it was displaced by GBR 12909, a selective DA uptake inhibitor, but not by citalopram, a selective serotonin (5-HT) uptake inhibitor. The inverse was true in the hypothalamic/midbrain area, suggesting that the uptake in this area was associated primarily with 5-HT transporters. Maprotiline, a selective norepinephrine uptake inhibitor, did not affect [I-123]beta-CIT uptake. In vivo site occupancy ED50 values of cocaine, 2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane (CFT), and beta-CIT were measured in the striatum with a stepwise displacement paradigm. In vivo ED50 values correlated strongly with in vitro IC50 values for binding to DA transporters. Infusion of high dose of L-DOPA (250 mumol/kg) failed to displace striatal [I-123]beta-CIT binding, suggesting that the binding would not be affected by L-DOPA administration in Parkinsonian patients. However, studies performed with injection of d-amphetamine indirectly suggested that high synaptic levels of DA may compete with [I-123]beta-CIT binding. These studies suggest that [I-123]beta-CIT will be a useful SPECT tracer of DA and 5-HT transporters in living human brain.