SPECT imaging of dopamine and serotonin transporters with [123I]β‐CIT: Pharmacological characterization of brain uptake in nonhuman primates

Abstract

Single photon emission computed tomography (SPECT) studies of regional kinetic uptake and pharmacological specificity of [¹²³I] methyl 3β‐ (4‐iodophenyl) tropane‐2β‐carboxylate ([¹²³I]β‐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 rations were 7.3 ± 0.9 (mean ± SEM) at 300 min. About 75% of striatal uptake was displaceable by injection of nonradioactive β‐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 [¹²³I]β‐CIT uptake. In vivo site occupancy ED₅₀ values of cocaine, 2β‐carbomethoxy‐3β‐(4‐fluorophenyl) tropane (CFT), and β‐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 μMol/kg) failed to displace striatal [¹²³I]β‐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 [¹²³I]β‐CIT binding, These studies suggest that [¹²³I]β‐CIT will be a useful SPECT tracer of DA and 5‐HT transporters in living human brain.