Single-photon emission tomography imaging of serotonin transporters in the non-human primate brain with the selective radioligand [123I]IDAM

A new radioligand, 5-iodo-2-2–2-(dimethylamino)methyl]phenyl]thio]benzyl alcohol (¹²³I]IDAM), has been developed for selective single-photon emission tomography (SPET) imaging of SERT. In vitro binding studies suggest a high selectivity of IDAM for SERT (K _i=0.097 nM), with considerably lower affinities for norepinephrine and dopamine transporters (NET K _i= 234 nM and DAT K _i>10 μM, respectively). In this study the biodistribution of SERT in the baboon brain was investigated in vivo using ¹²³I]IDAM and SPET imaging. Dynamic sequences of SPET scans were performed on three female baboons (Papio anubis) after injection of 555 MBq of ¹²³I]IDAM. Displacing doses (1 mg/kg) of the selective SERT ligand (+)McN5652 were administered 90–120 min after injection of ¹²³I]IDAM. Similar studies were performed using a NET inhibitor, nisoxetine, and a DAT blocker, methylphenidate. After 60–120 min, the regional distribution of tracer within the brain reflected the characteristic distribution of SERT, with the highest uptake in the midbrain area (hypothalamus, raphe nucleus, substantia nigra), and the lowest uptake in the cerebellum (an area presumed free of SERT). Peak specific binding in the midbrain occurred at 120 min, with a ratio to the cerebellum of 1.80±0.13. At 30 min, 85% of the radioactivity in the blood was metabolite. Following injection of a competing SERT ligand, (+)McN5652, the tracer exhibited rapid washout from areas with high concentrations of SERT (dissociation rate constant in the midbrain, averaged over three baboons, k _off=0.025±0.002 min^–1), while the cerebellar activity distribution was undisturbed (washout rate 0.0059± 0.0003 min^–1). Calculation of tracer washout rate pixel-by-pixel enabled the generation of parametric images of the dissociation rate constant. Similar studies using nisoxetine and methylphenidate had no effect on the distribution of ¹²³I]IDAM in the brain. These results suggest that ¹²³I]IDAM is suitable for selective SPET imaging of SERT in the primate brain, with high contrast, favorable kinetics, and negligible binding to either NET or DAT. Received: 1 February and in revised form 2 March 1999