Single-photon emission tomography imaging of serotonin transporters in the nonhuman primate brain with [¹²³I]ODAM

Abstract.

We have described previously a selective serotonin transporter (SERT) radioligand, [¹²³I]IDAM. We now report a similarly potent, but more stable IDAM derivative, 5-iodo-2-[2-[(dimethylamino)methyl]phenoxy]benzyl alcohol ([¹²³I]ODAM). The imaging characteristics of this radioligand were studied and compared against [¹²³I]IDAM. Dynamic sequences of single-photon emission tomography (SPET) scans were obtained on three female baboons after injection of 375 MBq of [¹²³I]ODAM. Displacing doses (1 mg/kg) of the selective SERT ligand (+)McN5652 were administered 120 min after injection of [¹²³I]ODAM. Total integrated brain uptake of [¹²³I]ODAM was about 30% higher than [¹²³I]IDAM. After 60–120 min, the regional distribution of tracer within the brain reflected the characteristic distribution of SERT. Peak specific binding in the midbrain occurred 120 min after injection, with an equilibrium midbrain to cerebellar ratio of 1.50±0.08, which was slightly lower than the value for [¹²³I]IDAM (1.80± 0.13). Both the binding kinetics and the metabolism of [¹²³I]ODAM were slower than those of [¹²³I]IDAM. Following injection of a competing SERT ligand, (+)McN5652, the tracer exhibited washout from areas with high concentrations of SERT, with a dissociation kinetic rate constant k _off=0.0085±0.0028 min^–1 in the midbrain. Similar studies using nisoxetine and methylphenidate showed no displacement, consistent with its low binding affinity to norepinephrine and dopamine transporters, respectively. These results suggest that [¹²³I]ODAM is suitable for selective SPET imaging of SERT in the primate brain, with higher uptake and slower kinetics and metabolism than [¹²³I]IDAM, but also a slightly lower selectivity for SERT.