Characterization of [¹²³I]IDAM as a novel single-photon emission tomography tracer for serotonin transporters

Abstract.

Development of selective serotonin transporter (SERT) tracers for single-photon emission tomography (SPET) is important for studying the underlying pharmacology and interaction of specific serotonin reuptake site inhibitors, commonly used antidepressants, at the SERT sites in the human brain. In search of a new tracer for imaging SERT, IDAM (5-iodo-2-[[2-2-[(dimethylamino)methyl]phenyl]thio]benzyl alcohol) was developed. In vitro characterization of IDAM was carried out with binding studies in cell lines and rat tissue homogenates. In vivo binding of [¹²⁵I]IDAM was evaluated in rats by comparing the uptakes in different brain regions through tissue dissections and ex vivo autoradiography. In vitro binding studyshowed that IDAM displayed an excellent affinity to SERT sites (K _i=0.097 nM, using membrane preparations of LLC-PK₁ cells expressing the specific transporter) and showed more than 1000-fold of selectivity for SERT over norepinehrine and dopamine (expressed in the same LLC-PK₁ cells). Scatchard analysis of [¹²⁵I]IDAM binding to frontal cortical membrane homogenates prepared from control or p-chloroamphetamine (PCA)-treated rats was evaluated. As expected, the control membranes showed a K _d value of 0.25 nM±0.05 nM and a B _max value of 272±30 fmol/ mg protein, while the PCA-lesioned membranes displayed a similar K _d, but with a reduced B _max (20±7 fmol/ mg protein). Biodistribution of[¹²⁵I]IDAM (partition coefficient =473; 1-octanol/buffer) in the rat brainshowed a high initial uptake (2.44%dose at 2 min after i.v. injection) with the specific binding peaked at 60 min postinjection (hypothalamus-cerebellum/cerebellum =1.75). Ex vivo autoradiographs of rat brain sections (60 min after i.v. injection of [¹²⁵I]IDAM) showed intense labeling in several regions (olfactory tubercle, lateral septal nucleus, hypothalamic and thalamic nuclei, globus pallidus, central gray, superior colliculus, substantia nigra, interpeduncular nucleus, dorsal and median raphes and locus coeruleus), which parallel known SERT density. This novel tracer has excellent characteristics for in vivo SPET imaging of SERT in the brain.