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

Development of selective serotonin transporter (SERT) tracers for single-ph oton emission tomography (SPET) is important for studying the underlying ph armacology and interaction of specific serotonin reuptake site inhibitors, commonly used antidepressants, at the SERT sites in the human brain. In sea rch 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 [I-125]IDAM was evaluated in rats by compar ing the uptakes in different brain regions through tissue dissections and e x vivo autoradiography. In vitro binding study showed that IDAM displayed a n excellent affinity to SERT sites (K-i=0.097 nM, using membrane preparatio ns of LLC-PK1 cells expressing the specific transporter) and showed more th an 1000-fold of selectivity for SERT over norepinehrine and dopamine (expre ssed in the same LLC-PK1 cells). Scatchard analysis of [I-125]IDAM binding to frontal cortical membrane homogenates prepared from control or p-chloroa mphetamine (PCA)-treated rats was evaluated. As expected, the control membr anes showed a Kd value of 0.25 nM+/-0.05 nM and a B-max value of 272+/-30 f mol/ max 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 [I-125]IDAM (partition coefficient =473; 1-octanol/buffer) in the rat brain showed a high initial uptake (2.44% dose at 2 min after i.v. injection) wi th the specific binding peaked at 60 min postinjection (hypothalamus-cerebe llum/cerebellum =1.75), Ex vivo autoradiographs of rat brain sections (60 m in after i.v. injection of [I-125]IDAM) showed intense labeling in several regions (olfactory tubercle, lateral septal nucleus, hypothalamic and thala mic nuclei, globus pallidus, central gray, superior colliculus, substantia nigra, interpeduncular nucleus, dorsal and median raphes and locus coeruleu s), which parallel known SERT density. This novel tracer has excellent char acteristics for in vivo SPET imaging of SERT in the brain.