title: Selective in vitro and in vivo binding of [(125)I]ADAM to serotonin transporters in rat brain.
abstract: An improved iodinated tracer, ADAM (2-((2-((dimethylamino)methyl)- phenyl)thio)-5-iodophenylamine) for imaging serotonin transporters (SERT) with single photon emission computerized tomography (SPECT), was prepared and characterized. Scatchard analysis of saturation binding of [(125)I]ADAM to rat frontal cortical membrane homogenates gave a K(d) value of 0.15 +/- 0.03 nM and a B(max) value of 194 +/- 65 fmol/mg protein. Biodistribution of [(125)I]ADAM in rat brain after an iv injection showed a high specific binding in the regions of hypothalamus, cortex, striatum, and hippocampus, where SERT are concentrated and the specific binding peaked at 120-240 min postinjection [(hypothalamus-cerebellum)/cerebellum = 4.3 at 120 min post-iv injection]. Moreover, the specific hypothalamic uptake was blocked by pretreatment with SERT selective competing drugs, such as paroxetine and (+)McN5652, while other noncompeting drugs, such as ketanserin, raclopride, and methylphenidate, showed no effect. The radioactive material recovered from rat brain homogenates at 120 min after [(125)I]ADAM injection showed primarily the original compound (>90%), a good indication of in vivo stability in the brain tissues. Both male and female rats showed similar and comparable organ distribution pattern and regional brain uptakes. Ex vivo autoradiograms of rat brain sections (120 min after iv injection of [(125)I]ADAM) 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 coerulus), which parallel known SERT density. These results strongly suggest that the novel tracer ADAM is superior to the congers (i.e., IDAM) reported previously. When labeled with I-123, ADAM will be an improved and useful SPECT imaging agent for SERT in the brain.
authors.affiliation: Departments of Radiology and Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: S R
authors.initials: SR
authors.lastname: Choi
authors.forename: C
authors.initials: C
authors.lastname: Hou
authors.forename: S
authors.initials: S
authors.lastname: Oya
authors.forename: M
authors.initials: M
authors.lastname: Mu
authors.forename: M P
authors.initials: MP
authors.lastname: Kung
authors.forename: M
authors.initials: M
authors.lastname: Siciliano
authors.forename: P D
authors.initials: PD
authors.lastname: Acton
authors.forename: H F
authors.initials: HF
authors.lastname: Kung
mesh_terms: D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002928:Cinanserin / Q000031:analogs & derivatives* / Q000378:metabolism*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D050486:Serotonin Plasma Membrane Transport Proteins; D012727:Sex Characteristics; D014018:Tissue Distribution
chemical_list: C413491:2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine; D002352:Carrier Proteins; D007457:Iodine Radioisotopes; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D002928:Cinanserin