Characterization of the binding sites for 123I-ADAM and the relationship to the serotonin transporter in rat and mouse brains using quantitative autoradiography.
Imaging of serotonin transporter (SERT) in the central nervous system may provide an important tool to evaluate some psychiatric disorders. Recently, a novel (123)I-labeled radiotracer, 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine ((123)I-ADAM), has been developed that exhibited a high selectivity for SERT. The aim of this study was to characterize the biodistribution and specificity of (123)I-ADAM to SERT using quantitative autoradiography in both control and neurotoxin-treated animals.


METHODS
(123)I-ADAM (74 MBq) was injected intravenously into the mice to access its biodistribution in the brain via quantitative autoradiography. Further, rats with serotonin depleted by intraperitoneal injection of p-chloroamphetamine (PCA) were used to evaluate the specificity of (123)I-ADAM to SERT. The levels of biogenic amines were then measured and correlated with quantitative (123)I-ADAM labeling in control and PCA-treated rat brains.


RESULTS
The autoradiographic results showed that (123)I-ADAM accumulated in SERT-rich brain areas after systemic injection, including the globus pallidus, thalamus, hypothalamus, substantia nigra, interpeduncular nucleus, amygdala, and raphe nucleus. The dorsal raphe nucleus had the highest initial uptake with a peak specific binding ratio (i.e., [target - cerebellum]/cerebellum) at 120 min after injection. (123)I-ADAM uptake was dramatically decreased in the hippocampus, thalamus, amygdala, geniculate nuclei, hypothalamus, raphe nucleus, and substantia nigra in PCA-lesioned rats. The decrement in radioactivity was more prominent at higher dosages of PCA and was in parallel with the changes in amounts of serotonin and 5-hydroxyindoleacetic acid in the prefrontal cortex.


CONCLUSIONS
This study demonstrates that regional distribution of (123)I-ADAM radioactivity is similar to the SERT localization in both rat and mouse brains. We also validated that destruction on central serotonergic neurons after PCA treatment inhibits the uptake of (123)I-ADAM in serotonin-rich brain regions. High specific binding to SERT in vivo makes (123)I-ADAM an appropriate radiotracer for solitary studies of serotonin functions in living humans.
Lin
Kun-Ju
KJ
Graduate Institute of Clinical Medical Sciences, Chang-Gung University, Tao-Yuan, Taiwan.
Yen
Tzu-Chen
TC
Wey
Shiaw-Pyng
SP
Hwang
Jeng-Jong
JJ
Ye
Xin-Xian
XX
Tzen
Kai-Yuan
KY
Fu
Ying-Kai
YK
Chen
Jin-Chung
JC
D000818:Animals; D001345:Autoradiography / Q000379:methods*; D001665:Binding Sites; D001679:Biogenic Amines / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002928:Cinanserin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins; D008657:Metabolic Clearance Rate / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D009419:Nerve Tissue Proteins; D011485:Protein Binding; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D050486:Serotonin Plasma Membrane Transport Proteins; D014018:Tissue Distribution / Q000187:drug effects; D010133:p-Chloroamphetamine / Q000494:pharmacology
C413491:2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine; D001679:Biogenic Amines; D002352:Carrier Proteins; D007457:Iodine Radioisotopes; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D019275:Radiopharmaceuticals; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; C493232:Slc6a4 protein, rat; D010133:p-Chloroamphetamine; D002928:Cinanserin