Characterization of Serotonin Transporter using Novel Radiotracer —123I-ADAM in Normal and Depressive Animals

• Main Authors: LIN KUN-JU, 林昆儒
• Other Authors: YEN TZU-CHEN
• Format: Others
• Language: zh-TW
• Published: 2004
• Online Access: http://ndltd.ncl.edu.tw/handle/98265848764140747183

博士 === 長庚大學 === 臨床醫學研究所 === 92 === The finding of taking drugs that increase monoamines in the synapse can improve the symptoms of depression lead to the establishment of “monoamine hypothesis” of depression. Accumulated evidence suggested that the deficiency of central monoamines may be the underlying neuroanatomical basis of depression and antidepressants that targeting this neuronal lesion would tend to restore normal function in depressed patients. Although the explanation for the action of antidepressants is inadequate and the pathophysiology of depression itself remains unknown, monoamine and its related transporter and receptor have become one of the most important targets in the drug development and understanding the pathophysiology of depression. Among monoamines, the serotonin has attracted much attention in the study of pathophysiology and treatment of depression due to the extensive use of selective serotonin reuptake inhibitors as an effective antidepressant. Also, studies showed that serotonin transporter (SERT) in postmortem brain of suicide victims were delined. Besides, evidences of SERT gene polymorphism in depressive patients were reported. Thus, the demand for quantification of SERT using scintigraphic method becomes more anxious. However, the development of an optimal radioliand as a key to success image SERT remains limited. Most selective radioligands for targeting SERT were using 11C as a gamma emitter for scitigraphic imaging due to the convenience of drug synthesis. However its ultra-short half-life (T1/2 = 20 min) of this radiotracer has limited its clinical applications due to need an on site cyclotron and a hot laboratory. Newly developed radiotracers for single emission computed tomography such as 123I -CIT have extended its usage for its optimal half-life (T1/2 = 13 h) and thus the ability to deliver from the pharmacy, even outside of hospital. Unfortunately, less selectivity to SERT with cross-talk to other monoamine species prohibited its clinical application due to it was not a precise targeting molecule. Recently, Kung and his colleagues have developed a new radiotracer for targeting SERT — 123I-ADAM. This new radioligand possess highest selectively to SERT among competitors up now. The more favorable radio-activity half life than 11C compound for drug transportation makes popularize the quantification of central SERT in human feasible. In order to test its ability in the quantification of central SERT, and determine its potential usage in the discrimination of SERT amount between normal, depressive subjects and response to antidepressants, we studied the biodistribution and observed the 123I-ADAM amounts in the rat brains of p-chloroamphetamine (PCA) treated and olfactory bulbectomized depressive animals. To precise quantify the SERT amount using 123I-ADAM, we developed quantification autoradiography using filter and tissue standards and correlate the results with SERT saturation binding assay. The successful of the establishment of depressive animal model was validated by examine the animal behavior, and quantity of serotonin and its metabolites in the prefrontal cortex of rat brains. The autoradiographic results showed that the 123I-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 peak specific binding ratio at 120 min after injection. 123I-ADAM uptake was dramatically decreased in the aforementioned areas 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. The 123I-ADAM was increased in amygdala of olfactory bulbectomized animals and was decreased after successful antidepressant treatment. In summary, 123I-ADAM can bind to SERT specifically after systemic injection. The quantification of 123I-ADAM binding was in linear correlation with the amounts of SERT determined by receptor saturation binding assay. SERT alternation could be observed using 123I-ADAM quantitative autoradiography, and the increase of 123I-ADAM binding returned to normal after successful antidepressant treatment. Our results showed good linear correlation between SERT amounts and quantity of 123I-ADAM binding in vivo. The alternation of SERT in depressive subjects and after successful antidepressant treatment can be observed using 123I-ADAM quantitative autoradiography. The novel radiotracer could be a potential tool to quantify SERT amount in living human brain. The investigation on depressive related disease using 123I-ADAM was warrant.