Microautoradiography of [ 123 I]ADAM in mice treated with fluoxetine and serotonin reuptake inhibitors Xin-Xian Ye a , Jyh-Cheng Chen a , Ren-Shen Liu b , Shiaw-Pyng Wey c , Jin-Shin Lee a , Chia-Chieh Chen d , Ying-Kai Fu d , Gann Ting d , Jeng-Jong Hwang a, * a Department of Medical Radiation Technology and Institute of Radiological Sciences, National Yang-Ming University, 155 Li-Nong St., Sec. 2, Pei-tou, Taipei 112, Taiwan b National PET and Cyclotron Center, Veterans General Hospital, Taipei, Taiwan c Chang Gung University, Taoyuan, Taiwan d Institute of Nuclear Energy Research, Taoyuan, Taiwan Abstract A radiopharmaceutical, 123 I-labeled 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine ([ 123 I]ADAM), has been developed recently for evaluation of how serotonin transporters (SERT) function in the brain. However, the detailed biodistribution and specific binding in certain brain areas are not well investigated. In this study, both phosphor plate imaging and microautoradiography were applied to explore the binding characteristics of [ 123 I]ADAM in SERT neurons. The effect of two psychotropics and one narcotic on the binding of [ 123 I]ADAM to SERT was also studied. Fluoxetine and desipramine, both are psychotropics and specific SERT ligands and decreased the affinity of [ 123 I]ADAM, while p-chloroamphetamine (PCA), a narcotic, destroyed most of serotonergic neurons, as well as reducing the concentration of serotonin and the number of SERT in the brain as shown by the biodistribution of [ 123 I]ADAM. Significant and selective accumulation of [ 123 I]ADAM in the areas from midbrain to brain stem in normal mice with maximum target-to-background ratio was found at 90 minutes postinjection. A rapid clearance of [ 131 I]ADAM at 120 minutes postinjection was found in the CA1, CA3 and ThN brain areas. In addition, the inhibition effect on binding ability of [ 123 I]ADAM to SERT by the psychotropics and the narcotic was found to have the order of: PCA  fluoxetine  desipramine. © 2004 Elsevier Inc. All rights reserved. Keywords: [ 123 I]ADAM; Microautoradiography; Phosphor plate imaging; Fluoxetine; Desipramine; p-Chloroamphetamine 1. Introduction Serotonin is an essential neurotransmitter for the normal functioning of the central nervous system (CNS). The se- rotonergic neurosystem is not only important physiologi- cally but also affects other behaviors such as the sleep– awake cycle, mood, appetite, body temperature, and depression [1]. Depression has been shown to be associated with abnormal functioning of the serotonergic system, pos- sibly because of stress or other psychiatric disorders [2–5]. Postmortem studies of patients treated with serotonin re- uptake inhibitors (SSRI) showed decreased serotonin or its metabolite, 5-hydroxyindolacetic acid, in the brain stem [2, 3, 6]. From the aspect of clinical diagnosis as well as medical expense, the development of radiopharmaceuticals to monitor SERT binding with single-photon emission com- puted tomography (SPECT) is needed [7–9]. [ 123 I]ADAM, a recently developed radioligand, has been demonstrated to have high affinity and selectivity for SERT, yet low affinities for both the norepinephrine transporter (NET) and the dopamine transporter (DAT) [1, 10, 11]. Patients with depression may be treated with psychotropic drugs, and one such drug that is widely used is fluoxetine. Fluoxetine functions as an SSRI and blocks serotonin re- uptake at presynaptic terminals, which results in the accu- mulation of serotonin in the extracellular fluid at synapses [9, 12]. Desipramine, a tricyclic antidepressant drug, has preference for NET but also blocks serotonin reuptake. On the other hand, certain compounds that have been abused as narcotics also affect SERT function, such as p-chloroam- phetamine (PCA). Prolonged or high dosage administration of PCA releases serotonin from axon terminals by nonexo- cytotic mechanisms and inhibits the affinity of tryptophan hydroxylase [13, 14]. It is suggested that oxidative meta- * Corresponding author. Tel.: 886-2-28267064; fax: 886-2-28201095. E-mail address: jjhwang@ym.edu.tw (J.-J. Hwang). Nuclear Medicine and Biology 31 (2004) 557–562 www.elsevier.com/locate/nucmedbio 0969-8051/04/$ – see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.nucmedbio.2003.12.002