Validation of 4-[18F]-ADAM as a SERT imaging agent using micro-PET and autoradiography

Serotonin transporters (SERTs) have been implicated in various neuropsychiatric disorders. We aim to validate 4-[(18)F]-ADAM (N,N-dimethyl-2-(2-amino-4-[(18)F]fluorophenylthio)benzylamine) as a SERT imaging agent in rats using micro-positron emission tomography (micro-PET) and autoradiography. Sixty to ninety min after injecting 4-[(18)F]-ADAM, specific uptake ratios (SURs) were determined by micro-PET measurements in various brain regions of normal control rats. For n=3, the SUR in the midbrain was 4.94+/-0.16, for the hypothalamus it was 4.39+/-0.031 and for the caudate it was 4.18+/-0.53. The retention of 4-[(18)F]-ADAM in the hypothalamus and midbrain regions increased rapidly between 5 to 10 min after injection and declined thereafter. The SURs determined by autoradiography were: 9.31+/-1.41 for the midbrain, 7.15+/-1.45 for the hypothalamus and 5.22+/-1.14 for the caudate putamen. Both micro-PET and autoradiography studies revealed a dose-dependent progressive inhibition of radioligand uptake in the frontal cortex, caudate putamen and hypothalamus in rats treated with 0.01 to 0.25 mg/kg paroxetine. A decrease in 4-[(18)F]-ADAM uptake of approximately 84% was observed in the midbrain of rats pretreated with 0.25 mg/kg paroxetine as compared to controls (4.94+/-0.16 versus 0.80+/-0.17, n=3). Both 5,7-dihydroxytryptamine and p-chloroamphetamine-treated rats showed pronounced reduction in 4-[(18)F]-ADAM binding when compared to normal controls. Rats pretreated with p-chloroamphetamine exhibited significant inhibition of 4-[(18)F]-ADAM uptake in brain regions rich in SERT over a period of four weeks. Thus, 4-[(18)F]-ADAM is a SERT-specific radioligand that may be useful for evaluating neuropsychiatric conditions involving serotonergic dysfunction.

[1]  G. Koob,et al.  Inhibition of 5-HT Neurotransmission Increases Clonidine Protective Effects on Naloxone-induced Conditioned Place Aversion in Morphine-dependent Rats , 2003, Neuropsychopharmacology.

[2]  B. Yamamoto,et al.  A frequency analysis of behavior components of the serotonin syndrome produced by p-chloroamphetamine , 1979, Pharmacology Biochemistry and Behavior.

[3]  H. Baumgarten,et al.  5,7‐Dihydroxytryptamine: improvement of its selectivity for serotonin neurons in the CNS by pretreatment with desipramine , 1975, Journal of neurochemistry.

[4]  D. Williams,et al.  Membrane cholesterol modulates serotonin transporter activity. , 2001, Biochemistry.

[5]  Yiyun Huang,et al.  Fluorinated diaryl sulfides as serotonin transporter ligands: synthesis, structure-activity relationship study, and in vivo evaluation of fluorine-18-labeled compounds as PET imaging agents. , 2005, Journal of medicinal chemistry.

[6]  C. Vorhees,et al.  p-Chloroamphetamine: Behavioral effects of reduced cerebral serotonin in rats , 1975, Pharmacology Biochemistry and Behavior.

[7]  Zsolt Szabo,et al.  Positron emission tomography imaging of serotonin transporters in the human brain using [11C](+)McN5652 , 1995, Synapse.

[8]  Renyi Liub,et al.  Microautoradiography of [ 123 I ] ADAM in mice treated with fluoxetine and serotonin reuptake inhibitors , 2004 .

[9]  R. V. Van Heertum,et al.  Occupancy of brain serotonin transporters during treatment with paroxetine in patients with social phobia: a positron emission tomography study with [11C]McN 5652 , 2002, Psychopharmacology.

[10]  Alan A. Wilson,et al.  Imaging the serotonin transporter with positron emission tomography: initial human studies with [11C]DAPP and [11C]DASB , 2000, European Journal of Nuclear Medicine.

[11]  M. Kuhar,et al.  Development of PET/SPECT ligands for the serotonin transporter. , 1994, NIDA research monograph.

[12]  Sylvain Houle,et al.  [11C]‐DASB, a tool for in vivo measurement of SSRI‐induced occupancy of the serotonin transporter: PET characterization and evaluation in cats , 2003, Synapse.

[13]  Iluminada Corripio,et al.  Serotonin transporter occupancy induced by paroxetine in patients with major depression disorder: a 123I-ADAM SPECT study , 2006, Psychopharmacology.

[14]  S. Houle,et al.  Novel radiotracers for imaging the serotonin transporter by positron emission tomography: synthesis, radiosynthesis, and in vitro and ex vivo evaluation of (11)C-labeled 2-(phenylthio)araalkylamines. , 2000, Journal of medicinal chemistry.

[15]  Ying-Kai Fu,et al.  Microautoradiography of [123I]ADAM in mice treated with fluoxetine and serotonin reuptake inhibitors. , 2004, Nuclear medicine and biology.

[16]  H N Wagner,et al.  [11C](+)McN5652 as a radiotracer for imaging serotonin uptake sites with PET. , 1993, Life sciences.

[17]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[18]  K. Ma,et al.  18F-ADAM PET in healthy and drug-naive depressant subjects , 2007 .

[19]  Joel S. Karp,et al.  Radioligand for Serotonin Transporters , 2003 .

[20]  Chyng-Yann Shiue,et al.  Synthesis of N,N-dimethyl-2-(2-amino-4-[18F]fluorophenylthio)benzylamine as a serotonin transporter imaging agent. , 2003, Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine.

[21]  O Sabri,et al.  In vivo Measurement of the Serotonin Transporter with (S)-([18F]fluoromethyl)-(+)-McN5652 , 2003, Neuropsychopharmacology.

[22]  M Bergström,et al.  Positron emission tomography and brain monoamine neurotransmission -- entries for study of drug interactions. , 2002, Current pharmaceutical design.

[23]  Yiyun Huang,et al.  A PET imaging agent with fast kinetics: synthesis and in vivo evaluation of the serotonin transporter ligand [11C]2-[2-dimethylaminomethylphenylthio)]-5-fluorophenylamine ([11C]AFA). , 2004, Nuclear medicine and biology.

[24]  A. Coppen.  The Biochemistry of Affective Disorders , 1967, British Journal of Psychiatry.

[25]  K. Lesch,et al.  Glucocorticoid‐regulated human serotonin transporter (5‐HTT) expression is modulated by the 5‐HTT gene‐promotor‐linked polymorphic region , 2003, Journal of neurochemistry.

[26]  D. Kupfer,et al.  Serotonin in Aging, Late-Life Depression, and Alzheimer's Disease: The Emerging Role of Functional Imaging , 1998, Neuropsychopharmacology.

[27]  H. Kung,et al.  2-(2'-((Dimethylamino)methyl)-4'-(3-[(18)F]fluoropropoxy)-phenylthio)benzenamine for positron emission tomography imaging of serotonin transporters. , 2008, Nuclear medicine and biology.

[28]  B. Pitt.  Psychopharmacology , 1968, Mental Health.

[29]  Clinton D Kilts,et al.  Synthesis and characterization of EADAM: a selective radioligand for mapping the brain serotonin transporters by positron emission tomography. , 2005, Nuclear medicine and biology.

[30]  G Jonsson,et al.  Chemical neurotoxins as denervation tools in neurobiology. , 1980, Annual review of neuroscience.

[31]  B. Cooper,et al.  Pharmacological Properties of 403U76, a New Chemical Class of 5‐Hydroxytryptamine‐ and Noradrenaline‐reuptake Inhibitor , 1995, The Journal of pharmacy and pharmacology.

[32]  K. Perry,et al.  Effects of p-chloroamphetamine on brain serotonin in immature rats. , 1978, Communications in psychopharmacology.

[33]  S H Snyder,et al.  Novel neurotransmitters and their neuropsychiatric relevance. , 2000, The American journal of psychiatry.

[34]  V. Arango,et al.  A serotonin transporter gene promoter polymorphism (5-HTTLPR) and prefrontal cortical binding in major depression and suicide. , 2000, Archives of general psychiatry.

[35]  F. Zhou,et al.  Serotonin transporters are located on the axons beyond the synaptic junctions: anatomical and functional evidence , 1998, Brain Research.

[36]  K. Lesch,et al.  Serotonin transporter function is modulated by brain-derived neurotrophic factor (BDNF) but not nerve growth factor (NGF) , 2000, Neurochemistry International.

[37]  K. Lesch,et al.  Modulation of serotonin transporter function by interleukin-4. , 2001, Life sciences.

[38]  R. Fuller.  Effects ofp-chloroamphetamine on brain serotonin neurons , 1992, Neurochemical Research.

[39]  H. Kung,et al.  New PET imaging agent for the serotonin transporter: [(18)F]ACF (2-[(2-amino-4-chloro-5-fluorophenyl)thio]-N,N-dimethyl-benzenmethanamine). , 2002, Journal of medicinal chemistry.

[40]  Wen-Sheng Huang,et al.  An automated synthesis of N,N-dimethyl-2-(2-amino-4-[18F]fluorophenylthio)benzylamine (4-[18F]-ADAM) for imaging serotonin transporters. , 2008, Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine.

[41]  I. Lucki,et al.  Norepinephrine-deficient mice lack responses to antidepressant drugs, including selective serotonin reuptake inhibitors. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[42]  B. Långström,et al.  Effect on [11C]DASB binding after tranylcypromine‐induced increase in serotonin concentration: Positron emission tomography studies in monkeys and rats , 2007, Synapse.