This is a competitive renewal application for a project (NS35120-04) on development of new single photon emission computed tomography (SPECT) imaging agents to evaluate serotonergic neurotransmission of the central nervous system (CNS). Serotonin (5-HT) is an essential neurotransmitter in the brain, which controls various important behaviors, including sleep awake cycle, mood, temperature, appetite, etc. In addition, commonly prescribed antidepressants, selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, sertraline and paroxetine, modulate 5-HT neurotransmission by blocking the serotonin transporters (SERT). Imaging of SERT in humans would provide a useful tool to understand how alterations of this system are related to depressive illness and other psychiatric disorders and therefore, potentially can benefit millions of patients who are being treated with SSRIs. Development of selective tracers for positron emission tomography (PET) and single photon emission tomography (SPECT) have made it possible to study in vivo neuroreceptors or specific transporter sites non-invasively in the human brain. The major objective of this project is to develop specific radioactive iodinated (I-123) tracers for in vivo SPECT imaging of SERT in the brain. A novel radioiodinated agent, 5-iodo-2-(2-(dimethylamino)methyl)phenyl)thio)-benzly alcohol (IDAM), was recently developed in our laboratory. IDAM displayed a high binding affinity to SERT (Ki = 0.097 nM). The binding affinity to the other two monoamine transporters is much lower (Ki = > 10,000 and 234 nM for dopamine and norepinephrine transporters, respectively). This novel tracer, who demonstrated a high affinity, excellent selectivity and good brain penetration, has excellent characteristics for SPECT imaging of SERT in the brain. Synthesis and structure-activity relationship studies of a series of IDAM derivatives are proposed. Selected compounds will be labeled and tested for in vivo biodistribution in rats and SPECT imaging study in non-human primates. In addition, behavioral study (forced swim test in rats) specific for antidepressive effect and microdialysis study (at the striatum of rat brain) for measuring the elevation of endogenous 5-HT levels will be performed to confirm the pharmacological mechanisms of the new SERT inhibitors. The novel imaging agents may lead to simple and useful routine diagnostic procedures for various mental health diseases involving SERT in the brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS035120-05
Application #
6039557
Study Section
Diagnostic Radiology Study Section (RNM)
Program Officer
Heetderks, William J
Project Start
1996-05-01
Project End
2005-02-28
Budget Start
2000-03-01
Budget End
2001-02-28
Support Year
5
Fiscal Year
2000
Total Cost
$352,929
Indirect Cost
Name
University of Pennsylvania
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Kung, Mei-Ping; Choi, Seok-Rye; Hou, Catherine et al. (2004) Selective binding of 2-[125I]iodo-nisoxetine to norepinephrine transporters in the brain. Nucl Med Biol 31:533-41
Acton, P D; Choi, S R; Hou, C et al. (2001) Quantification of serotonin transporters in nonhuman primates using [(123)I]ADAM and SPECT. J Nucl Med 42:1556-62
Choi, S R; Hou, C; Oya, S et al. (2000) Selective in vitro and in vivo binding of [(125)I]ADAM to serotonin transporters in rat brain. Synapse 38:403-12
Oya, S; Choi, S R; Hou, C et al. (2000) 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine (ADAM): an improved serotonin transporter ligand. Nucl Med Biol 27:249-54
Zhuang, Z; Choi, S; Hou, C et al. (2000) A novel serotonin transporter ligand: (5-iodo-2-(2-dimethylaminomethylphenoxy)-benzyl alcohol. Nucl Med Biol 27:169-75
Acton, P D; Mu, M; Plossl, K et al. (1999) Single-photon emission tomography imaging of serotonin transporters in the nonhuman primate brain with [(123)I]ODAM. Eur J Nucl Med 26:1359-62
Kung, M P; Hou, C; Oya, S et al. (1999) Characterization of [(123)I]IDAM as a novel single-photon emission tomography tracer for serotonin transporters. Eur J Nucl Med 26:844-53
Oya, S; Kung, M P; Acton, P D et al. (1999) A new single-photon emission computed tomography imaging agent for serotonin transporters: [123I]IDAM, 5-iodo-2-((2-((dimethylamino)methyl)phenyl)thio)benzyl alcohol. J Med Chem 42:333-5
Acton, P D; Kung, M P; Mu, M et al. (1999) Single-photon emission tomography imaging of serotonin transporters in the non-human primate brain with the selective radioligand [(123)I]IDAM. Eur J Nucl Med 26:854-61
Zhuang, Z P; Kung, M P; Mu, M et al. (1998) Isoindol-1-one analogues of 4-(2'-methoxyphenyl)-1-[2'-[N-(2""-pyridyl)-p-iodobenzamido]ethyl]pipera zine (p-MPPI) as 5-HT1A receptor ligands. J Med Chem 41:157-66