The objective of this grant is to evaluate serotonin reuptake sites (a.k.a. serotonin transporters, SERT) of the central nervous system (CNS) using F-18 labeled positron emission tomography (PET) imaging agents. Since the introduction of fluoxetine (Prozac) in 1988, the class of selective serotonin reuptake inhibitors (SSRIs), have been extensively prescribed for millions of patients with depressive, compulsive-obsessive, social phobic or other mental disorders. By blocking the reuptake sites the concentration of a neural chemical, serotonin, in the synapse is greatly increased. A substantial increase in serotonin signaling is credited for apparent symptomatic improvements. While the SSRI drugs have helped many patients, a significant segment of patients does not respond to the treatment. There is a compelling need to find a simple method to measure the drug occupancy (or the lack thereof) of the target sites in the brain of non-responders. The PET imaging methods proposed in this project are critically important for studying binding sites of psychoactive drugs and monitoring the effectiveness of such drug treatment in the living human brain. The ultimate goal of this project is to test the feasibility of the PET imaging technique for studying behavioral and emotional disorders and their treatment. A F-18 labeled serotonin transporter ligand for PET imaging will have a better chance than current ligands for widespread application due to its longer half-life and the existing infrastructure for delivering F-18 FDG for clinical studies. The hypothesis of this project is to test if a convenient PET imaging method could be utilized to quickly assess the degree of saturation of SERT sites in the brain by PET imaging.
Three specific aims are proposed for this project: 1) to synthesize and to characterize of a series of F-18 biphenylthiol derivatives as serotonin transporter ligands for PET imaging studies, 2) to perform in vivo PET imaging of serotonin transporters after an iv injection of F- 18 labeled ligand in non-human primates and to measure the occupancy of SERT after a competing dose of SSRI. Additional comparison studies on several newly reported F-18 labeled agents for PET imaging of SERT will provide semi-quantitative information for selecting a suitable candidate for human study in year 3 of this project.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH068782-01A1
Application #
6770853
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Desmond, Nancy L
Project Start
2004-04-01
Project End
2007-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
1
Fiscal Year
2004
Total Cost
$340,830
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
Qiao, Hongwen; Zhang, Yan; Wu, Zehui et al. (2016) One-step preparation of [(18)F]FPBM for PET imaging of serotonin transporter (SERT) in the brain. Nucl Med Biol 43:470-7
Lemoine, Laetitia; Lieberman, Brian P; Ploessl, Karl et al. (2013) Characterization of FlipIDAM as a SERT-selective SPECT imaging agent. Nucl Med Biol 40:879-86
Zheng, Pinguan; Lieberman, Brian P; Ploessl, Karl et al. (2013) A new single-photon emission computed tomography (SPECT) imaging agent for serotonin transporters: [(125)I]Flip-IDAM, (2-((2-((dimethylamino)methyl)-4-iodophenyl)thio)phenyl)methanol. Bioorg Med Chem Lett 23:869-72
Zhu, Lin; Li, Genxun; Choi, Seok Rye et al. (2013) An improved preparation of [18F]FPBM: a potential serotonin transporter (SERT) imaging agent. Nucl Med Biol 40:974-9
Qiao, Hongwen; Zhu, Lin; Lieberman, Brian P et al. (2012) Synthesis and evaluation of novel tropane derivatives as potential PET imaging agents for the dopamine transporter. Bioorg Med Chem Lett 22:4303-6
Wang, Julie L; Deutsch, Eric C; Oya, Shunichi et al. (2010) FlipADAM: a potential new SPECT imaging agent for the serotonin transporter. Nucl Med Biol 37:577-86
Wang, Julie L; Oya, Shunichi; Parhi, Ajit K et al. (2010) In vivo studies of the SERT-selective [18F]FPBM and VMAT2-selective [18F]AV-133 radiotracers in a rat model of Parkinson's disease. Nucl Med Biol 37:479-86
Wang, Julie L; Parhi, Ajit K; Oya, Shunichi et al. (2009) In vivo characterization of a series of 18F-diaryl sulfides (18F-2-(2'-((dimethylamino)methyl)-4'-(fluoroalkoxy)phenylthio)benzenamine) for PET imaging of the serotonin transporter. J Nucl Med 50:1509-17
Kung, Hank F; Lieberman, Brian P; Zhuang, Zhi-Ping et al. (2008) In vivo imaging of vesicular monoamine transporter 2 in pancreas using an (18)F epoxide derivative of tetrabenazine. Nucl Med Biol 35:825-37
Wang, Julie L; Parhi, Ajit K; Oya, Shunichi et al. (2008) 2-(2'-((Dimethylamino)methyl)-4'-(3-[(18)F]fluoropropoxy)-phenylthio)benzenamine for positron emission tomography imaging of serotonin transporters. Nucl Med Biol 35:447-58

Showing the most recent 10 out of 12 publications