The serotonin 5-HT2C receptor (5-HT2CR) is abundantly expressed throughout the central nervous system (CNS), and is involved in a variety of neuroendocrine and neurobehavioral processes. Evidence from animal models, postmortem tissues, and molecular neuroscience studies suggests that dysfunction of 5-HT2CR has been implicated in a number of significant neurological and psychiatric disorders, and 5-HT2CR has been identified as a target for the treatment of obesity, depression, anxiety, drug abuse, schizophrenia and Parkinson's disease. The unmet need is our inability to establish a direct relationship between 5-HT2CR physiology and brain diseases by accurately quantifying 5-HT2CR density and functional status in vivo using Positron Emission Tomography (PET), because there are no selective and specific PET radiotracer agonists or antagonists available for 5-HT2CR. The central objective of this proposal is to develop a carbon-11 5-HT2CR- specific radioligand antagonist with pharmacological and physiochemical properties for in vivo imaging studies by PET. The central hypothesis of this proposal is that a carbon-11 labeled bispyridyl-carbamoylindole derivative will enable mapping of both active and the resting states of 5-HT2C in a highly specific and sensitive manner. This hypothesis is based upon recent published reports and our preliminary findings on the excellent in vitro binding profiles of potent and selective 5-HT2CR antagonists, bispyridyl-carbamoylindoles. The central hypothesis will be tested by completing the following specific aims: 1. To synthesize and in vitro characterize bispyridyl-carbamoylindole derivatives. 2. To develop radiolabeling methods for the candidate 5-HT2CR ligand antagonist. 3. To determine whether radiolabeled candidate compounds will cross the blood brain barrier and the in vivo kinetic biodistribution in Sprague-Dawley rats is sufficient for quality PET imaging of 5-HT2CR. 4. To determine whether the lead candidate PET ligands show favorable distribution and kinetic properties for in vivo quantification of 5-HT2CR density in the brain of non-human primates.

Public Health Relevance

The serotonin 5-HT2C receptor (5-HT2CR) has been identified as a target for the treatment of obesity, depression, anxiety, drug abuse, schizophrenia and Parkinson's disease. However, a direct relationship between 5-HT2CR physiology and brain diseases has proven difficult to establish due to an inability to accurately quantify 5-HT2CR density and functional status in vivo. This project aims to satisfy this unmet need to develop carbon-11 5-HT2CR-specific radioligand antagonists with characteristics appropriate for in vivo imaging studies by PET.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21MH108928-03
Application #
9389009
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Michelotti, Enrique
Project Start
2016-01-01
Project End
2018-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Emory University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322