DRUG DISCOVERY FOR TREATMENT OF OBESITY

The goal of this research project is to define the structure and radioactive label for ligands that will permit quantitative measurement of serotonin transporter (5-HTT) sites in living brain by external imaging with positron or single-photon emission tomography (PET or SPECT). The serotonin transporter is known to play a role in several physiological and pathophysiological processes, especially in depression, anxiety, and psychosis, as demonstrated by post-mortem and preliminary imaging studies. A radiotracer that bound specifically to 5-HTT would be of great utility in diagnosis, monitoring treatment, and research of such disorders. However, there is not yet a suitable tracer that allows quantitation in areas of the brain with low densities of 5-HTT, such as the cortex. In this application we propose to test the hypothesis that a novel structure, aza-bicyclo-[3.2.2]-nonane, will have the right combination of transporter binding affinity and pharmacological specificity to allow us to detaect the serotonin transporter in the region of low density. In preliminary experiments using a classical structure-activity relationship (SAR) approach, we found that certain aza-bicyclo-[3.2.2]-nonane ethers showed nanomolar affinity to 5-HTT. We will extend this SAR to a larger library using parallel synthesis and purification. The ligand candidates will be screened for pharmacological affinity and specificity to 5-HTT versus competing binding sites. The most promising candidates will be radiolabeled with radionuclides, F-18, or I-123 as appropriate to the molecule, and evaluated by imaging in vivo in non-human primates in a dedicated PET or SPECT imaging device.