While most receptors are studied by binding techniques in vitro experiments, it is obviously important to carry out similar studies in vivo where receptors function normally. One of our goals is to study drug receptors related to addiction in vivo by ligand binding and imaging techniques. In the procedure of in vivo labeling, radioactive ligands are injected systemically into animals such that the ligands preferentially localize to drug receptor sites. In our structure- activity studies of the cocaine receptor with cocaine analogs, we found that RTI-55 was a very potent compound with high affinity for the dopamine transporter. Experiments carried out in vivo shows that RTI-55 can indeed bind to dopamine transporters in vivo. It accumulates in brain regions having high densities of transporter such as the striatum, accumulation in these regions are blocked by drugs which bind to the transporter and lesions of these dopaminergic nerve terminals result in a reduced accumulation in these regions. However, ligands such as RTI- 55, while they are useful imaging agents, are not selective for the dopamine transporter. For example, RTI-55 also binds with a relatively high affinity to the serotonin transporter. It is highly desirable that very selective binding compounds be generated. Accordingly, we have developed a number of compounds which are selective for the dopamine transporter. One of these compounds, RTI-121, is especially promising and will probably replace RTI-55 as an in vitro binding ligand and perhaps as an in vivo binding ligand as well. We have also made significant progress in further developing older, more established compounds. We have utilized carbon-11 labeled WIN 35,428 as a PET scanning ligand and have carried out preliminary modeling studies as well as pharmacological studies. The results clearly indicate that the compound can be used effectively to localize dopamine transporters in human populations by PET scanning. In summary, we have made significant progress in identifying and developing binding ligands which will allow us to study drug receptors in vivo.
