DRUG RECEPTORS IN VIVO--ANIMAL MODELS AND IMAGING

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The goal of this project is to develop in vivo receptor binding procedures whereby drug receptors can be studied in vivo. Most receptor studies are carried out in vitro where membrane preparations from brain are incubated in physiological buffer along with binding ligands. obviously, receptors normally function in vivo and we therefore must have the capability of studying receptors in vivo. In the procedure of in vivo labeling, radiolabeled ligands are injected systemically into animals and the ligands preferentially localize to drug receptor sites in the intact functioning animal. In our structure-activity studies, it was found that addition of a para-iodine to the phenyl group in the phenyltropane series (RTI-55) resulted in a compound with very high affinity for the dopamine transporter. Subsequent experiments with radiolabeled RTI-55 showed that it was a useful ligand in in vitro binding experiments. Accordingly, we have tested for its suitability as an in vivo binding ligand. By using radiolabeled RTI-55, it was shown that this compound does indeed bind to dopamine transporters after in vivo injection. Thus, it was possible to utilize RTI-55 as an imaging agent in a SPECT, PET or autoradiographic study. In these experiments, it was noted also that RTI-55 is not specific for dopamine transporters but also binds to serotonin transporters. Thus, while this compound is not specific, it may be possible under certain conditions, to image both serotonin and dopamine transporters at the same time by examining regions where the respective terminals are highly concentrated. Because of the lack in specificity, detailed studies are underway to find more specific binding ligands for both dopamine and serotonin transporters. The availability of these ligands will allow additional and more precise imaging studies of cocaine receptors in human populations.