DRUG RECEPTORS IN VIVO

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Considerable progress has been made in the area of imaging cocaine receptors in living animals. Our first efforts involved utilizing a known antidepressant drug, nomifensine. A detailed study of the in vivo binding characteristics of this compound revealed that it localized to dopamine transporters quite effectively but with a low specific to non-specific binding ratio. Because of this, we set out to develop more efficient binding ligands. Studies from our laboratory previously showed that cocaine analogs, WIN-35,065-2 and WIN-35,428 were better ligands for the dopamine transporter in that higher specific to non-specific binding ratios were obtained in vivo. More recently, we utilized WIN-35,428 in a more extensive study which conclusively showed that this compound localized to cocaine receptors/dopamine transporters in rat striatum. We are in the process of utilizing this compound in its positron emitting form to carry out PET scanning studies of dopamine transporters in vivo. One important use of in vivo labelling techniques is to examine the rate of occupancy of receptors in vivo by various drugs. Because of the availability of our in vivo labeling model using WIN-35,428, we were able to examine the relative rate of occupancy of cocaine receptor by mazindol, GBR-12,909 and cocaine. We clearly showed that cocaine enters the brain and occupies cocaine receptors much more rapidly than mazindol or GBR-12,909. It is known that abuse liability is greater for drugs that enter the brain and occupy receptors rapidly. Thus, this model will be useful in quantitatively assessing how rapidly drugs enter the brain and occupy receptors; this will be helpful in contributing quantitative knowledge of this factor for abuse liability assessment.