The proposed research has two objectives, to define the molecular targets of cocaine in human brain and to use positron emission tomography (PET) in the preclinical evaluation of potential cocaine substitutes. Our first goal is to systematically characterize [3H]cocaine binding sites in human brain regions including the nucleus accumbens, striatum, locus coeruleus, hippocampus, and amygdala. The research motivated by three preliminary findings that merit further investigation; (1) Using ex vivo autoradiography, we identified a number of regions in nonhuman primate brain that accumulate high levels of {3H}cocaine after i.v. administration of trace or pharmacologically relevant doses. We will characterize sites in these regions with a view to determining their functional significance. (2) In human post-mortem control striata, cocaine binding sites labeled by [3H]WIN 35, 428 were associated with the dopamine transporter. In Parkinson's diseased striata, [3H]WIN 35,428 binding sites differed from the dopamine transporter. We will compare sites labeled by [3H]WIN 35, 438 in these populations, with a view to assessing their relevance to the reinforcing properties of cocaine. (3) Preliminary data suggest that cocaine is metabolized more rapidly in the substantia nigra/ventral tegmental area of nonhuman primate brain than the striatum and we will extend these studies to human brain. Our second goal is focused on developing PET imaging techniques in nonhuman primate brain (Macaca fascicularis) to identify potential cocaine therapeutic agents. We will use positron emission tomography (PET) to image in vivo the direct (monoamine transporters) and indirect (D1 dopamine receptors) targets of cocaine in brain. Our objectives are to identify and to synthesize cocaine congeners with a view to developing high affinity long-acting cocaine substitutes. Their occupancy of the dopamine transporter will be measured by PET using [11C]WIN 35, 428 and occupancy of a broader spectrum of cocaine binding sites will be detected by the relatively non-selective cocaine congener [11C]CDCT. Candidate compounds will include high affinity long-acting dopamine transport inhibitors, novel cocaine congeners synthesized as a component of this program, and D1 dopamine receptor agonists. Occupancy of the D1 receptor will be measured by [11C]SCH 39166. We will evaluate dopamine transporter ligands (indirect dopamine agonists) and extend these studies to potent dopamine agonist drugs targeted to D1 dopamine receptors. This approach will provide fundamental information on [3H]cocaine binding sites in human brain tissue and utilize brain imaging techniques for identifying potential cocaine therapeutic agents.
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