This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In mild to moderate Parkinson's disease, dopamine (DA) neurons produce DA and express dopamine transporters (DAT), albeit at reduced levels. We postulated that potent DAT inhibitors may increase levels of released dopamine and provide therapeutic benefit. Eight potent DAT inhibitors, with low serotonin transporter activity were investigated in MPTP-treated cynomolgus monkeys. Efficacy was compared with DAT occupancy of normal brain striatum within 1 hour and DAT binding potential in experimental subjects. Of 8 compounds, 6 were eliminated from intense scrutiny for the following reasons: Three compounds were ineffective and failed to occupy the DAT in vivo. One compound occupied the DAT, but its pharmacological effects were short-lived (less than 90 minutes). Two compounds increased activity during the day and night. Difluoropine and O-1369 alleviated parkinsonian signs in parkinsonian monkeys, by increasing general activity, improving posture, reducing body freeze and sedation. O-1369 did not increase night time activity at therapeutic doses, whereas difluoropine promoted sleep fragmentation at high doses. In comparison with the D2-D3 DA receptor agonist quinelorane, O-1369 was less effective in increasing locomotor activity and produced oro-facial dyskinesias, whereas quinelorane reduced balance, did not improve posture and promoted stereotypies. Discussion: High DAT affinity in vitro may be necessary, but insufficient to predict a positive response. Improvements were predicated on high occupancy of the DAT in brain striatum in vivo and advanced parkinsonism in the subjects, equivalent to an 80% reduction of DAT binding potential. The therapeutic potential of dopamine transport inhibitors for Parkinson's disease warrants further investigation.
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