Dopamine transporter (DAT) inhibitors alleviate specific parkinsonian deficits in monkeys: association with DAT occupancy in vivo.

Abstract

Viable dopamine neurons in Parkinson's disease express the dopamine transporter (DAT) and release dopamine (DA). We postulated that potent DAT inhibitors, with low affinity for the serotonin transporter (SERT), may elevate endogenously released extracellular dopamine levels to provide therapeutic benefit. The therapeutic potential of eight DAT inhibitors was investigated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated cynomolgus monkeys (Macaca fascicularis), with efficacy correlated with DAT occupancy as determined by positron emission tomography imaging in striatum. Four potent DAT inhibitors, with relatively high norepinephrine transporter, but low SERT affinities, that occupied the DAT improved activity in parkinsonian monkeys, whereas three high-affinity DAT inhibitors with low DAT occupancy did not. 2beta-Carbomethoxy-3alpha-(3,4-dichlorophenyl)-7beta-hydroxy-8-methyl-8-azabicyclo[3.2.1.]octane (O-1163) occupied the DAT but had short-lived pharmacological effects. The benztropine analog difluoropine increased general activity, improved posture, reduced body freeze, and produced sleep disturbances at high doses. (1R)-2beta-(1-Propanoyl)-3alpha-(4-fluorophenyl)tropane (O-1369) alleviated parkinsonian signs in advanced parkinsonian monkeys, by increasing general activity, improving posture, reducing body freeze, and sedation, but not significantly reducing bradykinesia or increasing locomotor activity. In comparison with the D(2)-D(3) DA receptor agonist quinelorane, O-1369 elicited oral/facial dyskinesias, whereas quinelorane did not improve posture or reduce balance and promoted stereotypy. In conclusion, DAT inhibitors with therapeutic potential combine high DAT affinity in vitro and high DAT occupancy of brain striatum in vivo with enduring day-time effects that do not extend into the nighttime. Advanced parkinsonian monkeys (80% DAT loss) respond more effectively to DAT inhibitors than mild parkinsonian monkeys (46% DAT loss). The therapeutic potential of dopamine transport inhibitors for Parkinson's disease warrants preclinical investigation.

• Authors: Bertha K Madras, Michele A Fahey, Martin Goulet, Zhicheng Lin, Jacob Bendor, Claudia Goodrich, Peter C Meltzer, David R Elmaleh, Eli Livni, Ali A Bonab, Alan J Fischman
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 319 Issue 2 Pg. 570-85 (Nov 2006) ISSN: 0022-3565 [Print] United States
• PMID: 16885433 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Dopamine Plasma Membrane Transport Proteins
• Quinolines
• Receptors, Dopamine D2
• Receptors, Dopamine D3
• difluoropine
• (1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester
• Cocaine
• quinelorane

Topics

• Animals
• Cocaine (analogs & derivatives, metabolism, pharmacology)
• Dopamine Plasma Membrane Transport Proteins (antagonists & inhibitors, metabolism)
• Female
• Macaca fascicularis
• Male
• Parkinsonian Disorders (drug therapy)
• Quinolines (pharmacology)
• Receptors, Dopamine D2 (agonists)
• Receptors, Dopamine D3 (agonists)