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. 2β-Carbomethoxy-3α-(3,4-dichlorophenyl)-7β-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)-2β-(1-Propanoyl)-3α-(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 D2-D3 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.
Footnotes
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This study was supported by National Institutes of Health Grants NS30556 (NINDS), DA11558 and DA06303 (NIDA), and RR00168 (NCRR) and Boston Life Sciences, Inc. (Hopkinton, MA). The receptor-screening program was supported in part by the National Institute of Mental Health Psychoactive Drug Screening Program Grant NO1 MH80005.
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This study was presented in abstract form. Madras BK (2001) Occupancy of the dopamine transporter by a transport inhibitor, as measured by PET imaging, is predictive of therapeutic efficacy for parkinsonism. J Nucl Med42 (Suppl):210P; Madras BK (2002) The therapeutic potential of a dopamine transport (DAT) inhibitor for Parkinson's disease: comparison with a D2 dopamine agonist in MPTP-treated monkeys. Society for Neuroscience, Washington, DC.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.105312.
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ABBREVIATIONS: PD, Parkinson's disease; DAT, dopamine transporter; DA, dopamine; GBR 12909, 1-{2-[bis-(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; CFT (WIN 35,428), 2β-carbomethoxy-3β-4-(fluorophenyl)-tropane; SERT, serotonin transporter; NET, norepinephrine transporter; difluoropine or O-620, (S)-(+)-2β-carbomethoxy-3α-(di-4-fluorophenylmethoxy)tropane; O-1369, (1R)-2β-(1-propanoyl)-3α-(4-fluorophenyl)tropane; O-1014, 2-carbomethoxy-3-(3,4-dichlorophenyl)-8-oxabicyclo[3.2.1]oct-2-ene; O-1163, 2β-carbomethoxy-3α-(3,4-dichlorophenyl)-7β-hydroxy-8-methyl-8-azabicyclo[3.2.1.]octane; O-1231, 2-carbomethoxy-3-(3,4-dichlorophenyl)bicyclo[3.2.1]oct-2-ene; O-1973, 2β-(1-propanoyl)-3α-(4-chlorophenyl)-8-oxabicyclo[3.2.1]octane; O-2099, 2β-(1-propanoyl)-3α-(3,4-dichlorophenyl)-7β-hydroxy-8-methyl-8-azabicyclo[3.2.1]octane; O-2240, 2β-(1-propanoyl)-3α-(3,4-dichlorophenyl)-7β-hydroxy-8-methyl-8-azabicyclo[3.2.1]octane laurate; PET, positron emission tomography; Ctrl, control; veh, vehicle; BTS 74 398, (1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-(3-diaminethylaminopropylthio)ethanone monocitrate; NS 2330, tesofensine.
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↵1 Current affiliation: EnVivo Pharmaceuticals, Watertown, Massachusetts.
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↵2 Current affiliation: Laboratory of Cellular Molecular Neurosciences, Rockefeller University, New York, New York.
- Received March 27, 2006.
- Accepted August 1, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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Dopamine Transporter (DAT) Inhibitors Alleviate Specific Parkinsonian Deficits in Monkeys: Association with DAT Occupancy in Vivo
