Binding of d-threo-[11C]methylphenidate to the dopamine transporter in vivo: insensitivity to synaptic dopamine.
The regional distribution of [11C]d-threo-methylphenidate in mouse brain was very similar to that of [3H]WIN 35,428 ((-)-2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane), and the two radioligands were displaced from striatum similarly after administration of the potent cocaine analog RTI-55 ((-)-2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane). However, while striatal [3H]WIN 35,428 increased between 5 and 30 min, striatal [11C]d-threo-methylphenidate halved. Thus [11C]d-threo-methylphenidate binds similarly to but more reversibly than [3H]WIN 35,428. The methyl ester of L-DOPA (L-3,4-dihydroxyphenylalanine; 200 mg/kg) plus benserazide plus clorgyline, which markedly elevates rat striatal extracellular dopamine (Wachtel and Abercrombie, 1994, J. Neurochem. 63, 108), decreased the mouse striatum-to-cerebellum ratio for [11C]d-threo-methylphenidate at 30 min by 13% (P < 0.05). In positron emission tomographic (PET) baboon studies [11C]d-threo-methylphenidate binding was insensitive to drugs expected to lower endogenous dopamine. These experiments suggest that normal synaptic dopamine does not compete for binding with [11C]d-threo-methylphenidate, and will not affect PET measures of dopamine transporter availability.
Gatley
S J
SJ
Medical Department, Brookhaven National Laboratory Upton, NY 11973, USA.
Ding
Y S
YS
Volkow
N D
ND
Chen
R
R
Sugano
Y
Y
Fowler
J S
JS
D000818:Animals; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000378:metabolism*; D003042:Cocaine / Q000031:analogs & derivatives / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins; D004305:Dose-Response Relationship, Drug; D007700:Kinetics; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008774:Methylphenidate / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D009419:Nerve Tissue Proteins; D017729:Presynaptic Terminals / Q000378:metabolism*; D051381:Rats; D013997:Time Factors
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D008774:Methylphenidate; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D003042:Cocaine