Binding of d-threo-[ 11C]methylphenidate to the dopamine transporter in vivo: insensitivity to synaptic dopamine

• Published in: European journal of pharmacology 1995-08, Vol.281 (2), p.141-149
• Main Authors: Gatley, S.John, Ding, Yu-Shin, Volkow, Nora D., Chen, Ruoyan, Sugano, Yuichi, Fowler, Joanna S.
• Format: Article
• Language: English
• Subjects: Animals; Baboon; Binding, Competitive; Biological and medical sciences; Carrier Proteins - metabolism; Cocaine - analogs & derivatives; Cocaine - pharmacology; d-threo-Methylphenidate; Dopamine; Dopamine Plasma Membrane Transport Proteins; Dopamine transporter; Dose-Response Relationship, Drug; Kinetics; Male; Mammalia; Medical sciences; Membrane Glycoproteins; Membrane Transport Proteins; Methylphenidate; Methylphenidate - pharmacology; Mice; Mice, Inbred Strains; Miscellaneous; Mouse; Nerve Tissue Proteins; Neuropharmacology; PET (positron emission tomography); Pharmacology. Drug treatments; Presynaptic Terminals - metabolism; Rats; Time Factors; WIN 35,428
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/0014-2999(95)00233-B

The regional distribution of [ 11C] d-threo-methylphenidate in mouse brain was very similar to that of [ 3H]WIN 35,428 ((−)-2β-carbomethoxy-3β-(4-fluorophenyl)tropane), and the two radioligands were displaced from striatum similarly after administration of the potent cocaine analog RTI-55 ((−)-2β-carbomethoxy-3β-(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 position 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.