title: In vivo imaging of baboon and human dopamine transporters by positron emission tomography using [11C]WIN 35,428.
abstract: [11C]WIN 35,428 was evaluated as a specific in vivo radioligand for the dopamine transporter site by PET scanning in nonhuman primates and humans. In studies with a baboon (Papio anubis), [11C]WIN 35,428 accumulated in brain regions containing dopamine transporters, i.e., the striata. This accumulation was partially blocked by prior administration of (-)cocaine (4 mg/kg, i.v.). Placement of a unilateral lesion of dopamine-containing nerve terminals with MPTP resulted in a unilateral reduction in [11C]WIN 35,428 accumulation in the striatum on the side of the lesion. Imaging of D2 dopamine receptors with [11C]NMSP in the same MPTP-treated animals showed much less reduction in the postsynaptic D2 dopamine receptors as compared to the much larger reduction in the dopamine transporters labeled with [11C]WIN 35,428. A total of ten normal human volunteers (five males and five females) with ages ranging from 19 to 81 years were studied. The caudate/cerebellar and putamen/cerebellar ratios ranged from 4.4 to 5.7 90 min after injection of the tracer. Preliminary kinetic modeling with arterial plasma sampling resulted in an average binding potential (k3/k4) of 4.98 in the caudate nucleus and 5.13 in putamen. To demonstrate in vivo blockade with dopamine reuptake inhibitors, two subjects received prior oral doses of 6 mg mazindol. Subject 5 had significant reductions of 29% in the caudate/cerebellar ratio at 90 min, 35% in the putamen/cerebellar ratio at 90 min, 45% in the caudate k3/k4 ratio from 6.7 to 3.7, and 46% in the putamen k3/k4 from 4.7 to 2.5. Subject 8 had significant reductions of 20% in both the caudate/cerebellar ratio and the putamen/cerebellar ratio at 90 min. During the human PET studies, a number of neuropsychological tests and physiological measurements were performed. No significant changes were found after administration of the [11C]WIN 35,428 alone. Taken together, these data indicate that [11C]WIN 35,428 is a promising radioligand for future studies of neuropsychiatric disorders that involve the dopamine transporter site.
authors.affiliation: Department of Radiology, Johns Hopkins University and Medical Institution, Baltimore, Maryland 21205.
authors.forename: D F
authors.initials: DF
authors.lastname: Wong
authors.forename: B
authors.initials: B
authors.lastname: Yung
authors.forename: R F
authors.initials: RF
authors.lastname: Dannals
authors.forename: E K
authors.initials: EK
authors.lastname: Shaya
authors.forename: H T
authors.initials: HT
authors.lastname: Ravert
authors.forename: C A
authors.initials: CA
authors.lastname: Chen
authors.forename: B
authors.initials: B
authors.lastname: Chan
authors.forename: T
authors.initials: T
authors.lastname: Folio
authors.forename: U
authors.initials: U
authors.lastname: Scheffel
authors.forename: G A
authors.initials: GA
authors.lastname: Ricaurte
mesh_terms: D000328:Adult; D000339:Affect / Q000187:drug effects; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000000981:diagnostic imaging*; D001923:Brain Chemistry / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism*; D003042:Cocaine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006801:Humans; D008024:Ligands; D008297:Male; D008454:Mazindol / Q000494:pharmacology; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008875:Middle Aged; D009411:Nerve Endings / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010215:Papio; D011674:Pulse / Q000187:drug effects; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism; D014055:Tomography, Emission-Computed
chemical_list: D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011954:Receptors, Dopamine; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D008454:Mazindol; D003042:Cocaine